FEATURED ARTICLES INCLUDE: New Horizons in the Management of Alzheimer s Disease: Advances in Early Diagnosis and Treatment Strategies

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1 Vol. 21, No. 4, 2018 Educating Medical Directors of Employers, Health Plans and Provider Systems FEATURED ARTICLES INCLUDE: New Horizons in the Management of Alzheimer s Disease: Advances in Early Diagnosis and Treatment Strategies What s New in the Evolving Management of Type 2 Diabetes: Individualizing Therapy with Novel Treatment Options New Developments in the Diagnosis and Treatment of Psoriatic Arthritis

2 CAR T IS HERE YESCARTA, THE FIRST CAR T THERAPY FOR CERTAIN TYPES OF RELAPSED OR REFRACTORY LARGE B-CELL LYMPHOMA The following data reflect results from the ZUMA-1 pivotal trial* 1 // PROVEN EFFICACY // CYTOKINE RELEASE SYNDROME // RAPID & RELIABLE MANUFACTURING 51% 13% 94% 17 DAYS Patients achieved a best response of complete remission (CR) (52/101) NR 31% 87% Response duration was not reached at a median follow-up of 7.9 months in patients who achieved CR Grade 3 incidence Grade 3 incidence // NEUROLOGIC TOXICITIES Overall incidence Overall incidence Median turnaround time 99% Manufacturing success of CAR T cells engineered and expanded ex vivo VISIT YESCARTAHCP.COM/CENTERS TO FIND A LIST OF AUTHORIZED TREATMENT CENTERS * ZUMA-1 was an open-label, single-arm study in 101 adult patients who received YESCARTA therapy. Patients received lymphodepleting chemotherapy prior to a single infusion of YESCARTA at a target dose of 2 x 10 6 viable CAR T cells/kg body weight (maximum of 2 x 10 8 viable CAR T cells). Patients had refractory disease to their most recent therapy, or had relapsed within 1 year after autologous hematopoietic stem cell transplantation. The median time from leukapheresis to product delivery. INDICATION YESCARTA is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Limitation of Use: YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma. IMPORTANT SAFETY INFORMATION BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving YESCARTA. Do not administer YESCARTA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids. Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving YESCARTA, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with YESCARTA. Provide supportive care and/or corticosteroids as needed. YESCARTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA REMS. Important Safety Information continued on adjacent page. YESCARTA, the YESCARTA Logo, KITE, and the KITE Logo are trademarks of Kite Pharma, Inc. GILEAD is a trademark of Gilead Sciences, Inc Kite Pharma PRC /2018

3 IMPORTANT SAFETY INFORMATION (continued) CYTOKINE RELEASE SYNDROME (CRS): CRS occurred in 94% of patients, including 13% with Grade 3. Among patients who died after receiving YESCARTA, 4 had ongoing CRS at death. The median time to onset was 2 days (range: 1-12 days) and median duration was 7 days (range: 2-58 days). Key manifestations include fever (78%), hypotension (41%), tachycardia (28%), hypoxia (22%), and chills (20%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Ensure that 2 doses of tocilizumab are available prior to infusion of YESCARTA. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for 4 weeks after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated. NEUROLOGIC TOXICITIES: Neurologic toxicities occurred in 87% of patients. Ninety-eight percent of all neurologic toxicities occurred within the first 8 weeks, with a median time to onset of 4 days (range: 1-43 days) and a median duration of 17 days. Grade 3 or higher occurred in 31% of patients. The most common neurologic toxicities included encephalopathy (57%), headache (44%), tremor (31%), dizziness (21%), aphasia (18%), delirium (17%), insomnia (9%) and anxiety (9%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events including leukoencephalopathy and seizures occurred with YESCARTA. Fatal and serious cases of cerebral edema have occurred in patients treated with YESCARTA. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of neurologic toxicities. Monitor patients for signs or symptoms of neurologic toxicities for 4 weeks after infusion and treat promptly. YESCARTA REMS: Because of the risk of CRS and neurologic toxicities, YESCARTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA REMS. The required components of the YESCARTA REMS are: Healthcare facilities that dispense and administer YESCARTA must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after YESCARTA infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense or administer YESCARTA are trained about the management of CRS and neurologic toxicities. Further information is available at or KITE (5483). HYPERSENSITIVITY REACTIONS: Allergic reactions may occur. Serious hypersensitivity reactions including anaphylaxis may be due to dimethyl sulfoxide (DMSO) or residual gentamicin in YESCARTA. SERIOUS INFECTIONS: Severe or life-threatening infections occurred. Infections (all grades) occurred in 38% of patients, and in 23% with Grade 3. Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients, bacterial infections in 9%, and viral infections in 4%. YESCARTA should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after YESCARTA infusion and treat appropriately. Administer prophylactic anti-microbials according to local guidelines. Febrile neutropenia was observed in 36% of patients and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids and other supportive care as medically indicated. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing. PROLONGED CYTOPENIAS: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and YESCARTA infusion. Grade 3 or higher cytopenias not resolved by Day 30 following YESCARTA infusion occurred in 28% of patients and included thrombocytopenia (18%), neutropenia (15%), and anemia (3%). Monitor blood counts after YESCARTA infusion. HYPOGAMMAGLOBULINEMIA: B-cell aplasia and hypogammaglobulinemia can occur. Hypogammaglobulinemia occurred in 15% of patients. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following YESCARTA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during YESCARTA treatment, and until immune recovery following treatment. SECONDARY MALIGNANCIES: Patients may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Kite at KITE (5483) to obtain instructions on patient samples to collect for testing. EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following YESCARTA infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period. ADVERSE REACTIONS: The most common adverse reactions (incidence 20%) include CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections-pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias. Please see Brief Summary of Prescribing Information, including BOXED WARNING, on the following pages. Reference: 1. YESCARTA [package insert]. Santa Monica, CA: Kite Pharma; Santa Monica, CA

4 BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR YESCARTA (axicabtagene ciloleucel) suspension for intravenous infusion SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving YESCARTA. Do not administer YESCARTA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids [see Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.1)]. Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving YESCARTA, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with YESCARTA. Provide supportive care and/or corticosteroids, as needed [see Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.2)]. YESCARTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA REMS [see Warnings and Precautions (5.3)]. 1 INDICATIONS AND USAGE YESCARTA is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Limitation of Use: YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma. 2 DOSAGE AND ADMINISTRATION 2.2 Administration: YESCARTA is for autologous use only. The patient s identity must match the patient identifiers on the YESCARTA cassette and infusion bag. Do not infuse YESCARTA if the information on the patient-specific label does not match the intended patient [see Dosage and Administration(2.2.3)]. Preparing Patient for YESCARTA Infusion: Confirm availability of YESCARTA prior to starting the lymphodepleting regimen. Pre-treatment: Administer a lymphodepleting chemotherapy regimen of cyclophosphamide 500 mg/m 2 intravenously and fludarabine 30 mg/m 2 intravenously on the fifth, fourth, and third day before infusion of YESCARTA. Premedication: Administer acetaminophen 650 mg PO and diphenhydramine 12.5 mg intravenously or PO approximately 1 hour before YESCARTA infusion. Avoid prophylactic use of systemic corticosteroids, as it may interfere with the activity of YESCARTA. Preparation of YESCARTA for Infusion: Coordinate the timing of YESCARTA thaw and infusion. Confirm the infusion time in advance, and adjust the start time of YESCARTA thaw such that it will be available for infusion when the patient is ready. Confirm patient identity: Prior to YESCARTA preparation, match the patient s identity with the patient identifiers on the YESCARTA cassette. Do not remove the YESCARTA product bag from the cassette if the information on the patient-specific label does not match the intended patient. Once patient identification is confirmed, remove the YESCARTA product bag from the cassette and check that the patient information on the cassette label matches the bag label. Inspect the product bag for any breaches of container integrity such as breaks or cracks before thawing. If the bag is compromised, follow the local guidelines (or call Kite at KITE). Place the infusion bag inside a second sterile bag per local guidelines. Thaw YESCARTA at approximately 37 C using either a water bath or dry thaw method until there is no visible ice in the infusion bag. Gently mix the contents of the bag to disperse clumps of cellular material. If visible cell clumps remain continue to gently mix the contents of the bag. Small clumps of cellular material should disperse with gentle manual mixing. Do not wash, spin down, and/or re-suspend YESCARTA in new media prior to infusion. Once thawed, YESCARTA may be stored at room temperature (20 C to 25 C) for up to 3 hours. Administration: For autologous use only. Ensure that tocilizumab and emergency equipment are available prior to infusion and during the recovery period. Do NOT use a leukodepleting filter. Central venous access is recommended for the infusion of YESCARTA. Confirm the patient s identity matches the patient identifiers on the YESCARTA product bag. Prime the tubing with normal saline prior to infusion. Infuse the entire contents of the YESCARTA bag within 30 minutes by either gravity or a peristaltic pump. YESCARTA is stable at room temperature for up to 3 hours after thaw. Gently agitate the product bag during YESCARTA infusion to prevent cell clumping. After the entire content of the product bag is infused, rinse the tubing with normal saline at the same infusion rate to ensure all product is delivered. YESCARTA contains human blood cells that are genetically modified with replication incompetent retroviral vector. Follow universal precautions and local biosafety guidelines for handling and disposal to avoid potential transmission of infectious diseases. Monitoring: Administer YESCARTA at a certified healthcare facility. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of CRS and neurologic toxicities. Instruct patients to remain within proximity of the certified healthcare facility for at least 4 weeks following infusion. 2.3 Management of Severe Adverse Reactions Cytokine Release Syndrome (CRS): Identify CRS based on clinical presentation [see Warnings and Precautions (5.1)]. Evaluate for and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, manage according to the recommendations in Table 1. Patients who experience Grade 2 or higher CRS (e.g., hypotension, not responsive to fluids, or hypoxia requiring supplemental oxygenation) should be monitored with continuous cardiac telemetry and pulse oximetry. For patients experiencing severe CRS, consider performing an echocardiogram to assess cardiac function. For severe or life-threatening CRS, consider intensive care supportive therapy. Table 1. CRS Grading and Management Guidance CRS Grade (a) Tocilizumab Corticosteroids Grade 1 N/A N/A Symptoms require symptomatic treatment only (e.g., fever, nausea, fatigue, headache, myalgia, malaise). Grade 2 Symptoms require and respond to moderate intervention. Oxygen requirement less than 40% FiO 2 or hypotension responsive to fluids or low-dose of one vasopressor or Grade 2 organ toxicity (b). Grade 3 Symptoms require and respond to aggressive intervention. Oxygen requirement greater than or equal to 40% FiO 2 or hypotension requiring high-dose or multiple vasopressors or Grade 3 organ toxicity or Grade 4 transaminitis. Grade 4 Life-threatening symptoms. Requirements for ventilator support, continuous veno-venous hemodialysis (CVVHD) or Grade 4 organ toxicity (excluding transaminitis). Administer tocilizumab (c) 8 mg/kg intravenously over 1 hour (not to exceed 800 mg). Repeat tocilizumab every 8 hours as needed if not responsive to intravenous fluids or increasing supplemental oxygen. Limit to a maximum of 3 doses in a 24-hour period; maximum total of 4 doses. Per Grade 2 Per Grade 2 Manage per Grade 3 if no improvement within 24 hours after starting tocilizumab. Administer methylprednisolone 1 mg/kg intravenously twice daily or equivalent dexamethasone (e.g., 10 mg intravenously every 6 hours). Continue corticosteroids use until the event is Grade 1 or less, then taper over 3 days. Administer methylprednisolone 1000 mg intravenously per day for 3 days; if improves, then manage as above. (a) Lee et al 2014, (b) Refer to Table 2 for management of neurologic toxicity, (c) Refer to tocilizumab Prescribing Information for details Neurologic Toxicity: Monitor patients for signs and symptoms of neurologic toxicities (Table 2). Rule out other causes of neurologic symptoms. Patients who experience Grade 2 or higher neurologic toxicities should be monitored with continuous cardiac telemetry and pulse oximetry. Provide intensive care supportive therapy for severe or life threatening neurologic toxicities. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis for any Grade 2 or higher neurologic toxicities.

5 Table 2. Neurologic Toxicity Grading and Management Guidance Grading Concurrent CRS Assessment Grade 2 Administer tocilizumab per Table 1 for management of Grade 2 CRS. If no improvement within 24 hours after starting tocilizumab, administer dexamethasone 10 mg intravenously every 6 hours if not already taking other corticosteroids. Continue dexamethasone use until the event is Grade 1 or less, then taper over 3 days. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. Grade 3 Administer tocilizumab per Table 1 for management of Grade 2 CRS. In addition, administer dexamethasone 10 mg intravenously with the first dose of tocilizumab and repeat dose every 6 hours. Continue dexamethasone use until the event is Grade 1 or less, then taper over 3 days. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. Grade 4 Administer tocilizumab per Table 1 for management of Grade 2 CRS. Administer methylprednisolone 1000 mg intravenously per day with first dose of tocilizumab and continue methylprednisolone 1000 mg intravenously per day for 2 more days; if improves, then manage as above. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. No Concurrent CRS Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until the event is Grade 1 or less, then taper over 3 days. Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until the event is Grade 1 or less, then taper over 3 days. Administer methylprednisolone 1000 mg intravenously per day for 3 days; if improves, then manage as above. 4 CONTRAINDICATIONS: None. 5 WARNINGS AND PRECAUTIONS 5.1 Cytokine Release Syndrome (CRS): CRS,including fatal or life-threatening reactions, occurred following treatment with YESCARTA. In Study 1, CRS occurred in 94% (101/108) of patients receiving YESCARTA, including Grade 3 (Lee grading system) CRS in 13% (14/108) of patients. Among patients who died after receiving YESCARTA, four had ongoing CRS events at the time of death. The median time to onset was 2 days (range: 1 to 12 days) and the median duration of CRS was 7 days (range: 2 to 58 days). Key manifestations of CRS include fever (78%), hypotension (41%), tachycardia (28%), hypoxia (22%), and chills (20%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/ macrophage activation syndrome (HLH/MAS) [see Adverse Reactions (6)]. Ensure that 2 doses of tocilizumab are available prior to infusion of YESCARTA. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for 4 weeks after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time [see Patient Counseling Information (17)]. At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated [See Dosage and Administration (2.3)]. 5.2 Neurologic Toxicities: Neurologic toxicities, that were fatal or life-threatening, occurred following treatment with YESCARTA. Neurologic toxicities occurred in 87% of patients. Ninety-eight percent of all neurologic toxicities occurred within the first 8 weeks of YESCARTA infusion, with a median time to onset of 4 days (range: 1 to 43 days). The median duration of neurologic toxicities was 17 days. Grade 3 or higher neurologic toxicities occurred in 31% of patients. The most common neurologic toxicities included encephalopathy (57%), headache (44%), tremor (31%), dizziness (21%), aphasia (18%), delirium (17%), insomnia (9%) and anxiety (9%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events including leukoencephalopathy and seizures occurred with YESCARTA. Fatal and serious cases of cerebral edema have occurred in patients treated with YESCARTA. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of neurologic toxicities. Monitor patients for signs or symptoms of neurologic toxicities for 4 weeks after infusion and treat promptly [see Management of Severe Adverse Reactions (2.3); Neurologic Toxicities]. 5.3 YESCARTA REMS: Because of the risk of CRS and neurologic toxicities, YESCARTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA REMS [see Boxed Warning and Warnings and Precautions (5.1 and 5.2)]. The required components of the YESCARTA REMS are: Healthcare facilities that dispense and administer YESCARTA must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of two doses of tocilizumab are available for each patient for infusion within 2 hours after YESCARTA infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense or administer YESCARTA are trained about the management of CRS and neurologic toxicities. Further information is available at or KITE (5483). 5.4 Hypersensitivity Reactions: Allergic reactions may occur with the infusion of YESCARTA. Serious hypersensitivity reactions including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) or residual gentamicin in YESCARTA. 5.5 Serious Infections: Severe or life-threatening infections occurred in patients after YESCARTA infusion. In Study 1, infections (all grades) occurred in 38% of patients. Grade 3 or higher infections occurred in 23% of patients. Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients, bacterial infections in 9%, and viral infections in 4%. YESCARTA should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after YESCARTA infusion and treat appropriately. Administer prophylactic anti-microbials according to local guidelines. Febrile neutropenia was observed in 36% of patients after YESCARTA infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids and other supportive care as medically indicated. Viral Reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing. 5.6 Prolonged Cytopenias: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and YESCARTA infusion. In Study 1, Grade 3 or higher cytopenias not resolved by Day 30 following YESCARTA infusion occurred in 28% of patients and included thrombocytopenia (18%), neutropenia (15%), and anemia (3%). Monitor blood counts after YESCARTA infusion. 5.7 Hypogammaglobulinemia: B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with YESCARTA. In Study 1, hypogammaglobulinemia occurred in 15% of patients. Monitor immunoglobulin levels after treatment with YESCARTA and manage using infection precautions, antibiotic prophylaxis and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following YESCARTA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during YESCARTA treatment, and until immune recovery following treatment with YESCARTA. 5.8 Secondary Malignancies: Patients treated with YESCARTA may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Kite at KITE (5483) to obtain instructions on patient samples to collect for testing. 5.9 Effects on Ability to Drive and Use Machines: Due to the potential for neurologic events, including altered mental status or seizures, patients receiving YESCARTA are at risk for altered or decreased consciousness or coordination in the 8 weeks following YESCARTA infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period. 6 ADVERSE REACTIONS: The following adverse reactions are described in Warnings and Precautions: Cytokine Release Syndrome, Neurologic Toxicities, Hypersensitivity Reactions, Serious Infections, Prolonged Cytopenias, Hypogammaglobulinemia. 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described in this section reflect exposure to YESCARTA in the clinical trial (Study 1) in which 108 patients with relapsed/refractory B-cell NHL received CAR-positive T cells based on a recommended dose which was weight-based [see Clinical Trials (14)]. Patients with a history of CNS disorders (such as seizures or cerebrovascular ischemia) or autoimmune disease requiring systemic immunosuppression were ineligible. The median duration of follow up was 8.7 months. The median age of the study population was 58 years (range: 23 to 76 years); 68% were men. The baseline ECOG performance status was

6 43% with ECOG 0, and 57% with ECOG 1. The most common adverse reactions (incidence 20%) include CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections-pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias. Serious adverse reactions occurred in 52% of patients. The most common serious adverse reactions (> 2%) include encephalopathy, fever, lung infection, febrile neutropenia, cardiac arrhythmia, cardiac failure, urinary tract infection, renal insufficiency, aphasia, cardiac arrest, Clostridium difficile infection, delirium, hypotension, and hypoxia. The most common ( 10%) Grade 3 or higher reactions include febrile neutropenia, fever, CRS, encephalopathy, infections-pathogen unspecified, hypotension, hypoxia, and lung infections. Forty-five percent (49/108) of patients received tocilizumab after infusion of YESCARTA. Summary of Adverse Reactions Observed in at Least 10% of the Patients Treated with YESCARTA in Study 1 Cardiac disorders Gastrointestinal disorders General disorders and administration site conditions Immune system disorders Infections and infestations Investigations Musculoskeletal and connective tissue disorders Nervous system disorders Adverse Reaction Tachycardia Arrhythmia Diarrhea Nausea Vomiting Constipation Abdominal pain Dry mouth Fever Fatigue Chills Edema Cytokine release syndrome Hypogammaglobulinemia Infections-pathogen unspecified Viral infections Bacterial infections Decreased appetite Weight decreased Dehydration Motor dysfunction Pain in extremity Back pain Muscle pain Arthralgia Encephalopathy Headache Tremor Dizziness Aphasia Any Grade (%) Grades 3 or Higher (%) Psychiatric disorders Delirium 17 6 Respiratory, thoracic and mediastinal disorders Renal and urinary disorders Vascular disorders Hypoxia Cough Dyspnea Pleural effusion Renal insufficiency 12 5 Hypotension Hypertension Thrombosis The following events were also counted in the incidence of CRS: tachycardia, arrhythmia, fever, chills, hypoxemia, renal insufficiency, and hypotension. For a complete list of events that contributed to the incidence of certain adverse reactions, please see footnote below Table 3 in Section 6.1 of the Full Prescribing Information. Other clinically important adverse reactions that occurred in less than 10% of patients treated with YESCARTA include the following: blood and lymphatic system disorders: coagulopathy (2%); cardiac disorders: cardiac failure (6%) and cardiac arrest (4%); immune system disorders: hemophagocytic lymphohistiocytosis/ macrophage activation syndrome (HLH/MAS) (1%), hypersensitivity (1%); infections and infestations disorders: fungal infections (5%); nervous system disorders: ataxia (6%), seizure (4%), dyscalculia (2%), and myoclonus (2%); respiratory, thoracic and mediastinal disorders: pulmonary edema (9%); skin and subcutaneous tissue disorders: rash (9%); vascular disorders: capillary leak syndrome (3%). Grade 3 or 4 Laboratory Abnormalities Occurring in 10% of Patients in Study 1 Following Treatment with YESCARTA based on CTCAE (N=108) Lymphopenia 100%, Leukopenia 96%, Neutropenia 93%, Anemia 66%, Thrombocytopenia 58%, Hypophosphatemia 50%, Hyponatremia 19%, Uric acid increased 13%, Direct Bilirubin increased 13%, Hypokalemia 10%, Alanine Aminotransferase increased 10%. 6.2 Immunogenicity: YESCARTA has the potential to induce anti-product antibodies. The immunogenicity of YESCARTA has been evaluated using an enzyme-linked immunosorbent assay (ELISA) for the detection of binding antibodies against FMC63, the originating antibody of the anti-cd19 CAR. Three patients tested positive for pre-dose anti-fmc63 antibodies at baseline and Months 1, 3, or 6 in Study 1. There is no evidence that the kinetics of initial expansion and persistence of YESCARTA, or the safety or effectiveness of YESCARTA, was altered in these patients. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Risk Summary: There are no available data with YESCARTA use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with YESCARTA to assess whether it can cause fetal harm when administered to a pregnant woman. It is not known if YESCARTA has the potential to be transferred to the fetus. Based on the mechanism of action, if the transduced cells cross the placenta, they may cause fetal toxicity, including B-cell lymphocytopenia. Therefore, YESCARTA is not recommended for women who are pregnant, and pregnancy after YESCARTA infusion should be discussed with the treating physician. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% - 4% and 15% - 20%, respectively. 8.2 Lactation: Risk Summary: There is no information regarding the presence of YESCARTA in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother s clinical need for YESCARTA and any potential adverse effects on the breastfed infant from YESCARTA or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential: Pregnancy Testing: Pregnancy status of females with reproductive potential should be verified. Sexually-active females of reproductive potential should have a pregnancy test prior to starting treatment with YESCARTA. Contraception: See the prescribing information for fludarabine and cyclophosphamide for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy. There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with YESCARTA. Infertility: There are no data on the effect of YESCARTA on fertility. 8.4 Pediatric Use: The safety and efficacy of YESCARTA have not been established in pediatric patients. 8.5 Geriatric Use: Clinical trials of YESCARTA did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently or have different safety outcomes as compared to younger patients. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Ensure that patients understand the risk of manufacturing failure (1% in clinical trial). In case of a manufacturing failure, a second manufacturing of YESCARTA may be attempted. In addition, while the patient awaits the product, additional chemotherapy (not the lymphodepletion) may be necessary and may increase the risk of adverse events during the pre-infusion period. Advise patients to seek immediate attention for any of the following: Cytokine Release Syndrome, Neurologic Toxicities, Serious Infections, Prolonged Cytopenia [see Warnings and Precautions (5.1, 5.2, 5.3, 5.5) and Adverse Reactions (6) for more information and signs and symptoms]. Advise patients for the need to: Refrain from driving or operating heavy or potentially dangerous machinery after YESCARTA infusion until at least 8 weeks after infusion [see Warnings and Precautions (5.2)], Have periodic monitoring of blood counts. Contact Kite at KITE (5483) if they are diagnosed with a secondary malignancy [see Warnings and Precautions (5.8)]. Manufactured by, Packed by, Distributed by: Kite Pharma, Inc., Santa Monica, CA US License No 2064 YESCARTA and KITE are trademarks of Kite Pharma, Inc Kite Pharma PRC /2018

7 JMCM JOURNAL OF MANAGED CARE MEDICINE 4435 Waterfront Drive, Suite 101 Glen Allen, VA (804) fax (804) EDITOR-IN-CHIEF J. Ronald Hunt, MD PUBLISHER Jeremy Williams ADVERTISING REPRESENTATIVE Jen Callow American Medical Communications JOURNAL MANAGEMENT Douglas Murphy Communications Inc. P.O. Box Richmond, VA (804) fax (703) MANAGING EDITOR Barry Barnum GRAPHIC DESIGN Douglas Murphy Communications, Inc. Custom Article Reprints High quality reprints of individual articles are available in print and electronic formats. Contact Jeremy Williams, for reprints. ISSN: The v is Journal published of Managed by Association Care Services Medicine Inc. is published Corporate by NAMCP and Circulation Medical Directors offices: 4435 Institute. Waterfront Corporate Drive, and Suite Circulation 101, Glen offices: Allen, 4435 VA 23060; Tel (804) ; Fax (804) Editorial and Production offices: 2613 N. Parham Rd., Waterfront Drive, Suite 101, Glen Allen, VA 23060; Suite Tel (804) B, Richmond, ; Fax VA (804) 23294; Tel (804) Editorial ; and Fax Production (804) offices: Advertising P.O. Box 71895, offices: Richmond, Jack Klose, VA ; Broadway, Tel W. (804) Long ; Branch, Fax NJ 07764; (703) Tel (732) ; Advertising Fax offices: (856) Sloane Reed, Subscription 4435 Waterfront Rates: one Drive year Ste $95 101, in Glen the United Allen, VA States; one Tel year (804) $ in Canada; one year $120 international. Back issues 1905, Fax (804) All rights reserved. Copy- are available for $15 each. All rights reserved. Copyright No part No of part this of publication this publication may be may repro- be reproduced or transmitted or transmitted in any in form any or form by any or means, by any means, electronic electronic or mechanical, or mechanical, including including photocopy, photocopycording, recording, any information any information storage or storage retrieval or sys- re- retrievatem, without system, written without consent written from consent the publisher. from the publisher. The publisher does not guarantee, either expressly or by implication, the factual accu- The publisher does not guarantee, either expressly racy or by of implication, the articles the and factual descriptions accuracy of herein, the articles nor does and descriptions the publisher herein, guarantee nor does the accuracy the publisher of any views guarantee or opinions the accuracy offered by any the views authors opinions of said offered or by descriptions. the authors of said articles or descriptions. articles POSTMASTER: Send address changes to The POSTMASTER: Send address changes to The Journal of Managed Care Medicine, 4435 Waterfront Journal Drive, of Managed Suite 101, Care Glen Medicine, Allen, VA Waterfront Drive, Suite 101, Glen Allen, VA Journal of Managed Care Medicine The Official Journal of the NAMCP MEDICAL DIRECTORS INSTITUTE A Peer-Reviewed Publication TABLE OF CONTENTS Vol. 21, No. 4, 2018 New Horizons in the Management of Alzheimer s Disease: Advances in Early Diagnosis and Treatment Strategies Marwan N. Sabbagh, MD, FAAN... 9 Management of Metastatic Bladder Cancer: How Advances in Immunotherapy are Improving Patient Outcomes Matthew T. Campbell, MD, MS Clinical Updates in Cystic Fibrosis: Applying Recent Advances in CFTR Modulator Therapy for Improved Patient Outcomes Elliott Dasenbrook, MD, MHS Challenges and Strategies in an Evolving CLL Treatment Paradigm: What Managed Care Needs to Know Michael J. Keating, MD Novel Insights on the Current and Emerging Treatment Strategies of CRPC Channing J. Paller, MD Clinical Insights into the Diagnosis and Treatment of Epilepsy R. Edward Faught, MD What s New in the Evolving Management of Type 2 Diabetes: Individualizing Therapy with Novel Treatment Options Carol H. Wysham, MD Management Insights for Optimizing Outcomes in the Treatment of Hemophilia Mark T. Reding, MD The Future Management of IPF: Advanced Diagnostic and Treatment Strategies Charles Vega, MD, FAAFP Payer Challenges and Issues in the Management of OAB: Improving Patient Outcomes with Optimal Cost and Treatment Strategies Craig V. Comiter, MD, PhD New Developments in the Diagnosis and Treatment of Psoriatic Arthritis Atul A. Deodhar, MD, MRCP, FACP, FACR Optimizing Treatment Strategies in the Management of Rheumatoid Arthritis: Novel Therapies for Improved Patient Outcomes Maureen A. McMahon, MD Novel Treatment Advances and Approaches in the Management of Advanced Renal Cell Carcinoma (RCC) Robert A. Figlin, MD, FACP Vol. 21, No. 4 Journal of Managed Care Medicine 7

8 Editorial Review Board Alan Adler, MD, MS Medical Director Independence Blue Cross Devena Alston-Johnson, MD Medical Director CIGNA E. Paul Amundson, MD Chief Medical Officer Dakotacare Linda Ash-Jackson, MD Medical Director Hometown Health Paul Bluestein, MD Chief Medical Officer Connecticare Richard Bock, MD, MBA Chief Medical Officer Molina Health Care of California Anthony Bonagura, MD Chief Medical Officer Aetna, Inc. Salil V. Deshpande, MD Market Medical Officer United Healthcare Michael Fine, MD Medical Director Health Net John K. Fong, MD, MBA Vice President Blue Cross Blue Shield of North Carolina Stephen Friedhoff, MD Senior Vice President, National Medical Director Amerigroup/Wellpoint Ronald Y. Fujimoto, DO, FAAFP Chief Medical Officer United Healthcare Uwe G. Goehlert, MD, MSC, MPH, MBA Principal Goehlert & Associates Steven E. Goldberg, MD, MBA Vice President of Medical Affairs Coventry Health Care of Kentucky Humberto Guerra-Garcia, MD, MPH, FACP Chief Medical Officer MMM Healthcare, Inc./PMC Medicare Choice Puerto Rico Sarath Gunatilake, MD, DrPH Professor, Health Science Department California State University, Long Beach John W. Heryer, MD, FACS Medical Director Blue Cross Blue Shield of Kansas City Kathy Hudson, PhD Director, Genetics and Public Policy Center Johns Hopkins University Larry L. Hsu, MD Medical Director Blue Cross Blue Shield of Hawaii (HMSA) Stephen Keir, DrPH Co-Director, Center for Quality of Life Support Care Research Robert Preston Tisch Brain Tumor Center John Knispel, MD, CPE, FACOG Regional Medical Officer Humana Karen Knowles, MD Internal Medicine Physician HCA/Emcare Catherine Marino, MD Chief Medical Officer MagnaCare Jeff Martin, PharmD Clinical Account Director Innoviant, Inc. Monte Masten, MD, MBA, MPH Senior Consultant Health & Group Benefits, Tower Watson Wesley Mizutani, MD Director Clinical Research & Chairman Department of Rheumatology Healthcare Partners Thomas Morrow, MD Chief Medical Officer Next IT Barbara Nabrit-Stephens, MD, MBA Medical Director United Healthcare Tim Newman, MD Medical Director FirstEnergy Denis O Connell, MD Medical Director Blue Cross Blue Shield of North Carolina Arik Olson, MD, MBA Medical Director Samaritan Health Plans Gary Owens, MD Principal Gary Owens Associates Philip Painter, MD Chief Medical Officer Humana Mary H. Pak, MD Medical Director Unity Health Plans Insurance Corporation Gary R. Proctor, MD Associate Chief Medical Officer, Operations SVP, Chief Medical Officer, Federal Services Beacon Health Options Carlos Ramirez, MD Chief Medical Officer Valley Baptist Health Plans Paul Rein, DO Medical Director Port Warwick Ambulatory Surgery Center Kevin Roache, MD, MMM, CPE, FACPE President Medical Management Consulting, Inc. Joseph Schappert, MD Chief Medical Officer PAML Christine M. Seals, MD Medical Director Umpqua Health Alliance Jacque J. Sokolov, MD Chairman SSB Solutions Scott Spradlin, DO, FACPE, ACOI Vice President Medical Affairs/Chief Medical Officer Group Health Plan William D. Strampel, DO, FACOI Dean, College of Osteopathic Medicine Michigan State University Prentiss Taylor, MD Corporate Medical Director Advocate At Work at Advocate Health Care Riya Pulicharam, MD National Medical Director Population Health & Clinical Outcomes HealthCare Partners Medical Group Robert A. Ziff, MD, MBA, FACS, CPE Medical Director Medicare Humana 8 Journal of Managed Care Medicine Vol. 21, No. 4

9 New Horizons in the Management of Alzheimer s Disease: Advances in Early Diagnosis and Treatment Strategies Marwan N. Sabbagh, MD, FAAN For a CME/CEU version of this article please go to and then click the activity title. Summary Alzheimer s disease is a costly and devastating disease. There are now biomarkers for accurately diagnosing the disease and symptomatic treatments which can delay the need for long-term care. Numerous additional therapies are likely to reach the market in the next few years. Key Points Early diagnosis and management of AD is ethically, medically, scientifically, and economically supported. Comprehensive assessment of patients with suspected prodromal or atypical AD often benefits from the use of newer diagnostic biomarkers, including FDG PET, amyloid PET, or CSF examination. The current AD pharmacological paradigm involves combination treatment with symptom managing medications as individuals progress beyond mild stages. Several agents with different mechanisms of action are in clinical trials to evaluate whether disease progression can be slowed. ALZHEIMER S DISEASE (AD) AFFECTS APproximately five million individuals in the United States (U.S.), with a projected increase to almost 16 million by ,2 Almost 47 million people are affected worldwide. 3 AD is the sixth leading cause of death in the U.S., and AD-related deaths continue to increase. 1,2 In 2017, AD and other forms of dementia cost the nation $259 billion. 1 The average cost of caring for an AD patient over the disease course is estimated to be more than $200,000, making AD the nation s third most-costly disease, after heart disease and cancer. For patients with AD living in nursing homes or other long-term care facilities, the average cost of care is estimated as high as $42,000 per year. There is a great deal of lost economic opportunity for caregivers, nursing home, and out-ofpocket costs. It takes, on average, up to two years for an individual with significant symptoms to see a physician and up to one year to get a dementia diagnosis. 4,5 It is estimated that 20 percent of individuals in the U.S. who have AD are never clinically diagnosed. 6 A major issue in the delay of diagnosis and underdiagnosis is the reluctance of providers to make a diagnosis of dementia, mild cognitive impairment (MCI) or AD and to evaluate cognitive complaints in the first place. Many dismiss any cognitive complaints as stress, depression, or aging. Even though an annual dementia screening is part of good patient care, it has never been successfully implemented. However, many obvious benefits to an early diagnosis exist, and effective pharmacological and nonpharmacological treatments for symptoms of AD are available. 7 On average patients will live 10 years with AD, and 33 percent of that time is spent in some type of care outside the home. The goal of earlier diagnosis and treatment is to make that 33 percent a much lower number (i.e., 5 10%). The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) replaced dementia with major neurocognitive disorder. 8 Exhibit 1 shows the difference between mild and major neurocognitive disorders (NCD). 8 The NCDs can be Alzheimer s disease, vascular dementia, fronto- Vol. 21, No. 4 Journal of Managed Care Medicine 9

10 Exhibit 1: DSM-5 Syndromal Definitions 8 Mild neurocognitive disorder (NCD) (e.g., Mild Cognitive Impairment [MCI]/prodromal AD) Mild cognitive decline (preferably diagnosed by neurocognitive testing or, in its absence, other quantified clinical testing) Does not interfere with independence Not due to delirium Not attributed to another mental disorder (eg, major depression, schizophrenia) Major NCD (dementia, e.g., due to AD) Major cognitive decline (preferably diagnosed by neurocognitive testing or, in its absence, other quantified clinical testing) Interferes with independence Not due to delirium Not attributed to another mental disorder (eg, major depression, schizophrenia) Exhibit 2: NIA-AA and IWG Diagnostic Criteria for AD 9-13 AD dementia Cognitive impairment Impairment of activities of daily living Biomarker evidence of AD Prodromal AD (MCI of the AD type) Amnestic or non-amnestic cognitive impairment No or minor impairment of activities of daily living Biomarker evidence of AD AD at-risk state (preclinical AD) No cognitive impairment on testing (possible subjective impairment) No functional impairment Biomarker evidence of AD NIA-AA = National Institute on Aging-Alzheimer s Association IWG = International Work Group temporal (behavioral variant, semantic dementia, progressive aphasia, progressive supranuclear palsy, corticobasal degeneration), dementia with Lewy bodies, or medically induced (neoplasm, trauma/anoxia, normal pressure hydrocephalous, toxins, infections, neurologic illness, and organ failure). A major neurocognitive disorder is defined by evidence of significant cognitive decline from a previous level of performance that interferes with independence in everyday activities, based on individual, informant, and/or test data, and that is not accounted for by delirium or another mental disorder in one or more of the following cognition domains: complex attention, executive function, learning and memory, language, perceptual-motor, and social cognition. MCI is a subjective memory complaint that is corroborated by an informant and objectively demonstrated that does not interfere with independence; it is a transitional state of abnormal cognition that is not yet bad enough to be classified as dementia. Most neurologists have not changed their terminology. Their preferred terminology is to use MCI and dementia due to a particular disease (i.e., dementia due to AD or dementia due to Lewy bodies). The process of AD begins about 20 years before the development of symptoms. The term AD is now used to describe the preclinical phase, MCI phase, and dementia due to the AD phase. The National Institute on Aging-Alzheimer s Association (NIA- AA) and the International Work Group (IWG) diagnostic criteria for AD are shown in Exhibit The U.S. based NIA-AA group still uses the exclusionary approach to diagnosis and says that biomarker evidence is helpful, but it is not necessarily diagnostic. The European IWG guidelines rely more on biomarker evidence. Unfortunately, the diagnostic accuracy in the U.S. based on exclusion is never better than 70 percent and is about 60 percent in primary care. The use of targeted biomarker testing would improve the diagnostic accuracy; the 10 Journal of Managed Care Medicine Vol. 21, No. 4

11 Exhibit 3: Genetic Risk Factors for Early versus Late Onset Type of AD Chromosome Genes Early Onset (EOAD) Late Onset AD (LOAD) 1 Presenilin 2 14 Presenilin 1 21 APP (amyloid precursor protein) 1 CR-1 2 BIN1 5 MEF2C 6 CD2AP, TREM2 7 EPHA1, NME8, ZCWPW1 8 CLU, PTK2B 11 CELF, MS4A6A, PICALM, SORL1 14 FERMT2, SLC24A4/RIN3 18 DSG2 19 ABCA7, CD33, APOE-e4 20 CASS4 X INPP5D evolving clinical practice is to use these tests which are discussed later. Various risk factors for AD have been identified. AD risk factors include age, female gender, APOEe4 genotype, hypertension, diabetes, elevated homocysteine, elevated cholesterol, head trauma, and family history. At 65 years of age the rate of AD is 1 in 20, by age 80 it is 1 in 3, and by age 90 it is 4 in 10. AD is less likely to occur in those who have higher education levels, exercise regularly, maintain brain fitness, consume an antioxidant diet, maintain heart health, and maintain social activity. The best dementia prevention regimen is regular exercise, cognitive stimulation, and blood pressure control. Multiple studies have shown positive correlations between physical exercise in older individuals and maintenance or enhancement of cognition, especially executive function and lower rates of dementia. Exercise is thought to help by improving cerebral blood flow, decreasing loss of cortical tissue, and releasing neural growth factors (e.g., brain-derived neurotrophic factor). Various genetic mutations increase the risk of early versus late onset of AD (Exhibit 3) Late onset AD (LOAD) can be either sporadic or familial and accounts for 90 to 95 percent of cases. Most cases of early onset AD (EOAD) are not familial. Rarely, in familial cases, deterministic genes cause autosomal dominant inheritance. Annual wellness visits for adults should include structured questions about cognition and to help identify issues of cognition early. A cognitive screening test can be conducted if issues are identified. Various quick cognitive screening tools are available for use in the primary care setting. Screening lab tests can be done to identify reversible/ treatable causes of decreased cognition (e.g., CBC, Chem-20, TSH, B12, homocysteine, CRP, ESR). An MRI is typically ordered; however, these are not diagnostic for AD, but they can rule out other conditions. A newer type of MRI that looks specifically at hippocampal atrophy may be more useful. The hippocampus is the seat of short-term memory. The patient can be referred to a dementia specialist for neuropsychological testing, genetic testing, and other imaging. Apolipoprotein E (APOE) gets the most press as the AD gene. It is gene on chromosome 19 that has three major human isoforms (apoe2, apoe3, and apoe4), three alleles (e2, e3, and e4), and five common genotypes (3/3, 3/4, 2/3, 2/4, and 4/4). 22,23 APOE-e4 is found in approximately 20 percent of the population and increases risk and lowers the onset age for AD. 22,23 APOE-e4 may have a modest effect in predicting cognitive decline in older persons. Being an APOE-e4 carrier increases the risk for MCI progression to dementia due to AD, the probability of pathology in the brain is 26 times more likely, and the likelihood of amyloid positive brain scans compared with someone without this gene. Vol. 21, No. 4 Journal of Managed Care Medicine 11

12 Exhibit 4: Biomarkers for Alzheimer s Disease Biomarker Measurement Aβ 42 accumulation TAU HP accumulation Synaptic dysfunction Loss of brain volume Aβ42 = beta amyloid CSF = cerebrospinal fluids PET = positron emission tomography HP = hyperphosphorylated FDG = fluorodeoxyglucose MRI = magnetic resonance imaging Biomarker Changes Consistent with Alzheimer s Disease Aβ 42 levels decrease in CSF. Aβ 42 can be seen in amyloid-based PET scan TAU HP levels increase in CSF Hypometabolism is seen on FDG-PET Atrophy is seen on MRI and can be measured with MRI volumetrics Genetic testing for APOE-e4 is routinely done in some neurology practices but not in the majority in the workup for MCI and dementia. Some experts argue that APOE-e4 screening should be done for everyone, but this is a hot- button issue. The American Academy of Neurology does not recommend testing of asymptomatic people; however, people can order their own test through companies such as 23andMe (without genetic counseling). Various biomarkers beyond APOE-e4 have been investigated in AD. Beta amyloid (Aβ 42 ) accumulation in the brain, hyperphosphorylated TAU protein (TAU HP ) accumulation in the brain, synaptic dysfunction, and loss of brain volume are all proven biomarkers for this disease (Exhibit 4) If someone has MCI and positive amyloid and TAU cerebrospinal fluid (CSF) testing, the probably of progressing to AD in one year is 90 percent. CSF testing is less expensive than PET scan testing and highly predictive, but it is not yet routinely done in the U.S. CSF testing is much more common outside of the U.S. Some advanced neurology practices in the U.S. are doing it in select patients. Fluorodeoxyglucose positron emission tomography (FDG-PET) scans, which show changes in glucose metabolism, can be used to make the AD diagnosis; however, clinicians are moving away from these to a more accurate scan. Amyloid PET, using specific imaging tracers that are approved for identifying amyloid, is becoming the standard exam. Amyloid levels in the brain increase with age, and not all amyloid-positive individuals will develop cognitive symptoms, but those with MCI have increased prevalence of amyloid positivity and risk of AD. Older age and APOE-e4 genotype are associated with a higher frequency of an elevated amyloid PET signal. However, not all individuals with positive amyloid PET will develop significant clinical symptoms. A negative amyloid PET scan excludes amyloid pathology as contributing to dementia pathology. Appropriate use criteria for amyloid imaging are given in Exhibit Various groups are working toward approval for amyloid PET scanning through Medicare. It is not definitely known whether amyloid PET scans impact patient management. The IDEAS (Imaging Dementia Evidence for Amyloid Scanning) program, funded by Medicare, which scanned 18,000 people with MCI, is almost done and is assessing the impact of amyloid PET on shortterm patient management and on outcomes at 12 months versus matched controls. 30 In the initial cohort of scans, the results of the scan changed the patient management 63 percent of the time. The cost of amyloid PET is approximately $5,000; CSF testing can provide the same information for a significantly lower cost. Many clinicians think nothing can be done for the patient with AD, but effective treatments are available. Multifactorial AD care involves a combination of nonpharmacological and pharmacological approaches that can ameliorate current symptoms, reduce the pace of overall clinical decline, and provide meaningful benefits. Treatment of sleep issues, agitation and paranoia, caregiver support/treatment, and end-of-life planning are all important aspects of treatment. AD treatment domains include symptom improvement and disease modification. Currently, there are only two FDA approved treatments for symptom improvement acetylcholinesterase inhibitors 12 Journal of Managed Care Medicine Vol. 21, No. 4

13 Exhibit 5: Amyloid Imaging Taskforce Use Criteria 29 APPROPRIATE 1. A cognitive complaint with objectively confirmed impairment 2. Performed only after full standard workup is completed 3. AD is a possible diagnosis, but it is uncertain 4. Knowledge of Aβ pathology would increase diagnostic certainty and alter management 5. Should only be ordered by experts in dementia INAPPROPRIATE 1. Used for evaluation of individuals without cognitive complaints; however, preclinical AD may become an indication for amyloid imaging if preventative treatments are proved to be effective 2. When standard recommended clinical diagnostic testing has not been ordered for initial assessment 3. As a stand-alone diagnostic for AD dementia 4. To assess disease progression (AChEIs) and N-methyl-D-aspartate (NMDA) receptor antagonists. These agents improve the symptoms of AD for a while, but the disease inevitably progresses. There are multiple additional agents in clinical trials for symptom improvement. The available AChEIs include donepezil, rivastigmine (oral and patch), and galantamine. Memantine (immediate release, extended release) is the only NMDA-receptor antagonist available. These therapies are very inexpensive, especially when compared with the cost of nursing home care. There is also a combination product of memantine extended release and donepezil which is much more expensive than giving each component separately. These agents are generally well tolerated; the adverse effects that occur can many times be managed by reducing the dose and slow up titration of dosing. AChEIs cause nausea, vomiting, diarrhea, loss of appetite and dizziness. Weight loss is common from both the disease and AChEIs use, is a predictor of mortality, and they should be carefully monitored. Memantine can cause confusion, sedation, and constipation. Clinical trials have shown additive benefits of AChEIs and memantine for cognitive function, activities of daily living, global status, and behavior/ neuropsychiatric symptoms The rate of decline is slowed by approximately 25 percent. Longterm use of the combination can delay long-term care placement by six to 18 months. The European Academy of Neurology Guidelines recommend a combination of AChEI plus memantine rather than AChEI alone in patients with moderate to severe AD. 33 The current AD pharmacological paradigm involves combination treatment with symptomatic medications as individuals progress beyond mild stages. Currently, there are no FDA approved medications which are disease modifying. Clinical trials are in progress on a variety of mechanisms, including neuronal protection, protein synthesis or aggregation inhibition, immunologic priming with antibodies, vaccines, and secretase inhibition. For example, aducanumab is a monoclonal antibody against amyloid which is being investigated for AD. A Phase I trial of this agent found significantly reduced brain amyloid and mental status stabilization. 34 The most common adverse effects (AEs) with aducanumab were amyloid-related imaging abnormalities (ARIAs), vasogneic edema, cerebral microhemorrhages and headache. Lower dose (particularly in APOE-e4 positive patients) and slower titration mitigated ARIA. Trials of anti-amyloid antibodies are showing that the potential therapeutic effects may be larger in mild-stage, very mild, or MCI stages than in moderate-stage AD. Data from these trials are suggesting dose adjustments in APOE-e4 carriers with greater risk of ARIAs to maximize potential for therapeutic benefits and reduce adverse effects. Increasingly, immunotherapy trials are looking to intervene at earlier stages to see if disease progression can be interrupted prior to symptomatic onset of AD. The Alzforum (alzforum.org) lists 32 agents targeting amyloid, two cholinergic agents, 13 agents targeting inflammation, 11 agents targeting Tau, and 56 targeting other mechanisms of action as under investigation. These agents are all in Phase I to III trials. Several agents which are already FDA Vol. 21, No. 4 Journal of Managed Care Medicine 13

14 approved for other indications, such as statins and various anti-hypertensives, are in Phase IV studies for MCI or AD. Solanezumab, crenezumab, gantenerumab, and pioglitazone (FDA approved agent for type 2 DM) are all under study for prevention. Several supplements and medical foods have been investigated for treatment and prevention; unfortunately most have not been successful. High dose vitamin E (2000 IU) in combination with AChEIs (but not memantine) showed modest functional benefit over placebo. 35,36 Conclusion Early diagnosis and management of AD is ethically, medically, scientifically, and economically supported. Diagnostic biomarkers, including FDG PET, amyloid PET, or CSF examination are available for AD diagnosis. The current AD pharmacological paradigm involves combination treatment with symptomatic medications as individuals progress beyond mild stages. AD care requires a combination of nonpharmacological and pharmacological approaches that can ameliorate current symptoms, reduce the pace of overall clinical decline, and provide meaningful benefits. Several agents with different mechanisms of action are in clinical trials to evaluate whether disease progression can be slowed. Marwan N. Sabbagh, MD, FAAN, is the Karsten Solheim Chair for Dementia, Professor of Neurology, Director of the Alzheimer s and Memory Disorders Division at the Barrow Neurological Institute and Research Professor of Neurology at the University of Arizona College of Medicine Phoenix, in Phoenix, AZ. References 1. Alzheimer s Association. Facts and Figures, Available at documents_custom/2017-facts-and-figures.pdf. 2. Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the United States ( ) estimated using the 2010 census. Neurology. 2013;80(19): Alzheimer s Disease International. World Alzheimer Report Available at 4. Balasa M, Gelpi E, Antonell A, et al. Clinical features and APOE genotype of pathologically proven early-onset Alzheimer disease. Neurology. 2011;76(20): Boise L, Camicioli R, Morgan DL, et al. Diagnosing dementia: perspectives of primary care physicians. Gerontologist. 1999;39(4): Mok W, Chow TW, Zheng L, et al. Clinicopathological concordance of dementia diagnoses by community versus tertiary care clinicians. Am J Alzheimers Dis Other Demen. 2004;19(3): Alzheimer s Disease International. World Alzheimer Report 2011: the Benefits of Early Diagnosis and Intervention. Available at WoirldAlzheimerReport2011ExecutiveSummary.pdf 8. American Psychiatric Association (APA). Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). Arlington, VA: APA; Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007;6(8): Dubois B, Feldman HH, Jacova C, et al. Revising the definition of Alzheimer s disease: a new lexicon. Lancet Neurol. 2010;9(11): McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer s disease: recommendations from the National Institute on Aging-Alzheimer s Association workgroups on diagnostic guidelines for Alzheimer s disease. Alzheimers Dement. 2011;7(3): Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer s disease: recommendations from the National Institute on Aging-Alzheimer s Association workgroups on diagnostic guidelines for Alzheimer s disease. Alzheimers Dement. 2011;7(3): Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer s disease: recommendations from the National Institute on Aging-Alzheimer s Association workgroups on diagnostic guidelines for Alzheimer s disease. Alzheimers Dement. 2011;7(3): Bird TD. Genetic aspects of Alzheimer disease. Genet Med. 2008;10(4): Hollingworth P, Harold D, Sims R, et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer s disease. Nat Genet. 2011;43(5): Naj AC, Jun G, Beecham GW, et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer s disease. Nat Genet. 2011;43(5): Lambert JC, Ibrahim-Verbaas CA, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer s disease. Nat. Genet. 2013;45(12): Seshadri S, Fitzpatrick AL, Ikram MA, et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA ;303(18): Harold D, Abraham R, Hollingworth P, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer s disease. Nat Genet. 2009;41(10): Wijsman EM, Pankratz ND, Choi Y, et al. Genome-wide association of familial late-onset Alzheimer s disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE. PLoS Genet. 2011;7(2):e Guerreiro R, Wojtas A, Bras J, et al. TREM2 variants in Alzheimer s disease. N Engl J Med. 2013;368(2): Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer s disease in late onset families. Science. 1993;261(5123): Raber J, Huang Y, Ashford JW. ApoE genotype accounts for the vast majority of AD risk and AD pathology. Neurobiol Aging. 2004;25(5): Sperling RA, Laviolette PS, O Keefe K. Amyloid deposition is associated with impaired default network function in older persons without dementia. Neuron. 2009;63(2): Morris JC, Roe CM, Grant EA, et al. Pittsburgh compound B imaging and prediction of progression from cognitive normality to symptomatic Alzheimer disease. Arch Neurol. 2009;66(12): Fagan AM, Roe CM, Xiong C, et al. Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol. 2007;64(3): de Leon MJ, Ferris SH, George AE, et al. Positron emission tomographic studies of aging and Alzheimer disease. AJNR Am J Neuroradiol. 1983;4(3): Atiya M, Hyman BT, Albert MS, Killiany R. Structural magnetic resonance imaging in established and prodromal Alzheimer disease: a review. Alzheimer Dis Assoc Disord. 2003;17(3): Johnson KA, Minoshima S, Bohnen NI, et al. Update on appropriate use 14 Journal of Managed Care Medicine Vol. 21, No. 4

15 criteria for amyloid PET imaging: dementia experts, mild cognitive impairment, and education. Amyloid Imaging Task Force of the Alzheimer s Association and Society for Nuclear Medicine and Molecular Imaging. Alzheimers Dement. 2013;9(4):e Atri A, Shaughnessy LW, Locascio JJ, Growdon JH. Long-term course and effectiveness of combination therapy in Alzheimer disease. Alzheimer Dis Assoc Disord. 2008;22(3): Tariot PN, Farlow MR, Grossberg GT, et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004;291(3): Deardorff WJ, Grossberg GT. A fixed-dose combination of memantine extended-release and donepezil in the treatment of moderate-to-severe Alzheimer s disease. Drug Des Devel Ther. 2016;10: Schmidt R, Hofer E, Bouwman FH, et al. EFNS-ENS/EAN Guideline on concomitant use of cholinesterase inhibitors and memantine in moderate to severe Alzheimer s disease. Eur J Neurol. 2015;22(6): Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer s disease. Nature. 2016;537(7618): Dysken MW, Sano M, Asthana S, et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA. 2014;311(1): Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005;352(23): Genomics, Biotech and Emerging Medical Technologies Council Declare the past, Diagnose the present, Foretell the future. Specialized resources, valuable networking, leadership opportunities, education & more for Medical Directors from purchasers, plans & provider systems. Vol. 21, No. 4 Journal of Managed Care Medicine 15

16 Management of Metastatic Bladder Cancer: How Advances in Immunotherapy are Improving Patient Outcomes Matthew T. Campbell, MD, MS For a CME/CEU version of this article please go to and then click the activity title. Summary Treatment of bladder cancer is changing rapidly, with several new immunotherapies reaching the market in Immunotherapy is replacing chemotherapy as firstand second-line therapy for metastatic disease in many cases. Survival is improving, but there is still a long way to go to optimize outcomes. Key Points Avelumab, durvalumab, atezolizumab, nivolumab, and pembrolizumab are all FDA approved for treating locally advanced or metastatic bladder cancers that have progressed on chemotherapy. Pembrolizumab is the NCCN preferred agent, but the others are alternative agents over additional chemotherapy after progression on chemotherapy. Atezolizumab and pembrolizumab are FDA approved and NCCN recommended as first-line therapy in locally advanced or metastatic bladder cancer for cisplatin ineligible patients. MORE THAN 81,000 CASES OF BLADDER cancer will be diagnosed in the United States (U.S.) in 2018 and about 17,000 deaths due to this cancer will occur. 1 Approximately 2.3 percent of men and women will be diagnosed with bladder cancer at some point during their lifetime, based on 2013 to 2015 data. 1 Overall, the five-year survival for bladder cancer is 78 percent (2010). This is one cancer where the majority of the cases (85%) are diagnosed when the disease is still localized (in situ or confined to primary site). There are three types of bladder cancer that begin in cells in the lining of the bladder: transitional cell carcinoma, squamous cell carcinoma, and adenocarcinoma. Cancer that is confined to the lining of the bladder is called superficial bladder cancer. Cancer that begins in the transitional cells may spread through the lining of the bladder and invade the muscle wall of the bladder or spread to nearby organs and lymph nodes. Transitional cell carcinoma of the bladder can be low- or high-grade. Low-grade bladder cancer often recurs in the bladder after treatment, but rarely invades the muscular wall of the bladder or spreads to other parts of the body. Patients rarely die from lowgrade bladder cancer. High-grade bladder cancer commonly recurs and also has a strong tendency to invade the muscular wall of the bladder and spread to other parts of the body. Almost all deaths from bladder cancer result from high-grade disease. 2 From 1985 to 2015, metastatic bladder cancer was treated with surgical removal and neoadjuvant cisplatin-based chemotherapy regimens. Overall, with cisplatin chemotherapy regimens, the response rate was around 60 percent. Patients who were unfit for cisplatin therapy had inferior outcomes of lower response rates and worse survival. 3 Cisplatin ineligibility can generally be defined as a patient with renal impairment (creatinine clearance less than 60 ml/min,), poor performance status (Eastern Co- 16 Journal of Managed Care Medicine Vol. 21, No. 4

17 Exhibit 1: FDA Approved Indications for Immunotherapy in Bladder Cancer Treatment Agent MOA Indication Atezolizumab Anti-PD-L1 Locally advanced or metastatic urothelial carcinoma in patients who: Are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] covering 5% of the tumor area), as determined by an FDA-approved test, OR Are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status, OR Have disease progression during or following any platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant chemotherapy Avelumab Anti-PD-L1 Locally advanced or metastatic urothelial carcinoma in patients who: Have disease progression during or following platinum-containing chemotherapy Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy Durvalumab Anti-PD-L1 Locally advanced or metastatic urothelial carcinoma in patients who: Have disease progression during or following platinum-containing chemotherapy Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy Pembrolizumab Anti-PD-1 Locally advanced or metastatic urothelial carcinoma in patients who: Are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) 10], OR Are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status, OR Have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy Have Unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options Nivolumab Anti-PD-1 Locally advanced or metastatic urothelial carcinoma in patients who: Have disease progression during or following platinum-containing chemotherapy have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy operative Oncology Group performance status of 2 or worse), peripheral neuropathy (grade > 2), heart failure (New York Heart Association Class III or worse), or other serious comorbid conditions. Various second-line chemotherapies have been tried for metastatic disease. The response rates to single-agent chemotherapy have been about 10 percent and durable responses are rare. There have been no standard second-line treatments. 4 Combination chemotherapy has been studied, but it is more toxic than monotherapy in the second-line setting. A paradigm shift occurred with the first approval of immunotherapy for bladder cancer. Immunotherapy is unique among treatment options because it adapts, is specific, and retains memory. The most interesting part of immunotherapy for cancer is in the patients who have a durable response if they make it to the tail of the curve, they will essentially be cured. Immunotherapy also tends to be much better tolerated than chemotherapy, and it does not cause long-term adverse effects, such as neuropathy, heart failure, or secondary hematologic cancers, as does some chemotherapy. Normally, effector T cells of the immune system recognize and destroy foreign tissue/cells or cancer cells; many cancer cells have various mechanisms for Vol. 21, No. 4 Journal of Managed Care Medicine 17

18 avoiding being recognized by the immune system. In metastatic bladder cancer, various receptors on dendritic cells, tumor cells, regulatory T cells, and tissue macrophages can be targeted to stimulate effector T-cell proliferation and function. One of these receptors on T cells is programmed cell death one (PD-1). It normally acts as an off switch that helps keep the T cells from attacking other cells in the body. It does this when it attaches to programmed death ligand one (PD-L1), a protein found on normal cells and some cancer cells. When PD-1 binds to PD-L1, it basically tells the T cell to leave the other cell alone. Some cancer cells express large amounts of PD-L1, which helps them evade immune attack. Blocking PD-L1 or PD-1 allows T cells to remain active and recognize tumor cells. Anti-PD therapy has substantial activity across numerous diseases, including melanoma, renal cell cancer, non-small cell lung cancer, and bladder cancer. The currently available therapies are anti-pd-l1 and anti-pd-1. Atezolizumab (Tecentriq ), avelumab (Bavencio ), durvalumab (Imfinzi ), pembrolizumab (Keytruda ), and nivolumab (Opdivo ) are the currently approved immunotherapies for bladder cancer. The approved indications and mechanism of action for each are shown in Exhibit 1. Treatment with each of the approved immunotherapies produces similar response rates and similar rates of long-term/durable responses in patients with metastatic bladder cancer (Exhibit 2) None of these agents have been compared directly with each other. The most common adverse effects with immunotherapy are fatigue, nausea, and decreased appetite. The serious, but relatively rare, adverse effects include pneumonitis and colitis. One minor difference in the agents is that avelumab causes a higher rate of infusion reactions than the others. Immunotherapy is replacing chemotherapy as first- and second-line therapy for metastatic disease in many cases. The National Comprehensive Cancer Network (NCCN) guidelines recommend atezolizumab or pembrolizumab as first-line treatment in those who are platinum ineligible for locally advanced or metastatic disease. 13 Pembrolizumab is the preferred agent for subsequent systemic therapy for locally advanced or metastatic disease (Stage IV), after platinum-based chemotherapy. 13 The other FDA approved immunotherapies are considered alternative preferred regimens over additional chemotherapy. Even when a patient s disease responds to immunotherapy initially, response can be lost over time. In a second-line setting study of pembrolizumab, 72 percent of patients maintained response, whereas 28 percent lost their initial response. 6 Researchers need to discover the underlying mechanisms for loss of response (i.e., what is changing with the immune system or tumor microenvironment). Researchers and clinicians are searching for biomarkers to predict response to immunotherapy. PD- L1 expression has been used in trials and specific cut-points for expression are part of some of the FDA approvals for immunotherapy, but it does not always predict response. Lymphocytic tumor infiltration is another biomarker that appears to predict response and prognosis. Patients with mild to moderate lymphocyte infiltration into the tumor microenvironment have improved prognosis. Improved outcomes have been shown in patients with increased PD-L1 expression in tumor infiltrating mononuclear cells. 14 PD-L1 expression is not a static marker. It can rapidly go up and down. Many of the specimens that are sent off for PD-L1 testing may be archived tissue samples from prior biopsy; archived tissue was used in many of the immunotherapy clinical trials. PD- L1 expression is not a perfect biomarker. Mismatch repair (MMR) deficiency is another biomarker of response to immunotherapy. The MMR pathway is a major way that cells fix DNA base-pair mistakes that occur during DNA replication; MMR-deficient cells have a large number of mutations 1,700 on average, compared with just 70 in a typical cancer cell. MMR deficiency is indicated by high levels of microsatellite instability (MSI) on testing of cells. The more DNA mutations a cancer cell has, the higher the likelihood it will be recognized by the immune system as foreign and killed and the more likely that the patient will benefit from immunotherapy. Bladder cancer is the third highest mutated cancer. 15,16 Pembrolizumab is FDA approved for unresectable or metastatic, MSIhigh or MMR-deficient solid tumors that have progressed following prior treatment and that have no satisfactory alternative treatment options. With anti PD-1 therapy, approximately 10 percent of patients can have pseudoprogression. The tumor can appear to be growing; however, this may be due to immune infiltration and inflammation. When pain, worsening anemia, worsening albumin, or worsening performance status are occurring, it is not likely pseudoprogression. There are a few cases where immunotherapy cannot be used or must be carefully considered. The pros and cons of immunotherapy will have to be weighed carefully for patients with an organ transplant who are on active immune suppression or have an active autoimmune disease. Additionally, patients with liver metastases have done very poorly in the immunotherapy trials, but this is not necessarily a contraindication to use. 18 Journal of Managed Care Medicine Vol. 21, No. 4

19 Exhibit 2: Efficacy of Immunotherapy in Bladder Cancer 5-12 Drug Ab type PD-l IHC-Ab IC Cut Point TC Cut Point Phase/line No. of Subjects Comparator Tissue ORR total (%) ORR based on PD-L status Atezolizumab (prior platinum) VENTANA SP142 IC 0-0% IC 1 <5% IC2/3 5% None Phase II N = 310 patients Single arm ARCHIVED Response 15% all comers 26% IC 2/3 (11% CR), 18% IC 1/2/3(6% CR), 10% IC 1 (2%), 8% IC0 (2%) Atezolizumab (cis-ineligible) Front line VENTANA SP142 IC 0-0% IC 1 <5% IC2/3 5% None Phase II N = 123 patients Single arm ARCHIVED Response 23% all comers 28% IC 2/3 (13%) 24% IC 1/2/3 (10% CR) 21% IC 1 (8.3% CR), 21% IC 0 (7.7% CR) Nivolumab (prior platinum) DAKO 28-8 None TC<1% TC 1% Phase II N = 78 patients Single arm ARCHIVED Response 24% all comers (6% CR) 26% ORR PD-L negative (11/42) (2.3% CR, 1CR), 25% ORR PD-L positive 6/25 (16% CR, 4/25) Durvalumab (prior platinum) VENTANA SP263 Combined score IC or TC IC<25% - IC 25%+ TC<25% - TC 25%+ Phase II N = 61 patients (after initial 20, only IC>5% allowed) ARCHIVED or FRESH Response 31% 5% CR (only 42 evaluable patients) 67% PD-L positive (28/42 with + in either domain) 46.4% PD-L positve (13/28) 46.6% TC positive (7/15), TC negative 22% (6/27) 55.5% IC positive (10/18), IC negative 12.5% (3/24) 0% if negative both demains (0/14) Avelumab (prior platinum) DAKO clone None TC<5% - TC 5%+ Phase Ib N = 44 patients single arm ARCHIVED Response 18% (11% CR) 64% TC 5% (7/13, 4 CR) 4.2% TC <5% (1/24 if TC PD-L1 <5% Pembrolizumab vs Chemo (prior platinum) DAKO 22C3 Combined score IC or TC IC<10% - IC 10%+ Combined TC<10% - TC 10%+ Phase III N = 542 patients 270 pembro (74PD-L +) 272 chemo (90 PD-L+) ARCHIVED Response 21% versus 11% chemo PD-L+ pembro 22% (CR 7%) PD-L + chemo 7% (CR 2%) Pembrolizumab Front line DAKO 22C3 Combined IC<1% - IC 1%+ Combined TC<1% - TC 1%+ Phase II N = 374 patients Single arm FRESH Response 24% CR 5% 38% combined PD-L 10% (42 of 110) 27% combined PD-L 1% (75 of 282) 11% combined PD-L <1% (5 of 26) PD-L = programmed death ligand IHC = immunohistochemistry IC = immune cell TC = tumor cell CR, complete reponse; cis, cisplatin Immune checkpoint therapy may be setting patients up for the next therapy. Synergy has been seen with using immunotherapy and chemotherapy together in lung cancer. This may become an option in bladder cancer and is currently under investigation. Immunotherapy is also likely going to be used in earlier stages of this disease as more studies are completed. Conclusion Immunotherapy has added an important new treatment option for patients with metastatic bladder cancer. Understanding which patients will benefit from single-agent therapy with anti PD-1/PD-L1 agents and which patients will not is of considerable importance but not yet answered. A large number of studies are ongoing that will shape the field for the next decade with the exploration of using these drugs earlier in the disease setting. Matthew T. Campbell, MD, MS, is an Assistant Professor in the Department of Genitourinary Medical Oncology at the MD Anderson Cancer Center, Houston, TX. Vol. 21, No. 4 Journal of Managed Care Medicine 19

20 References 1. Cancer Stat Facts: Bladder Cancer. Available at seer.cancer.gov/statfacts/ html/urinb.html. Accessed 7/18/ Bladder Cancer Treatment (PDQ). Available at bladder/hp/bladder-treatment-pdq. Accessed 7/18/ Galsky MD, Hahn NM, Rosenberg J, et al. Treatment of patients with metastatic urothelial cancer unfit for cisplatin-based chemotherapy. J Clin Oncol. 2011;29(17): Yafi FA, North S, Kassouf W. First- and second-line therapy for metastatic urothelial carcinoma of the bladder. Curr Oncol. 2011;18(1):e Plimack ER, Bellmunt J, Gupta S, et al. Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEY- NOTE-012): a non-randomized, open-label, Phase Ib study. Lancet Oncol. 2017;18(2): Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017;376(11): Balar AV, Castellano D, O Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(11): Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031): Balar AV, Galsky M, Rosenberg JE, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064): Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3): Massard C, Gordon MS, Sharma S, et al. Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol. 2016;34(26): Patel MR, Ellerton J, Infante JR, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 2018;19(1): National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Bladder Cancer. Version Available at www. nccn.org. Accessed 7/18/ Bellmunt J, Mullane SA, Werner L, et al. Association of PD-L1 expression on tumor-infiltrating mononuclear cells and overall survival in patients with urothelial carcinoma. Ann Oncol. 2015;26(4): Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463): Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507(7492): Online CME credits at your finger tips on: Health Management Oncology Genomics Biotech & Emerging Medical Technologies Join NAMCP Medical Directors Institute today! 20 Journal of Managed Care Medicine Vol. 21, No. 4

21 For the treatment of mild-to-moderate plaque psoriasis in patients 18 years of age or older SHOW YOUR UNEXPECTED SPRAY ON A FORMULATION WITH HIGH PENETRATION & LOW SYSTEMIC ABSORPTION a SERNIVO (betamethasone dipropionate) Spray, 0.05% is a novel, lotion-like spray formulated to stay local in the epidermis and dermis, with low systemic absorption. 1,2 Significantly more patients using SERNIVO achieved treatment success versus vehicle at Day 15 (20.3% vs 5%; p<0.001) and Day 29 (38.7% vs 12.6%; p<0.001 [N=538]). 3,b After 4 days of treatment, patient-reported itching decreased by approximately 50% 3,c Effective on hard-to-reach plaques on the back, in addition to hard-to-treat elbows and knees 3 and hairy areas. Nearly 75% of plaques on elbows and knees were clear or almost clear of redness and scaling after 29 days of treatment 5 With the SERNIVO Patient Savings Program, eligible patients can save on their prescription. d SPRAY ON SERNIVO a Of several prototype formulations tested in vitro, SERNIVO provided the best balance of high penetration/permeation and low absorption. 1 b Pooled data from 2 clinical studies of 538 patients with mild-to-moderate plaque psoriasis. In clinical studies, treatment success was defined as an IGA of 0 or 1 (clear or almost clear) and at least a 2-grade reduction from baseline. Patients in clinical studies were adults (18 years and older) and had plaque psoriasis on 10% to 20% of their body surface area (BSA). 3 c Itching was assessed proactively using Fisher s exact test, with subjects asked if they were experiencing itching (yes/no) at each visit (Days 4, 8, 15, and 29) or had experienced itching since their last visit. 4 d Visit SERNIVO.com for terms and conditions and full eligibility requirements. IMPORTANT SAFETY INFORMATION SERNIVO Spray can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency. Systemic effects of topical corticosteroids may also manifest as Cushing s syndrome, hyperglycemia or unmasking of latent diabetes mellitus, and glucosuria. These events are rare and generally occur after prolonged exposure to larger than recommended doses, particularly with high-potency topical corticosteroids. Do not use if atrophy is present at the treatment site. Do not use with occlusive dressings. Avoid use on the face, scalp, axilla, groin or other intertriginous areas. Use of SERNIVO Spray is not recommended in pediatric patients as they are more susceptible to systemic toxicity. Allergic contact dermatitis may occur. The most common adverse reactions ( 1%) were application site pruritus, burning and/or stinging, pain, and atrophy. Local reactions and skin atrophy are more likely to occur with occlusive use, prolonged use, or use of higher potency corticosteroids. These are not all the possible side effects of SERNIVO Spray. To report SUSPECTED SIDE EFFECTS, call Promius Pharma at or contact the FDA at FDA References: 1. Kircik L, Okumu F, Kandavilli S. Permeation analysis of novel steroid vehicle to deliver and retain steroid in layers of skin associated with psoriasis. Poster presented at Winter Clinical, Koloa, HI, January 15-20, SERNIVO Prescribing Information. Promius Pharma, LLC. Princeton, NJ. February Gold LS, Jackson JM, Knuckles MLF, Weiss JS. Improvement in extensive moderate plaque psoriasis with a novel emollient spray formulation of betamethasone dipropionate 0.05%. J Drugs Dermatol. 2016;15(3): Zirwas M, Hebert A. Fast relief of itching in psoriasis with DFD-01, a novel medium-potency emollient spray formulation of betamethasone dipropionate 0.05%. Poster presented at Winter Clinical, Kona, HI, January 13-18, Kircik L, Bagel J. DFD-01, a novel emollient spray formulation of 0.05% betamethasone dipropionate, effectively treats plaque psoriasis on knees and elbows. Poster presented at Winter Clinical, Koloa, HI, January 15-20, Please see Full Prescribing Information at SERNIVO.com and Brief Summary of Prescribing Information on adjacent page. SERNIVO is a registered trademark of Promius Pharma, LLC Promius Pharma, LLC. All rights reserved. SER April 2017

22 Rx Only BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE SERNIVO Spray is indicated for the treatment of mild to moderate plaque psoriasis in patients 18 years of age or older. DOSAGE AND ADMINISTRATION Apply SERNIVO Spray to the affected skin areas twice daily and rub in gently. Use SERNIVO Spray for up to 4 weeks of treatment. Treatment beyond 4 weeks is not recommended. Avoid use on the face, scalp, axilla, groin, or other intertriginous areas. SERNIVO Spray is for topical use only. It is not for oral, ophthalmic, or intravaginal use. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression and Other Unwanted Systemic Glucocorticoid Effects SERNIVO Spray can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency. This may occur during or after withdrawal of treatment. Factors that predispose to HPA axis suppression include the use of high-potency corticosteroids, large treatment surface areas, prolonged use, use of occlusive dressings, altered skin barrier, liver failure, and young age. Evaluation for HPA axis suppression may be done by using the adrenocorticotropic hormone (ACTH) stimulation test. In a study including 48 evaluable subjects 18 years of age or older with moderate to severe plaque psoriasis, abnormal ACTH stimulation test results suggestive of adrenal suppression were identified in 5 out of 24 (20.8%) subjects after treatment with SERNIVO Spray twice daily for 15 days. No subject (0 out of 24) had abnormal ACTH stimulation test results after treatment with SERNIVO Spray twice daily for 29 days [see Clinical Pharmacology]. If HPA axis suppression is documented, gradually withdraw the drug, reduce the frequency of application, or substitute with a less potent corticosteroid. If signs and symptoms of steroid withdrawal occur, supplemental systemic corticosteroids may be required. Systemic effects of topical corticosteroids may also manifest as Cushing s syndrome, hyperglycemia, and glucosuria. These events are rare and generally occur after prolonged exposure to larger than recommended doses, particularly with high-potency topical corticosteroids. Minimize the unwanted risks from endocrine effects by mitigating the risk factors favoring increased systemic bioavailability and by using the product as recommended [see Dosage and Administration]. Pediatric patients may be more susceptible to systemic toxicity due to their larger skin surface to body mass ratios. Use of SERNIVO Spray is not recommended in pediatric patients [see Use in Specific Populations]. Allergic Contact Dermatitis Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation. Corroborate such an observation with appropriate diagnostic patch testing. If irritation develops, discontinue the topical corticosteroid and institute appropriate therapy. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In two randomized, multicenter, prospective vehicle-controlled clinical trials, subjects with moderate plaque psoriasis of the body applied SERNIVO Spray or vehicle spray twice daily for 4 weeks. A total of 352 subjects applied SERNIVO Spray and 180 subjects applied vehicle spray. Adverse reactions that occurred in at least 1% of subjects treated with SERNIVO Spray for up to 28 days are presented in Table 1. Table 1: Adverse Reactions Occurring in 1% of Subjects Treated with SERNIVO Spray for up to Four Weeks Application site pruritus Application site burning and/or stinging SERNIVO Spray b.i.d. (N=352) Vehicle Spray b.i.d (N=180) 6.0% 9.4% 4.5% 10.0% Application site pain 2.3% 3.9% Application site atrophy 1.1% 1.7% Less common adverse reactions (with occurrence lower than 1% but higher than 0.1%) in subjects treated with SERNIVO spray were application site reactions including telangiectasia, dermatitis, discoloration, folliculitis and skin rash, in addition to dysgeusia and hyperglycemia. These adverse reactions were not observed in subjects treated with vehicle. Postmarketing Experience Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Postmarketing reports for local adverse reactions to topical corticosteroids have also included striae, irritation, dryness, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, hypertrichosis, and miliaria. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. SERNIVO Spray should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Betamethasone dipropionate has been shown to be teratogenic in rabbits when given by the intramuscular route at doses of 0.05 mg/kg. The abnormalities observed included umbilical hernias, cephalocele, and cleft palate. Nursing Mothers Systemically administered corticosteroids appear in human milk and can suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids can result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when SERNIVO Spray is administered to a nursing woman. Pediatric Use Safety and effectiveness of SERNIVO Spray in patients younger than 18 years of age have not been studied; therefore use in pediatric patients is not recommended. Because of a higher ratio of skin surface area to body mass, pediatric patients are at greater risk of systemic toxicity, including HPA axis suppression and adrenal insufficiency, when treated with topical drugs. [see Warnings and Precautions] Rare systemic effects such as Cushing s syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients, especially those with prolonged exposure to large doses of high potency topical corticosteroids. Local adverse reactions including skin atrophy have also been reported with use of topical corticosteroids in pediatric patients. Geriatric Use Clinical studies of SERNIVO Spray did not include sufficient numbers of subjects who were 65 years of age or older to determine whether they respond differently from younger subjects. Manufactured by: DPT Laboratories, Ltd., San Antonio, TX Distributed by: Promius Pharma, LLC., Princeton, NJ Sernivo is a trademark of Promius Pharma, LLC. Issued: 02/2016

23 Clinical Updates in Cystic Fibrosis: Applying Recent Advances in CFTR Modulator Therapy for Improved Patient Outcomes Elliott Dasenbrook, MD, MHS For a CME/CEU version of this article please go to and then click the activity title. Summary It is an exciting time to be managing a patient with cystic fibrosis (CF). There are now therapies which correct the underlying pathophysiologic defect in this disease. These therapies have been shown to be disease modifying, which is a tremendous advance. Key Points Survival for patients with CF has improved with traditional treatments targeting the end result of CFTR dysfunction. Ivacaftor, lumacaftor/ivacaftor, and tezacaftor/ivacaftor are disease-modifying therapeutics in CF which slow the rate of lung function decline, improve quality of life, reduce medical resource utilization, and will hopefully continue to improve survival to a normal life span. CFTR modulator therapies are available for approximately 95 percent of CF patients in United States (U.S.). CYSTIC FIBROSIS (CF) IS AN ORPHAN DISease. CF affects approximately 30,000 adults and children in the U.S. 1 Among white individuals in the U.S., it is the most common lethal autosomal recessive disease; one in 25 people is a CF carrier and one in 2,500 live births have CF disease. Carrier frequency and incidence vary with race and ethnicity; there are approximately five million carriers in the U.S. The first comprehensive description of cystic fibrosis was in In the very early era of CF, it was uniformly fatal, with survival measured in days and months. Comprehensive and prophylactic treatment before symptoms developed and the evolvement of Foundation CF center programs led to major advances in survival. In the current era, the median age of survival is As shown in Exhibit 1, the percentage of CF patients who are adults has grown from 29.2 percent in 1986 to over 50 percent in CF adults are living productive lives. In the future, care will likely transition to a life-long condition with which patients will live, but not die. CF is a disease that affects the entire body and is caused by dysfunction in the protein cystic fibrosis transmembrane conductance regulator (CTFR), which is found on the surface of epithelial cells. The CTFR protein is a chloride channel present in the epithelium of most lumens of the body, and contributes to sodium and water balance. CF is a multi-organ system disorder that leads to significant bronchiectasis, chronic pulmonary infections, but also causes chronic sinus disease, pancreatic insufficiency, CF respiratory disease (CFRD), CF- related liver disease (CFRLD), and infertility. It can affect any part of the body with epithelial cells. In the absence of CFTR function, chloride is not secreted extracellularly, and therefore sodium is hyper-absorbed from the airway into the epithelial cells to maintain isoelectric potential. Water fol- Vol. 21, No. 4 Journal of Managed Care Medicine 23

24 Exhibit 1: Number of Adults and Children with CF ( ) 1 30,000 25,000 Adults 18 Years and Older Children Under 18 Years 51.6% Number of Patients 20,000 15,000 10, % 70.8% 48.4% 5, Year lows sodium into the cells, subsequently disrupting the water balance. This leads to dehydration of the airway surface liquid, resulting in impaired mucociliary clearance. Cilia become damaged (shortened or nonexistent), bacteria become trapped, and mucous is thickened. Chronic infection from decreased clearance of bacteria/mucus leads to permanent damage in the lungs (Exhibit 2). CF is an autosomal recessive disorder, requiring two copies of a mutation for the disease to be manifested. More than 1,600 mutations, which alter the function of CTFR, have been identified and give the CF phenotype. These mutations are divided into five different classes. The most common mutation is DF508, and 70 percent of U.S. patients have at least one copy. People with CF can have a variety of symptoms as a result of the chloride channel defect, including: very salty-tasting skin; persistent coughing, at times with phlegm; frequent lung infections including pneumonia or bronchitis; wheezing or shortness of breath; poor growth or weight gain in spite of a good appetite; frequent greasy, bulky stools or difficulty with bowel movements; and male infertility. The majority of CF patients die from respiratory complications. Traditional treatment of CF has targeted secondary effects of CFTR dysfunction in the lung and pancreas mucosal clearance, pancreatic insufficiency, infection, and inflammation by using airway clearance techniques, nutritional support with pancreatic enzymes, inhaled antibiotics, and oral antibiotics. Some airway clearance techniques require help from family members, friends, or respiratory therapists and can consume two hours of the patient s day. Many people with CF use an inflatable vest that vibrates the chest at a high frequency to help loosen and thin mucus. These traditional treatments improved outcomes and improved medial survival, but did not by themselves slow progression of the disease. Novel therapeutics that would improve the root cause of the disease throughout the body (defective CFTR function) were needed and have been developed. These newest treatments in CF are CFTR gene correctors or potentiators. Restoring CFTR function with these agents results in dramatic improvements in clinical outcomes for individuals with CF. CFTR mutations can be categorized into five different classes, which are grouped by the problems that they cause in the production of the CFTR protein. Class I are protein production mutations, Class II are protein processing mutations, Class III are gating mutations, Class IV are conduction mutations, and Class V are insufficient protein mutations. 1 F508del, a Class II mutation that results in defective processing, is the most common mutation in CF patients. Ivacaftor (Kalydeco ), a potentiator in those with a Class III defect which is approximately 4 percent of CF patients, increases the time the chloride channel remains open. Studies have shown tremendous improvements in lung function (forced expiratory volume in 1 second (FEV 1 ) (10% absolute increase), reduction in pulmonary exacerbations by 55 percent, improved symptoms, and decreased lung function decline by 50 percent. 3-6 Improvements have been shown to be sustained over three years of follow-up. Importantly, the trials with iva- 24 Journal of Managed Care Medicine Vol. 21, No. 4

25 Exhibit 2: The Cycle of CF CFTR gene defect Abnormal CFTR protein Defective ion transport Airway surface liquid depletion Defective mucociliary clearance Mucus obstruction Scarring Cycle of destruction Infection Inflammation End stage lung disease caftor proved that restoring CFTR function results in dramatic improvements in clinical outcomes for individuals with CF and provided an understanding of the clinical benefits of restoring CFTR function. Ivacaftor is now FDA indicated for CF in patients aged two years and older who have one mutation in the CFTR gene that is responsive to ivacaftor based on clinical and/or in vitro assay data. This includes 38 different mutations, which accounts for about 10 percent of the CF population. Slowing the decline in lung function is very important. By the age of 46, many patients will have such poor lung function that they will need a lung transplant. Cutting lung function decline by 50 percent with CFTR modulation over a lifetime will likely lead to a normal life span and significantly reduce, if not eliminate, the need for lung transplantation. The long-term impact of CFTR modulation will have to be monitored over time. Although clinicians may focus on improvements in FEV 1, patients care about how they feel and are able to function. Reducing the rate of exacerbations has a huge impact on patients because each exacerbation can lead to a month or more of decreased quality of life, additional health care costs from hospitalization, intravenous or inhaled antibiotics, and inability to work or go to school. The majority of genotyped patients with CF have at least one copy of F508del, a Class II mutation. Forty-seven to 50 percent of patients with CF are homozygous for F508del, and approximately 39 percent are heterozygous. The second CFTR modulator approved was lumacaftor, a corrector of F508del, and is only used in combination with ivacaftor. Lumacaftor binds to the misfolded CFTR protein so the cell does not discard it and thus it can move to the cell surface. It is combined with ivacaftor, which enhances the CFTR function once it reaches the cell surface. Lumacaftor-ivacaftor (Orkambi ) is FDA approved for CF patients aged six years and older who are homozygous for the F508del mutation in the CFTR gene. Studies of lumacaftor/ivacaftor in Vol. 21, No. 4 Journal of Managed Care Medicine 25

26 patients homozygous for F508del showed FEV 1 improvement, reduction in exacerbations by 30 to 39 percent, reduction in hospitalizations, reduced intravenous antibiotic use, and reduced rate of decline in FEV 1 by 40 percent. 7,8 Although not yet FDA approved for heterozygous F508del, the combination provided similar benefits in this patient population. 9 Lumacaftor can interact with birth control pills, antifungals, and immunosuppressants. Overall lumacaftor/ivacaftor is well tolerated. Adverse effects of concern with the combination include chest discomfort and dyspnea (especially occurs in those with low FEV 1 ) and menstrual irregularities. Tezacaftor/ivacaftor (Symdeko ) is the most recently approved combination. In patients F508del homozygous, this combination resulted in a 4 percent improvement in FEV 1, a 35 percent reduction in pulmonary exacerbations, and in adverse effects similar to placebo. 10,11 In those with F508del and residual function, tezacaftor/ivacaftor provided additional benefit compared to ivacaftor alone. 11,12 This combination is FDA approved for treatment of patients with CF aged 12 years and older who are homozygous for the F508del mutation or who have at least one mutation in the CFTR gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence. Thus, this combination is indicated for heterozygous patients. Hopefully, those who cannot tolerate lumacaftor/ivacaftor can be treated with tezacaftor/ivacaftor. Triple therapy is under investigation. Tezacaftor/ ivacaftor, along with four different next- generation modulators (VX-440, VX-152, VX-659, VX- 445, VX-371), are in Phase II or Phase III trials. It patients with heterozygous F508del, triple therapy provided a 12 percent additional absolute improvement in FEV 1 compared to tezacaftor/ivacaftor. In patients with one F508del allele, there was a 10 percent absolute improvement in FEV 1 compared to placebo, approximately a 30 mmol/l drop in sweat chloride, and improvement in quality of life. The current goal of CF therapy is to preserve lung function by maximizing current treatment regimens, while awaiting future therapies targeted at basic defects. Clinicians are trying to make CF a chronic disease with which patients live. At least 11 different agents are under study for restoring CFTR function. 13 Where CF treatment appears to be going, like HIV treatment, where depending on the underlying mutations, each patient with CF will receive an individualized treatment. CFTR dysfunction. The new era of disease-modifying therapeutics in CF is slowing the rate of lung function decline, improving quality of life, reducing medical resource utilization, and will hopefully continue to improve survival to a normal life span. CFTR modulator therapies are available for approximately 95 percent of U.S. CF patients. Elliott Dasenbrook, MD, MHS, is the Director of the Cleveland Clinic Adult Cystic Fibrosis Program and the Bronchiectasis Center in the Respiratory Institute, Cleveland, OH. References 1. Cystic Fibrosis Foundation. About CF. Available at What-is-CF/About-Cystic-Fibrosis/Accessed 7/12/ Cystic Fibrosis Foundation Patient Registry Annual Data Report, Bethesda, Maryland. 3. Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18): McKone EF, Borowitz D, Drevinek P, et al. Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST). Lancet Respir Med. 2014;2(11): Sawicki GS, McKone EF, Pasta DJ, et al. Sustained benefit from ivacaftor demonstrated by combining clinical trial and cystic fibrosis patient registry data. Am J Respir Crit Care Med. 2015;192(7): Davies JC, Wainwright CE, Canny GJ, et al. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med. 2013;187(11): Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med. 2015;373(3): Konstan MW, McKone EF, Moss RB, et al. Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study. Lancet Respir Med. 2017;5(2): Rowe SM, McColley SA, Rietschel E, et al. Lumacaftor/ivacaftor treatment of patients with cystic fibrosis heterozygous for F508del-CFTR. Ann Am Thorac Soc. 2017;14(2): Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Engl J Med. 2017;377(21): Donaldson SH1, Pilewski JM2, Griese M3, et al. Tezacaftor/ivacaftor in subjects with cystic fibrosis and F508del/F508del-CFTR or F508del/G551D- CFTR. Am J Respir Crit Care Med. 2018;197(2): Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor-ivacaftor in residualfunction heterozygotes with cystic fibrosis. N Engl J Med. 2017;377(21): Cystic Fibrosis Foundation. Drug Development Pipeline. Available at Accessed 7/12/2018 Conclusion Survival of patients with CF has improved with traditional treatments targeting the end result of 26 Journal of Managed Care Medicine Vol. 21, No. 4

27 Challenges and Strategies in an Evolving CLL Treatment Paradigm: What Does Managed Care Need to Know? Michael J. Keating, MD For a CME/CEU version of this article please go to and then click the activity title. Summary Very high rates of long-term durable response are being seen with targeted therapy in chronic lymphocytic leukemia (CLL) treatment. Targeted therapies are better tolerated than chemotherapy regimens and reduce the risk of secondary hematologic malignancies. Additional targeted therapies and combinations of targeted therapies are likely to be in common use in the very near future. Key Points The use of newer targeted agents, instead of chemotherapy/rituximab, results in improved survival with low rates of secondary hematologic malignancies. Secondary solid tumors are still an issue after CLL treatment. A cure, defined as 10-year progression-free survival, is now possible for a large segment of the CLL population. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), the most common leukemia in adults, is basically the accumulation of an abnormal clone of mature looking lymphocytes which crowd out normal cells in the bone marrow. Many, if not most, patients are diagnosed before they have symptoms because the disease is picked up on a routine CBC. Not all patients with CLL need treatment; many can be managed with just monitoring. The need for treatment is determined by the size of the lymph glands, the level of the white blood cell count, the degree of anemia and thrombocytopenia, and prognostic factors (Exhibit 1). Thirty years ago, chlorambucil and prednisone were the only two treatment choices. This combination resulted in 5 to 10 percent of patients having a complete response (CR). The next advance in therapy was the development of fludarabine, which was initially studied in acute leukemia. The standard first-line treatment for those with CLL who are 65 and younger became chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR), which results in a 72 percent CR rate. Approximately 95 percent of patients will have a CR, a partial response (PR), or a nodular PR on this regimen. With the FCR regimen, progression-free survival (PFS) is improved in those with an immunoglobulin heavy chain variable (IGHV) mutation. At a median follow-up of 12.8 years, PFS was 30.9 percent. 1 The 12.8-year PFS was 53.9 percent for patients with mutated IGHV and 8.7 percent for patients with unmutated IGHV. 1 The patients with mutated IGHV, who have not progressed, have very little, if any, residual evidence of disease (minimal residual disease, MRD) on bone marrow biopsy. Achieving MRD-negative is increasingly an endpoint of studies in CLL; the FDA choose this measure given that survival is measured in years in this disease and thus changes in survival are harder to measure in short-term studies. Flow cytometry Vol. 21, No. 4 Journal of Managed Care Medicine 27

28 Exhibit 1: Prognostic Factors in CLL Parameter B 2 Microglobulin FISH VH Mutation Status Poor Prognosis Increased 11q-, 17p- Unmutated Exhibit 2: Risk of Second Malignancies for FCR-Based versus Non-Genotoxic Regimens as Initial Therapy for CLL in Patients Over 65 years Malignancy FCR-Based (N = 120) Non-Genotoxic (N = 170) Solid tumors 13 (11%) 18 (11%) Richter s transformation 8 (7%) 2 (1%) Acute leukemia/ Myelodysplastic syndrome 10 (8%) 7 (4%) and polymerase chain reaction (PCR)-based methods can detect MRD to a sensitivity of 1:10,000. Achieving bone marrow MRD-negative CR is associated with superior PFS and overall survival (OS); MRD status is the single best post-treatment predictor of long-term outcomes after chemoimmunotherapy. Beyond IGHV mutation testing for predicting benefit from the FCR regimen, combining that testing with chromosomal loss testing (del17p, del11q) improves prediction of benefit. Patients can be grouped into risk categories low, medium, and high. Low-risk is mutated IGHV and no del11q or del17p, medium-risk is unmutated IGHV or del11q, and high-risk is del17p. 2 Low-risk patients gain the greatest benefit from chemoimmunotherapy, have very high response rates from treatment, and, out to 12 years of follow-up, have a normal life expectancy. Patients with CLL are at risk for developing secondary solid tumors and leukemic transformations, such as (Richter s syndrome). People with CLL can get any type of second cancer, but they have an increased risk of melanoma, cancer of the larynx, lung cancer, colon cancer, Kaposi sarcoma, and soft tissue sarcoma. Deaths in remission due to Richter s syndrome occurs in 5 to 10 percent of all patients with CLL, including those treated with the FCR regimen. A consequence of the chemotherapy portion of FCR is secondary hematologic malignancies, including myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). About 12 percent of those with CLL treated with chemotherapy will develop secondary non-hematologic cancers. 3 Exhibit 2 shows the risk of second malignancies for CLL in patients greater than 65 years of age. Fortyfive percent of deaths of CLL patients are associated with second malignancies, including 73 percent of deaths in first remission. Despite success with FCR, the hope from clinicians was that eventually chemotherapy would not be needed to treat CLL to prevent the long-term consequences. Another reason to replace chemotherapy as the standard treatment is that patients do not like the thought of having to endure it. Replacement of chemotherapy is now possible with targeted agents. With the development of these newer therapies, FCR and other chemotherapy regimens are not being used in very many patients. The targeted agents include ibrutinib (Imbruvica ), idelalisib (Zydelig ), obinutuzumab (Gazyva ), and venetoclax (Venclexta ). Ibrutinib forms a specific bond with cysteine Journal of Managed Care Medicine Vol. 21, No. 4

29 Exhibit 3: Five-Year Experience With Ibrutinib Monotherapy 7 Median PFS Five-year PFS Median OS Five-year OS First-Line (N = 31) Relapsed/Refractory (N = 101) PFS = progression free survival OS = overall survival NR = not yet recorded NR 92% NR 92% 52 months 43% NR 57% in Bruton s tyrosine kinase (BTK). In CLL cells, ibrutinib promotes apoptosis and inhibits CLL-cell migration and adhesion. 4 There are no cytotoxic effect on T cells or natural killer (NK)-cells, so it does not cause the same immunosuppression as chemotherapy. It is orally administered with once-daily dosing, resulting in 24-hour target inhibition. As monotherapy, it improves OS as first-line therapy and in those with relapsed/refractory disease. 5,6 The five-year OS rate with first-line therapy is 92 percent and 57 percent in the relapsed/refractory setting (Exhibit 3). 7 It appears to work equally well in those with and without the IGHV mutation. Adverse effects include body aches and pains, bruising, and atrial fibrillation (5 10%) Lowered dosing than the current FDA approved dose has been investigated for reducing adverse effects in a non-randomized trial and may be cost saving. A randomized trial is needed before official changes to the recommended dosing are made. At this time, this therapy is continued until relapse occurs, and it costs approximately $140,000 annually. Idelalisib, an oral blocker of the delta isoform of phosphoinositide 3-kinase inhibitor (PI3K-Delta), is a second-line drug for patients with relapsed CLL. Idelalisib is effective in patients who have a p53 mutation, which is a marker of poor prognosis. Obinutuzumab is an injectable, humanized anti- CD20 monoclonal antibody that is an alternative to rituximab. It is used in combination with chlorambucil as a first-line treatment for CLL. Compared with the rituximab/chlorambucil combination, obinutuzumab/chlorambucil improves PFS, but not OS. 8 Venetoclax is an oral inhibitor of B-cell lymphoma two (BCL2), which functions to keep B cells alive for long periods of time. BCL2 is dramatically elevated in most CLL patients. In the del17p CLL population, which is high-risk and difficult to treat, this agent produces a 79 percent response rate. 9 Because of the possibility of tumor lysis syndrome (hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and acute kidney injury), the dose is gradually escalated over the course of four weeks. Venetoclax is effective in ibrutinib and idelalisib refractory or intolerant patients. In a retrospective analysis, adverse effects included neutropenia (47.4%), thrombocytopenia (36%), tumor lysis syndrome (13.4%), neutropenic fever (11.6%), and diarrhea (7.3%). 10 The optimal duration of therapy is not well defined; stopping venetoclax after a patient has been disease free for six months has been studied, with only two of the 20 patients studied having recurrent disease. As are the other targeted agents, venetoclax is expensive, costing $180,000 annually. Combinations of targeted agents to achieve even higher MRD-negative rates are the next wave of CLL treatment. The combination of fludarabine, cyclophosphamide, obinutuzumab, and ibrutinib is being studied in IVHG-mutated CLL and is producing very high MRD-negative rates (80% at 3 months), compared with FCR (26%). Ibrutinib and venetoclax are also being studied in combination. Traditionally, CLL has been considered incurable in the majority of patients. Given the advances in treatment, a large percentage of patients are achieving very durable responses and clinicians are now debating how best to define cure in CLL. Some propose 10-year PFS as a useful endpoint. Conclusion Opportunities to modify survival of CLL are numerous; however, clinicians also need to minimize the risks of therapy. The newer targeted agents are replacing chemotherapy because they improve OS with low rates of secondary hematologic malignancies. Secondary solid tumors are still an issue with CLL treatment. A cure, defined as 10-year PFS, is possible now for a large segment of the CLL population. Hopefully, 95 percent of patients will be curable in the next five years. Vol. 21, No. 4 Journal of Managed Care Medicine 29

30 Michael J. Keating, MB, MS, is Clinical Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX. References 1. Thompson PA, Tam CS, O Brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHVmutated chronic lymphocytic leukemia. Blood ;127(3): Rossi D, Terzi-di-Bergamo L, De Paoli L, et al. Molecular prediction of durable remission after first-line fludarabine-cyclophosphamide-rituximab in chronic lymphocytic leukemia. Blood. 2015;126(16): Benjamini O, Jain P, Trinh L, et al. Second cancers in patients with chronic lymphocytic leukemia who received frontline FCR therapy Distribution and clinical outcomes Leuk Lymphoma. 2015;56(6): Vela CM, McBride A, Jaglowski SM, Andritsos LA. Ibrutinib for treatment of chronic lymphocytic leukemia. Am J Health Syst Pharm. 2016;73(6): Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as Initial Therapy for Patients LOSS healthcare Body INVASIVE CT GENETIC with Chronic Lymphocytic Leukemia. N Engl J Med. 2015;373(25): Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1): O Brien SM, Furman RR, Coutre SE, et al. Five-year experience with single-agent ibrutinib in patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia. Blood. 2016;128: Evans SS, Clemmons AB Obinutuzumab: A Novel Anti-CD20 Monoclonal Antibody for Chronic Lymphocytic Leukemia. J Adv Pract Oncol. 2015;6(4): Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17(6): Mato AR, Thompson M, Allan JN, et al. Real world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States. Haematologica. 2018; pii: haematol Byrd JC, Harrington B, O Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4): RESEARCH oncology PALLIATIVE QUALITY DIAGNOSIS Lung Lump resuscitate DNA Lab treatm culture histology scan council prognosis disease Radiotherapy practitioner MRI test Join progression the NAMCP Oncology Council & our quest to provide cancer informative resources for Medical Directors from Purchasers, Health Plans and Provider Systems. We compile the data, you learn the trends. MALIGNANCY Journal of Managed Care Medicine Vol. 21, No. 4

31 NOW APPROVED ONPATTRO is the first and only FDA-approved RNAi treatment for the polyneuropathy of hereditary transthyretin-mediated (hattr) amyloidosis in adults. 1 For the latest news and updates, sign up at Indication ONPATTRO (patisiran) is indicated for the treatment of the polyneuropathy of hereditary transthyretinmediated amyloidosis in adults. Important Safety Information Infusion-Related Reactions Infusion-related reactions (IRRs) have been observed in patients treated with ONPATTRO. In a controlled clinical study, 19% of ONPATTRO-treated patients experienced IRRs, compared to 9% of placebo-treated patients. The most common symptoms of IRRs with ONPATTRO were flushing, back pain, nausea, abdominal pain, dyspnea, and headache. To reduce the risk of IRRs, patients should receive premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) at least 60 minutes prior to ONPATTRO infusion. Monitor patients during the infusion for signs and symptoms of IRRs. If an IRR occurs, consider slowing or interrupting the infusion and instituting medical management as clinically indicated. If the infusion is interrupted, consider resuming at a slower infusion rate only if symptoms have resolved. In the case of a serious or life-threatening IRR, the infusion should be discontinued and not resumed. Reduced Serum Vitamin A Levels and Recommended Supplementation ONPATTRO treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance (RDA) of vitamin A is advised for patients taking ONPATTRO. Higher doses than the RDA should not be given to try to achieve normal serum vitamin A levels during treatment with ONPATTRO, as serum levels do not reflect the total vitamin A in the body. Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g. night blindness). Adverse Reactions The most common adverse reactions that occurred in patients treated with ONPATTRO were upper respiratory tract infections (29%) and infusion-related reactions (19%). Please see Brief Summary of Full Prescribing Information on the adjacent page. Reference: 1. ONPATTRO [package insert]. Cambridge, MA: Alnylam Pharmaceuticals, Inc; ONPATTRO is a trademark of Alnylam Pharmaceuticals, Inc Alnylam Pharmaceuticals, Inc. All rights reserved. TTR02-USA

32 Brief summary of Full Prescribing Information for ONPATTRO (patisiran) injection Please consult Full Prescribing Information. INDICATIONS AND USAGE ONPATTRO is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. DOSAGE AND ADMINISTRATION General Dosing Information ONPATTRO should be administered by a healthcare professional. ONPATTRO is administered via intravenous (IV) infusion. Dosing is based on actual body weight. For patients weighing less than 100 kg, the recommended dosage is 0.3 mg/kg once every 3 weeks. For patients weighing 100 kg or more, the recommended dosage is 30 mg once every 3 weeks. Missed Dose If a dose is missed, administer ONPATTRO as soon as possible. If ONPATTRO is administered within 3 days of the missed dose, continue dosing according to the patient s original schedule. If ONPATTRO is administered more than 3 days after the missed dose, continue dosing every 3 weeks thereafter. Required Premedication All patients should receive premedication prior to ONPATTRO administration to reduce the risk of infusion-related reactions (IRRs) [see Warnings and Precautions (5.1)]. Each of the following premedications should be given on the day of ONPATTRO infusion at least 60 minutes prior to the start of infusion: intravenous corticosteroid (e.g., dexamethasone 10 mg, or equivalent); oral acetaminophen (500 mg); intravenous H1 blocker (e.g., diphenhydramine 50 mg, or equivalent); and intravenous H2 blocker (e.g., ranitidine 50 mg, or equivalent). For premedications not available or not tolerated intravenously, equivalents may be administered orally. For patients who are tolerating their ONPATTRO infusions but experiencing adverse reactions related to the corticosteroid premedication, the corticosteroid may be reduced by 2.5 mg increments to a minimum dose of 5 mg of dexamethasone (intravenous), or equivalent. Some patients may require additional or higher doses of one or more of the premedications to reduce the risk of IRRs [see Warnings and Precautions (5.1)]. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Infusion-Related Reactions Infusion-related reactions (IRRs) have been observed in patients treated with ONPATTRO. In clinical studies, all patients received premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) to reduce the risk of IRRs. In a controlled clinical study, 19% of ONPATTRO-treated patients experienced IRRs, compared to 9% of placebo-treated patients. Among ONPATTRO-treated patients who experienced an IRR, 79% experienced the first IRR within the first 2 infusions. The frequency of IRRs decreased over time. IRRs led to infusion interruption in 5% of patients. IRRs resulted in permanent discontinuation of ONPATTRO in less than 1% of patients in clinical studies. Across clinical studies, the most common symptoms (reported in greater than 2% of patients) of IRRs with ONPATTRO were flushing, back pain, nausea, abdominal pain, dyspnea, and headache [see Adverse Reactions (6.1)]. One patient in the ONPATTRO expanded access program had a severe adverse reaction of hypotension and syncope during an ONPATTRO infusion. Patients should receive premedications on the day of ONPATTRO infusion, at least 60 minutes prior to the start of infusion [see Dosage and Administration (2.2)]. Monitor patients during the infusion for signs and symptoms of IRRs. If an IRR occurs, consider slowing or interrupting the ONPATTRO infusion and instituting medical management (e.g., corticosteroids or other symptomatic treatment) as clinically indicated. If the infusion is interrupted, consider resuming at a slower infusion rate only if symptoms have resolved. In the case of a serious or life-threatening IRR, the infusion should be discontinued and not resumed. Some patients who experience IRRs may benefit from a slower infusion rate or additional or higher doses of one or more of the premedications with subsequent infusions to reduce the risk of IRRs. [see Dosage and Administration (2.2)]. Reduced Serum Vitamin A Levels and Recommended Supplementation ONPATTRO treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance of vitamin A is advised for patients taking ONPATTRO. Higher doses than the recommended daily allowance of vitamin A should not be given to try to achieve normal serum vitamin A levels during treatment with ONPATTRO, as serum vitamin A levels do not reflect the total vitamin A in the body. Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness). ADVERSE REACTIONS Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of ONPATTRO cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. A total of 224 patients with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hattr amyloidosis) received ONPATTRO in the placebo-controlled and open-label clinical studies, including 186 patients exposed for at least 1 year, 137 patients exposed for at least 2 years, and 52 patients exposed for at least 3 years. In the placebo-controlled study, 148 patients received ONPATTRO for up to 18 months (mean exposure 17.7 months). Upper respiratory tract infections and infusion-related reactions were the most common adverse reactions. One patient (0.7%) discontinued ONPATTRO because of an infusion-related reaction. Table 1: Adverse Reactions from the Placebo-Controlled Trial that Occurred in at Least 5% of ONPATTRO-treated Patients and at Least 3% More Frequently than in Placebo-treated Patients Adverse Reaction ONPATTRO N=148 % Placebo N=77 % Upper respiratory tract infections a Infusion-related reaction b 19 9 Dyspepsia 8 4 Dyspnea c,d 8 0 Muscle spasms c 8 1 Arthralgia c 7 0 Erythema c 7 3 Bronchitis e 7 3 Vertigo 5 1 a Includes nasopharyngitis, upper respiratory tract infection, respiratory tract infection, pharyngitis, rhinitis, sinusitis, viral upper respiratory tract infection, upper respiratory tract congestion. b Infusion-related reaction symptoms include, but are not limited to: arthralgia or pain (including back, neck, or musculoskeletal pain), flushing (including erythema of face or skin warm), nausea, abdominal pain, dyspnea or cough, chest discomfort or chest pain, headache, rash, chills, dizziness, fatigue, increased heart rate or palpitations, hypotension, hypertension, facial edema. c Not part of an infusion-related reaction. d Includes dyspnea and exertional dyspnea. e Includes bronchitis, bronchiolitis, bronchitis viral, lower respiratory tract infection, lung infection. Four serious adverse reactions of atrioventricular (AV) heart block (2.7%) occurred in ONPATTRO-treated patients, including 3 cases of complete AV block. No serious adverse reactions of AV block were reported in placebo-treated patients. Ocular adverse reactions that occurred in 5% or less of ONPATTROtreated patients in the controlled clinical trial, but in at least 2% of ONPATTRO-treated patients, and more frequently than on placebo, include dry eye (5% vs. 3%), blurred vision (3% vs. 1%), and vitreous floaters (2% vs. 1%). Extravasation was observed in less than 0.5% of infusions in clinical studies, including cases that were reported as serious. Signs and symptoms included phlebitis or thrombophlebitis, infusion or injection site swelling, dermatitis (subcutaneous inflammation), cellulitis, erythema or injection site redness, burning sensation, or injection site pain. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary There are no available data on ONPATTRO use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. ONPATTRO treatment leads to a decrease in serum vitamin A levels, and vitamin A supplementation is advised for patients taking ONPATTRO. Vitamin A is essential for normal embryofetal development; however, excessive levels of vitamin A are associated with adverse developmental effects. The effects on the fetus of a reduction in maternal serum TTR caused by ONPATTRO and of vitamin A supplementation are unknown [see Clinical Pharmacology (12.2), Warnings and Precautions (5.2)]. In animal studies, intravenous administration of patisiran lipid complex (patisiran-lc) to pregnant rabbits resulted in developmental toxicity (embryofetal mortality and reduced fetal body weight) at doses that were also associated with maternal toxicity. No adverse developmental effects were observed when patisiran-lc or a rodentspecific (pharmacologically active) surrogate were administered to pregnant rats (see Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Intravenous administration of patisiran-lc (0, 0.15, 0.50, or 1.5 mg/ kg) or a rodent-specific (pharmacologically active) surrogate (1.5 mg/kg) to female rats every week for two weeks prior to mating and continuing throughout organogenesis resulted in no adverse effects on fertility or embryofetal development. Intravenous administration of patisiran-lc (0, 0.1, 0.3, or 0.6 mg/kg) to pregnant rabbits every week during the period of organogenesis produced no adverse effects on embryofetal development. In a separate study, patisiran-lc (0, 0.3, 1, or 2 mg/kg), administered to pregnant rabbits every week during the period of organogenesis, resulted in embryofetal mortality and reduced fetal body weight at the mid and high doses, which were associated with maternal toxicity. Intravenous administration of patisiran-lc (0, 0.15, 0.50, or 1.5 mg/ kg) or a rodent-specific surrogate (1.5 mg/kg) to pregnant rats every week throughout pregnancy and lactation resulted in no adverse developmental effects on the offspring. Lactation Risk Summary There is no information regarding the presence of ONPATTRO in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother s clinical need for ONPATTRO and any potential adverse effects on the breastfed infant from ONPATTRO or from the underlying maternal condition. In lactating rats, patisiran was not detected in milk; however, the lipid components (DLin-MC3-DMA and PEG 2000-C-DMG) were present in milk. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use No dose adjustment is required in patients 65 years old [see Clinical Pharmacology (12.3)]. A total of 62 patients 65 years of age, including 9 patients 75 years of age, received ONPATTRO in the placebocontrolled study. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Hepatic Impairment No dose adjustment is necessary in patients with mild hepatic impairment (bilirubin 1 x ULN and AST >1 x ULN, or bilirubin >1.0 to 1.5 x ULN) [see Clinical Pharmacology (12.3)]. ONPATTRO has not been studied in patients with moderate or severe hepatic impairment. Renal Impairment No dose adjustment is necessary in patients with mild or moderate renal impairment (estimated glomerular filtration rate [egfr] 30 to <90 ml/min/1.73m 2 ) [see Clinical Pharmacology (12.3)]. ONPATTRO has not been studied in patients with severe renal impairment or end-stage renal disease. Manufactured for: Alnylam Pharmaceuticals, Inc. 300 Third Street, Cambridge, MA By: Ajinomoto Althea, Inc Roselle Street, San Diego, CA ONPATTRO is a trademark of Alnylam Pharmaceuticals, Inc Alnylam Pharmaceuticals, Inc. All rights reserved.

33 Novel Insights on the Current and Emerging Treatment Strategies of CRPC Channing J. Paller, MD For a CME/CEU version of this article please go to and then click the activity title. Summary Although many patients with prostate cancer will be successfully treated initially, about one- third will develop castration-resistant disease (CRPC). These patients have many different treatment options, including chemotherapy, androgen-targeting agents, and immunotherapy. Each of the FDA approved therapies for CRPC have been shown to provide survival benefits. Key Points Docetaxel is the first-line chemotherapy agent for symptomatic metastatic CRPC. Cabazitaxel is second-line chemotherapy and provides a survival benefit in docetaxel-pretreated patients. Sipuleucel-T is a first-line treatment in patients with asymptomatic or minimally symptomatic metastatic CRPC. Abiraterone and enzalutamide are FDA approved for all patients with metastatic CRPC and provide survival benefit in post- and pre-docetaxel patients. Apalutamide is the newest approved agent and is indicated for the treatment of patients with nonmetastatic CRPC. Radium-223 is currently approved for metastatic CRPC with symptomatic bone metastases (pre- or post-docetaxel). PROSTATE CANCER IS THE MOST COMMON malignancy in men in the United States (U.S.), and the second leading cause of mortality, next to lung cancer. 1 Prostate cancer can go through many different clinical stages (Exhibit 1). Many cases of prostate cancer are discovered when still localized and are cured, but about a third progress and become metastatic. Castration-resistant prostate cancer (CRPC) is defined as prostate-specific antigen (PSA) or radiologic progression despite androgen deprivation therapy (ADT) with a serum testosterone less than 50 mg/dl, or progression despite addition of antiandrogen therapy, or progression after anti-androgen withdrawal. CRPC can be metastatic (M1) or not (M0). Despite low serum testosterone levels, CRPC remains androgen-driven. There is persistent adrenal and intratumoral testosterone production and overexpression/amplification of androgen receptors (AR) in the tumor. Numerous therapies are now FDA approved for CRPC (Exhibit 2). Each of the therapies provides a survival benefit. Abiraterone (Zytiga ) is an androgen synthesis inhibitor, which irreversibly blocks cytochrome P (CYP17). Because of CYP17 inhibition, there is an upregulation of adrenocorticotropic hormone (ACTH) which can lead to hypertension, hypokalemia, and fluid overload. This agent is given with prednisone 5 mg daily to prevent these adverse effects. This agent provides a survival benefit in both the pre-chemotherapy and post-chemotherapy CRPC setting. 2-3 Enzalutamide (Xtandi ) is a second-generation AR antagonist that binds AR more potently than bicalutamide (Casodex ) and does not function as a partial agonist of AR. It inhibits translocation of the AR and decreases AR binding to DNA. In the postdoxetaxel setting, it reduced the risk of death by 37 Vol. 21, No. 4 Journal of Managed Care Medicine 33

34 Exhibit 1: Prostate Cancer Clinical States Death from Other Causes Clinically Localized Disease Rising PSA Clinical Metastases: Noncastrate Rising PSA: Castrate Clinical Metastases: Noncastrate 1 st Line Clinical Metastases: Noncastrate 2 nd Line Death due to Disease Exhibit 2: Approved Therapies for CRPC Hormonal Terapies Abiraterone Enzalutamide Apalutamide Immunotherapy Sipuleucel-T Targeted Radiation Radium-223 Chemotherapy Docetaxel Cabazitaxel percent. 4 In the pre-doxetaxel setting, it reduced the risk of death by 29 percent. 5 Apalutamide (Erleada ) is the newest approved agent for CRPC and is indicated for the treatment of patients with nonmetastatic CRPC. Approval was based on a multicenter, double-blind, clinical trial randomizing 1,207 patients with nonmetastatic CRPC, to receive either apalutamide, 240 mg orally once daily in combination with ADT (medical castration or surgical castration), or placebo once daily with ADT. The estimated median metastasis-free survival (MFS) was 40.5 months for patients receiving apalutamide and 16.2 months for those receiving placebo (hazard ratio 0.28; 95% CI: 0.23, 0.35; p < ). 6 Sipuleucel-T (Provenge ) is an immunotherapy. With this treatment, a patient s antigen-presenting cells (APCs) are extracted in a leukapheresis procedure. The APCs are incubated with a fusion protein (PA2024) consisting of two parts, the antigen prostatic acid phosphatase (PAP), which is present in 95 percent of prostate cancer cells, and granulocytemacrophage colony stimulating factor that helps the APCs to mature. When reinfused back into a patient, the mature APCs present PAP peptide to T cells, which begins a lytic anti-tumor response. It is given in two-week cycles for three cycles and costs approximately $90,000. There is no effect on PSA or progression-free survival (PFS), but median overall survival (OS) is improved by 4.1 months. 7 It appears to work best in those whose PSA is less than 22 mg/dl and have low volume disease. Biomarkers for response have not yet been identified. The most common adverse effects are chills (54%), fever (29%), headache (16%), flu-like illness (10%), and sweating (5%) for a few days after infusion. It is FDA approved for metastatic CRPC patients who are asymptomatic or minimally symptomatic and can be performed before or after chemotherapy. Radium-223 (Xofigo ) is an alpha (a)-emitter with an 11-day half-life. It is administered intravenously every four weeks for six doses. It is a calcium mimetic that targets new bone growth at bone metastatic sites. It produces less myelotoxicity than earlier agents (β emitters) and provides a survival benefit. 8 The best survival benefit is seen in men with two or more bone metastases and bone pain. The main adverse effects are diarrhea (25%), 34 Journal of Managed Care Medicine Vol. 21, No. 4

35 Exhibit 3: Decision Schema Using AR-V7 Status 12 Cabazitaxel Docetaxel Recurrence AR-V7+ AR-V7 Recurrence with symptoms GnRH agonist or antagonist +/ AR-V7+ bicalutamide Breakthrough standard ADT AR-V7 Abiraterone or ezalutamide Docetaxel Abiraterone or ezalutamide Recurrence AR-V7+ AR-V7 Switch AR inhibitors nausea (36%), vomiting (19%), neutropenia (18%), and thrombocytopenia (31%). The rates of serious neutropenia and thrombocytopenia are only 2 percent and 3 percent, respectively. This agent should be avoided when patients have visceral metastases or bulky (> 3cm) lymph nodes and in patients with myelosuppression. Docetaxel chemotherapy, given every three weeks, is the current first-line standard for symptomatic metastatic CRPC. It causes the classic adverse effects of chemotherapy, including myelosuppression, and can cause neuropathy. Cabazitaxel (Jevtana ), a novel semi-synthetic taxane, is secondline chemotherapy in metastatic CRPC. It is active in taxane-resistant cells and improves OS by about three months, compared to mitoxantrone (older chemotherapy no longer commonly used). 9 It provides a survival benefit in the post-docetaxel setting. The National Comprehensive Cancer Network (NCCN) guidelines provide guidance on choosing therapy in nonmetastatic and metastatic CRPC. 10 Various mechanisms by which prostate cancer becomes resistant to blocking the AR or reduced production of testosterone have been investigated. One of these mechanisms is variation in the AR that prevent drug binding. Androgen receptor variant-7 (AR-V7) is a truncated form of the AR that lacks the ligand-binding domain (LBD), the target of abiraterone and enzalutamide, but remains constitutively active as a transcription factor. 11 Agents are being investigated that target the AR- V7 variant. Galeterone is an investigational 17, 20-lyase inhibitor and AR inhibitor. Galeterone essentially combines the mechanisms of abiraterone and enzalutamide and additionally increases the degradation of the AR. It inhibits the AR-V7 variant to overcome resistance to ADT. Biomarkers, such as the presence of AR-V7, are not yet frequently used in prostate cancer treatment; however, they will likely be incorporated into the treatment guidelines in the very near future. Exhibit 3 shows a yet to be validated example using AR-V7 status to select the most appropriate therapy. 12 Various other therapies are under investigation for CRPC. Other novel androgen receptor/cyp17 targeting agents include TAK-700, and ODM-201. Olaparib (poly (ADP-ribose) polymerase (PARP) inhibitor), lutetium-177 (targeted radiation), and immunotherapy with ipilimumab and nivolumab are all also being investigated. PARP inhibitors are already approved for treating breast cancer and are under investigation for CRPC. Patients with DNA repair genes (i.e., BRCA1/2, ATM, Fanconi anemia genes, and Check2) have the highest response (88%) to PARP inhibition, compared with the overall studied population (33%). 13 Approximately 12 to 20 percent of the general population have these mutations. Additionally, patients with CRPC and DNA repair gene mutations also appear to respond best to immunotherapy (ipilimumab combined with nivolumab). Vol. 21, No. 4 Journal of Managed Care Medicine 35

36 The major challenge to optimal management of CRPC is the cost of therapy. Patients who lack insurance coverage for the more expensive therapies end up receiving chemotherapy or ketoconazole, which may not provide the optimal outcomes or survival benefit. Conclusion There are now numerous therapies for CRPC which provide a survival benefit. The biggest challenges to optimal patient management are the cost of the therapies and adverse effects. Most adverse effects can be managed with dose reductions or by changing agents. Channing J. Paller, MD, is a Medical Oncologist at the Prostate Cancer Multidisciplinary Clinic at Sibley Memorial Hospital in Washington, D.C. and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, MD. She is also an Assistant Professor of Oncology at the Johns Hopkins University School of Medicine, Baltimore, MD. References 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, CA Cancer J Clin. 2018;68(1): de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21): Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2): Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13): Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371(5): FDA approves apalutamide for non-metastatic castration-resistant prostate cancer. Available at Accessed 7/25/ Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5): Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3): de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376(9747): National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer. Version Available at www. nccn.org. 11. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371(11): Sprenger C, Uo T, Plymate S. Androgen receptor splice variant V7 (AR-V7) in circulating tumor cells: a coming of age for AR splice variants? Ann Oncol. 2015;26(9): Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18): CALLING ALL EXHIBITORS EXHIBITOR PERKS: All breakfasts, lunches, breaks & a Welcome Reception are held in the exhibit hall for networking time with our Medical Director and Nurse Care Manager attendees! Spring Managed Care Forum 2019 April 25-26, 2019, Rosen Shingle Creek, Orlando, Florida 36 Journal of Managed Care Medicine Vol. 21, No. 4

37 IT IS SAID THAT INNOVATION IS OUR NATION S GREATEST NATURAL RESOURCE. OUR THOUGHTS EXACTLY. The first FDA-approved, noninvasive sdna colon cancer screening test. Developed right here in the USA. Cologuard is intended for individuals who are 50 years or older and at average risk for colorectal cancer. Cologuard is not right for everyone. Talk to your doctor to see if Cologuard is right for you.

38 Clinical Insights into the Diagnosis and Treatment of Epilepsy R. Edward Faught, MD For a CME/CEU version of this article please go to and then click the activity title. Summary There are numerous options for managing seizures in patients with epilepsy. Depending on the ease of controlling an individual s seizures, they may need to be cared for by an epilepsy specialist or comprehensive epilepsy center. Key Points Epilepsy is the second most common neurological problem. There are four levels of care for patients with epilepsy. Antiepileptic medications, surgery, and neurostimulation are the major treatment options for epilepsy. Managed care formularies should include a wide range of antiepileptic medications. EPILEPSY IS A SYMPTOM OF DAMAGE TO the brain and is defined as two or more unprovoked seizures, or one unprovoked seizure with at least a 70 percent chance of recurrence. If the patient has an identified ongoing underlying cause for seizures, such as a brain tumor, they have a high likelihood of recurrence. The epilepsy definition excludes seizures due to acute provoking factors, such as drug withdrawal, acute trauma, and correctable metabolic causes. Epilepsy is the second most common neurological problem, after headache. The incidence of epilepsy is approximately 50 in 100,000 people per year. The incidence is 43 in developed countries and 80-plus in developing countries. About one in 2,000 people will receive a new diagnosis of epilepsy each year (500 per million). The prevalence is 0.5 or 1 percent of the population. Higher risk populations for developing epilepsy include Medicaid recipients, African Americans, and those residing in developing countries. Medicaid recipients have threefold incidence rates, compared with other insured popluations. 1 All of these reasons are associated with socioeconomic factors, but how that translates into the etiology of epilepsy is unknown. Etiology of seizures vary by populations. About 50 percent of the time the cause is unknown, 10 percent are genetic, 10 percent are due to birth defects, and 5 percent are due to damage to the brain (head trauma, infections, and stroke). The burden of epilepsy is significant. Both the direct and indirect costs are high, with cognitive impairment and depression as common comorbidities. Seizure-related injuries and death also occur. Sudden Unexpected Death in Epilepsy (SUDEP) accounts for 30 percent of deaths in epilepsy. Psychosocial problems with family, driving, employment, and stigma have a major impact on a patient s quality of life. Even an occasional seizure can be devastating socially and psychologically. There are two major categories of seizures. Focal (partial) seizures start in one part of the brain from a focal lesion. There are focal aware (simple partial) and focal with change in awareness (complex partial). These are most common in adults and can 38 Journal of Managed Care Medicine Vol. 21, No. 4

39 Exhibit 1: Anti-Epileptic Agents Mechanism of Action Agents Main Adverse Effect Sodium channel blockers GABAergic agents phenytoin, carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, lacosamide, rufinamide phenobarbital, benzodiazepines, vigabatrin Dizziness Sedation Calcium channel agent ethosuximide GI upset Synaptic release inhibitors gabapentin, pregabalin Sedation Synaptic protein binders levetiracetam, brivaracetam Irritable mood AMPA type glutamate blocker perampanel Irritable mood Multiple mechanisms valproate, topiramate, zonisamide, felbamate Variable spread to become a tonic-clonic seizure. Generalized seizures are the other type and start bilaterally in the brain. Absence (staring spell, petit mal) and tonic-clonic (convulsion, grand mal) are the two generalized seizure types. Generalized seizures are most common in children and usually have a genetic cause. The type of seizure makes a difference in therapy selection. There are four levels of care for patients with epilepsy. The initial diagnosis, which may occur in an Emergency Department or in a primary care office, is Level 1 care. Patients may or may not be started on antiepileptic drugs (AEDs) at this point. Level 2 care is with a neurologist, Level 3 care is with an epileptologist (a neurologist with one to two additional years as a fellow in the area of epilepsy or clinical neurophysiology), and Level 4 is care within a comprehensive epilepsy center. Specific indications for level 2 to 4 care are discussed later. AEDs are used in most patients with epilepsy and 75 percent can achieve seizure control with good adherence. Thirty percent do not get good control with medication. Approximately 10 percent of patients are candidates for brain surgery, which provides a seizure cure between 40 and 80 percent of cases. Electrical neuromodulation is an option for about 10 percent of patients; this treatment is palliative at this point and does not cure seizures. Many parents inquire about ketogenic diets; these are appropriate for around 1perecnt of patients most of which are children. The first step in the initial diagnosis is to determine if the episode or episodes that someone has had was actually a seizure. Many other things can look like a seizure, including fainting, a transient ischemic attack, or an anxiety attack. A good history and eyewitness description are helpful in making a diagnosis. A general and neurologic examination, blood tests (CBC and chemistry screen, urine for drugs of abuse), and CT scan or MRI are helpful in determining the cause. Once a diagnosis of unprovoked seizure is made, a decision to treat or not to treat is made. Treatment of a first seizure is based on the likelihood of recurrence. Those with focal seizure, abnormal physical exam, abnormal epileptiform electroencephalogram (EEG), or structural lesion on MRI are at higher likelihood of recurrence. Early pharmaceutical treatments for seizures were purgatives, emetics, blistering, cod liver oil, valerian, opiates, ergotamine, nitroglycerin, and strychnine. Physical treatments included skull trephining or cauterization, bleeding, and carotid ligation. The first effective treatments were bromides in 1857, phenobarbital in 1910, and phenytoin in Carbamazepine and valproate were developed in the 1970s. The 1990s brought an explosion of agents, includ- Vol. 21, No. 4 Journal of Managed Care Medicine 39

40 ing felbamate, topiramate, lamotrigine, levetiracetam, gabapentin, tiagabine, vigabatrin, zonisamide, and oxcarbazepine. The explosion continued in the 2000s with pregabalin, perampanel, brivaracetam, eslicarbazepine, and clobazam. Exhibit 1 lists the available AEDs by mechanism of action. Nearly all FDA approved drugs are equally effective at controlling seizures in populations of patients. The choice depends on the acuity of the situation, type of seizure, age, gender (some are teratogenic), comorbidities, adverse effects, ease of use, and cost. Sixty percent of patients will be seizure free with the first drug tried; 75 percent will be seizure free eventually, with various drug trials. About 25 percent have seizures that are refractory to medications. Popular first drugs for epilepsy are levetiracetam, carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, topiramate, and valproate. Levetiracetam is most commonly chosen first, but not if depression or irritability are already present. Carbamazepine, oxcarbazepine, or eslicarbazepine are commonly used for focal or generalized tonic-clonic seizures. Lamotrigine is a popular agent for women during child bearing years because it does not appear to cause birth defects. Topiramate is an option if migraine headaches are also a problem. Valproate is still the drug of choice for generalized epilepsies, except in woman of childbearing age. Choosing which AEDs to have on a managed care formulary can be difficult. Step therapy restrictions are not appropriate for epilepsy medications because there is no one first agent that will work for all types of seizures and patients. Individual response to a given drug varies widely and is unpredictable. Clinicians do not really know why certain AEDs work in some patients, but not in others. Formularies should contain commonly used drugs (listed previously) and probably at least one drug from each category of mechanism of action. Drugs with the same mechanism of action are not necessarily interchangeable because nearly all AEDs have more than one mechanism of action, often unknown. Phenytoin, phenobarbital, and carbamazepine are mostly obsolete drugs because of side effects, but they are inexpensive and still taken by many people, so these should be on formularies. Niche, but essential, drugs for a formulary include ethosuximide (for absence seizures in children) and adrenocorticotropic hormone (ACTH, for infantile spasms). Unique mechanism of action agents include perampanel and clobazam so these should also be available with minimal restrictions. Useful drugs, but secondary at present, are brivaracetam, pregabalin, and eslicarbazepine. Perampanel, clobazam, brivaracetam, pregabalin, and eslicarbazepine are usually better tolerated than older agents but are also more expensive. Rarely used but sometimes essential agents are felbamate, vigabatrin, and rufinamide. As medications go, AEDs are relatively safe. Frequent lab monitoring is not needed except for obsolete drugs which are hard to adjust and require serum level monitoring. Common side effects are sleepiness and dizziness. The AED side effects are additive, so using only one drug is best if seizures are controlled. Refractory epilepsy is when two different appropriate AEDs at appropriate doses do not control seizures. These patients should be referred to an epileptologist or epilepsy center and considered for surgery, if the type of epilepsy is amenable. EEG combined with video monitoring is the gold standard for diagnosis of epilepsy and is useful particularly if a patient is not responding appropriately to AEDs or has refractory epilepsy. Sixty-five percent of seizures captured on EEG/video monitoring can be placed into a seizure category (generalized or focal) and if focal, lobe or side of onset can be identified. Twenty-five percent of cases will be a nonepileptic event and most of these are psychogenic nonepileptic seizures (PNES). PNES are a physical manifestation of a psychological disturbance and are a type of somatoform conversion disorder. In 10 percent of cases, a diagnosis cannot be made with EEG/video monitoring because no events are captured or the EEG is normal. Inpatient is the preferred setting over home-based studies because medication doses can be safely reduced to allow seizures to occur, continuous video monitoring is available, and nursing staff are immediately available. Outpatient (ambulatory) monitoring is sometimes helpful, but often a waste of time and money because the EEG recording will be full of artifacts, no video monitoring can be done, medications cannot safely be reduced, and patients and families cannot be counseled if psychogenic events are recorded. The average inpatient length of stay or inpatient EEG/video monitoring is 3.5 days, which allows for a safe, gradual reduction in medication, recording a typical event, and if for seizure localization for surgery, usually need four or more seizures to be sure. Managed care approval for only 24 to 48 hours of inpatient monitoring is not helpful. PNES can be a very expensive condition when misdiagnosed as epilepsy. It can take years of suffering and exposure to AEDs side effects before a diagnosis is made because diagnosis requires inpatient EEG/video monitoring at Level 3 or 4 care. Once diagnosed, treatment with cognitive behavioral therapy is often effective and medical costs plummet. 40 Journal of Managed Care Medicine Vol. 21, No. 4

41 There has been much in the news about medical marijuana and its derivatives and seizure disorders. Some components of the marijuana plant may have antiepileptic action but anecdotal experience is mixed. The most promising derivative may be cannabidiol (CBD), which is less psychoactive than tetrahydrocannabinol (THC) and is currently in clinical trials with encouraging early results for some severe childhood epilepsies. The FDA approved CBD oral solution (Epidiolex ) in June 2018 for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, in patients two years of age and older. The legal issues related to prescribing this product in various states has yet to be resolved. Most persons with new-onset epilepsy should have a neurological consultation within three months of the seizure onset. 2 If complete seizure control is not achieved within three months under primary care, care for the epilepsy should be transferred to a neurologist. Neurologist referral is also appropriate for epilepsy-specific MRI to identify birth defects that are causing seizures, even in adult-onset epilepsy. Adjustment of medications based on serum levels and consideration of whether to add a second drug for seizure control are other appropriate reasons for referral to a neurologist. Some patients should be referred to level 3 care with an epileptologist. These specialists have epilepsy-specific MRI protocols, inpatient EEG/video monitoring and a referral relationship to a Level 4 Epilepsy Center. They have the knowledge of second-level drugs, how to prescribe and manage drug combinations, diagnosis of PNES, and the ability to identify surgical candidates. Level 4 care in a comprehensive epilepsy center is mostly found at university hospitals. To be a comprehensive epilepsy center, epilepsy surgical capability as well as Level 3 resources must be available. These centers have access to neuropsychology, rehabilitation, and social services. They also usually have special test ability, including positron emission tomography (PET), single-photon emission computerized tomography (SPECT), magnetoencephalography (MEG, recording brain waves with magnets), and intracranial EEG monitoring with implanted electrodes. This is also the appropriate level of care for management of unusual drugs and clinical trials of experimental drugs. Surgical therapy for epilepsy should be considered if refractory epilepsy is present. 2 Surgery is highly effective for selected patients with focal seizures, and 60 to 80 percent will be cured. The cure rates are lower with other seizure types (40 to 60). Surgical treatment causes relatively minor adverse effects. Good candidates for surgical treatment are those with mesial temporal sclerosis (MTS), the most common brain lesion that causes seizures in adults. Only 11 to 30 percent of patients with MTS epilepsy became seizure free on medication. 3 Seizures secondary to MTS are very amenable to temporal lobectomy, but this sacrifices too much of the brain. The new therapy for this is laser interstitial thermal therapy (LITT). This laser surgery only requires a 24-hour hospitalization and small bandage over a hole drilled for the laser probe to be placed into brain. There is minimal patient discomfort and recovery time, compared to open resection. There are also potentially improved neurocognitive impacts over temporal lobectomy, especially when the lesion is in the dominant hemisphere. LITT may be an effective treatment for other lesional epileptic foci and is under study for those. If resection or laser is not possible, a responsive neurostimulator is an option. With this treatment, an electrical lead is implanted into the brain. The device monitors brain waves and then interrupts seizure activity. People cannot feel the stimulation once it is programmed, and it does not cause pain or any unusual feelings. This treatment has been shown to reduce seizures and improve quality of life. Conclusion Most patients can effectively be treated with medication, surgery, or neurostimulation; however, there are some who still will not have seizure control. On the horizon are more minimally invasive procedures, including laser, radiofrequency, and ultrasound targeting of brain lesions, which are all being investigated. Gene therapy for inherited forms of epilepsy is also likely coming. Medications currently treat the seizure; epilepsy prevention medication is needed to prevent seizures after head trauma and stroke. R. Edward Faught, MD, is a Professor of Neurology at the Emory University School of Medicine and Director of the Emory Epilepsy Program in Atlanta, GA. References 1. Helmers SL, Thurman DJ, Durgin TL, et al. Descriptive epidemiology of epilepsy in the U.S. population: A different approach. Epilepsia. 2015;56(6): American Academy of Neurology. Evidence-based Guideline: Management of an Unprovoked First Seizure in Adults Available at com/guidelines/home/guidelinedetail/687. Accessed 10/17/ Brodie MJ. Pharmacological treatment of drug-resistant epilepsy in adults: A practical guide. Curr Neurol Neurosci Rep. 2016;16(9):82. Vol. 21, No. 4 Journal of Managed Care Medicine 41

42 Provide your members with the option that s FDA APPROVED FOR INTERMEDIATE OR HIGH-RISK MYELOFIBROSIS In COMFORT-I* and COMFORT-II, Jakafi (ruxolitinib) significantly reduced spleen volume compared with patients receiving placebo or best available therapy, respectively 1-3 The primary end point was the proportion of patients achieving a 35% reduction in spleen volume from baseline at week 24 as measured by CT or MRI1,2 The primary end point was the proportion of patients achieving a 35% reduction in spleen volume from baseline at week 48 as measured by CT or MRI1,3 COMFORT-I Primary End Point: Spleen Volume Reduction at Week 241,2 COMFORT-II Primary End Point: Spleen Volume Reduction at Week 481,3 Patients (%) 40 Jakafi (n = 155) Placebo (n = 154) 42% 40 (n = 65) 20 0 P < P < Jakafi (n = 146) BAT (n = 73) 50 Patients (%) % (n = 1) 35% Spleen Volume Reduction From Baseline 29% 30 (n = 41) % 0 (n = 0) 35% Spleen Volume Reduction From Baseline BAT, best available therapy. * COMFORT-I (COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment-I) was a randomized, double-blind, placebo-controlled phase 3 study with 309 patients with intermediate-2 risk or high-risk myelofibrosis.1,2 COMFORT-II (COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment-II) was a randomized, open-label phase 3 study with 219 patients with intermediate-2 risk or high-risk myelofibrosis.1,3 Best available therapy in COMFORT-II included hydroxyurea (46.6%) and glucocorticoids (16.4%), as well as no medication, anagrelide, epoetin alfa, thalidomide, lenalidomide, mercaptopurine, thioguanine, danazol, peginterferon alfa-2a, interferon-α, melphalan, acetylsalicylic acid, cytarabine, and colchicine.4 Important Safety Information Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose-related effects. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi Severe neutropenia (ANC < /L) was generally reversible by withholding Jakafi until recovery Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly Jakafi is a registered trademark of Incyte. 2017, Incyte Corporation. All rights reserved. RUX /17 Tuberculosis (TB) infection has been reported. Observe patients taking Jakafi for signs and symptoms of active TB and manage promptly. Prior to initiating Jakafi, evaluate patients for TB risk factors and test those at higher risk for latent infection. Consult a physician with expertise in the treatment of TB before starting Jakafi in patients with evidence of active or latent TB. Continuation of Jakafi during treatment of active TB should be based on the overall risk-benefit determination Progressive multifocal leukoencephalopathy (PML) has occurred with Jakafi treatment. If PML is suspected, stop Jakafi and evaluate Advise patients about early signs and symptoms of herpes zoster and to seek early treatment Increases in hepatitis B viral load with or without associated elevations in alanine aminotransferase and aspartate aminotransferase have been reported in patients with chronic hepatitis B virus (HBV) infections. Monitor and treat patients with chronic HBV infection according to clinical guidelines

43 Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis and post essential thrombocythemia myelofibrosis. Overall survival was a prespecified secondary end point in COMFORT-I and COMFORT-II 1 COMFORT-I: At 3 years, survival probability was 70% for patients originally randomized to Jakafi and 61% for those originally randomized to placebo1 COMFORT II: At 3 years, survival probability was 79% for patients originally randomized to Jakafi and 59% for those originally randomized to best available therapy1 COMFORT-I Overall Survival: Kaplan-Meier Curves by Treatment Group1 COMFORT-II Overall Survival: Kaplan-Meier Curves by Treatment Group Median crossover: 9 months Jakafi (n = 155) Placebo (n = 154) 0.3 % 1-year survival 91% 84% 0.2 % 2-year survival 80% 69% 0.1 % 3-year survival 70% 61% Time (Months) Median crossover: 17 months BAT (n = 73) % 1-year survival 96% 94% 0.2 % 2-year survival 86% 81% 0.1 % 3-year survival 79% 59% 0 6 Number of patients at risk Jakafi BAT Jakafi (n = 146) Number of patients at risk Jakafi Placebo Jakafi BAT BAT 0.9 Survival Probability 0.9 Survival Probability 1.0 Jakafi Placebo Time (Months) BAT, best available therapy. Patients randomized to placebo (COMFORT-I) or best available therapy (COMFORT-II) were eligible to cross over to receive Jakafi because of progression-driven events or at the physician s discretion; however, these patients continued to be grouped within their original randomized assignment for analysis purposes 4 All patients in the control group either crossed over or discontinued1 When discontinuing Jakafi, myeloproliferative neoplasmrelated symptoms may return within one week. After discontinuation, some patients with myelofibrosis have experienced fever, respiratory distress, hypotension, DIC, or multi-organ failure. If any of these occur after discontinuation or while tapering Jakafi, evaluate and treat any intercurrent illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi without consulting their physician. When discontinuing or interrupting Jakafi for reasons other than thrombocytopenia or neutropenia, consider gradual tapering rather than abrupt discontinuation Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred. Perform periodic skin examinations Treatment with Jakafi has been associated with increases in total cholesterol, low-density lipoprotein cholesterol, and triglycerides. Assess lipid parameters 8-12 weeks after initiating Jakafi. Monitor and treat according to clinical guidelines for the management of hyperlipidemia The three most frequent non-hematologic adverse reactions (incidence >10%) were bruising, dizziness and headache A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or fluconazole or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breastfeed during treatment and for two weeks after the final dose Please see Brief Summary of Full Prescribing Information for Jakafi on the following pages. To learn more about Jakafi, visit Jakafi.com/HCP. References: 1. Jakafi Prescribing Information. Wilmington, DE: Incyte Corporation. 2. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9): Harrison C, Kiladjian J-J, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9): Data on file. Incyte Corporation. Wilmington, DE.

44 BRIEF SUMMARY: For Full Prescribing Information, see package insert. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Prescribing Information]. Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in Full Prescribing Information]. Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi. Severe neutropenia (ANC less than 0.5 X 10 9 /L) was generally reversible by withholding Jakafi until recovery [see Adverse Reactions (6.1) in Full Prescribing Information]. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in Full Prescribing Information]. Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting therapy with Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly. Tuberculosis Tuberculosis infection has been reported in patients receiving Jakafi. Observe patients receiving Jakafi for signs and symptoms of active tuberculosis and manage promptly. Prior to initiating Jakafi, patients should be evaluated for tuberculosis risk factors, and those at higher risk should be tested for latent infection. Risk factors include, but are not limited to, prior residence in or travel to countries with a high prevalence of tuberculosis, close contact with a person with active tuberculosis, and a history of active or latent tuberculosis where an adequate course of treatment cannot be confirmed. For patients with evidence of active or latent tuberculosis, consult a physician with expertise in the treatment of tuberculosis before starting Jakafi. The decision to continue Jakafi during treatment of active tuberculosis should be based on the overall risk-benefit determination. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) has occurred with Jakafi treatment. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected [see Adverse Reactions (6.1) in Full Prescribing Information]. Hepatitis B Hepatitis B viral load (HBV-DNA titer) increases, with or without associated elevations in alanine aminotransferase and aspartate aminotransferase, have been reported in patients with chronic HBV infections taking Jakafi. The effect of Jakafi on viral replication in patients with chronic HBV infection is unknown. Patients with chronic HBV infection should be treated and monitored according to clinical guidelines. Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi Following discontinuation of Jakafi, symptoms from myeloproliferative neoplasms may return to pretreatment levels over a period of approximately one week. Some patients with MF have experienced one or more of the following adverse events after discontinuing Jakafi: fever, respiratory distress, hypotension, DIC, or multi-organ failure. If one or more of these occur after discontinuation of, or while tapering the dose of Jakafi, evaluate for and treat any intercurrent illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi therapy without consulting their physician. When discontinuing or interrupting therapy with Jakafi for reasons other than thrombocytopenia or neutropenia [see Dosage and Administration (2.5) in Full Prescribing Information], consider tapering the dose of Jakafi gradually rather than discontinuing abruptly. Non-Melanoma Skin Cancer Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred in patients treated with Jakafi. Perform periodic skin examinations. Lipid Elevations Treatment with Jakafi has been associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined in patients treated with Jakafi. Assess lipid parameters approximately 8-12 weeks following initiation of Jakafi therapy. Monitor and treat according to clinical guidelines for the management of hyperlipidemia. ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Thrombocytopenia, Anemia and Neutropenia [see Warnings and Precautions (5.1) in Full Prescribing Information] Risk of Infection [see Warnings and Precautions (5.2) in Full Prescribing Information] Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi [see Warnings and Precautions (5.3) in Full Prescribing Information] Non-Melanoma Skin Cancer [see Warnings and Precautions (5.4) in Full Prescribing Information]. Clinical Trials Experience in Myelofibrosis Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with MF in two Phase 3 studies. In these two Phase 3 studies, patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 89% of patients treated for more than 6 months and 25% treated for more than 12 months. One hundred and eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In patients starting treatment with 15 mg twice daily (pretreatment platelet counts of 100 to 200 X 10 9 /L) and 20 mg twice daily (pretreatment platelet counts greater than 200 X 10 9 /L), 65% and 25% of patients, respectively, required a dose reduction below the starting dose within the first 8 weeks of therapy. In a double-blind, randomized, placebo-controlled study of Jakafi, among the 155 patients treated with Jakafi, the most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2 ]. Thrombocytopenia, anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of causality, was observed in 11% of patients treated with Jakafi and 11% of patients treated with placebo. Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment. Table 1: Myelofibrosis: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled Study During Randomized Treatment Adverse Reactions Bruising b 23 < Dizziness c 18 < Headache Urinary Tract Infections d <1 <1 Weight Gain e 7 <1 0 1 <1 0 Flatulence <1 0 0 Herpes Zoster f <1 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere s Disease, labyrinthitis d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present e includes weight increased, abnormal weight gain f includes herpes zoster and post-herpetic neuralgia Description of Selected Adverse Drug Reactions: Anemia In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (<1%) discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g/dl below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g/dl below baseline. This pattern was observed in patients regardless of whether they had received transfusions during therapy. In the randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo treated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 X 10 9 /L was 14 days. Platelet transfusions were administered to 5% of patients receiving Jakafi and to 4% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in <1% of patients receiving Jakafi and <1% of patients receiving control regimens. Patients with a platelet count of 100 X 10 9 /L to 200 X 10 9 /L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 10 9 /L (17% versus 7%). Neutropenia In the two Phase 3 clinical studies, 1% of patients reduced or stopped Jakafi because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study. Table 2: Myelofibrosis: Worst Hematology Laboratory Abnormalities in the Placebo-Controlled Study a Laboratory Parameter All Grades a (%) All Grades b (%) Jakafi (N=155) Grade 3 (%) Jakafi (N=155) Grade 3 (%) Grade 4 (%) Grade 4 (%) All Grades (%) All Grades (%) Placebo (N=151) Grade 3 (%) Placebo (N=151) Grade 3 (%) Grade 4 (%) Grade 4 (%) Thrombocytopenia Anemia Neutropenia <1 1 a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 Additional Data from the Placebo-controlled Study 25% of patients treated with Jakafi and 7% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 2% for Jakafi with 1% Grade 3 and no Grade 4 ALT elevations. 17% of patients treated with Jakafi and 6% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST elevations was <1% for Jakafi with no Grade 3 or 4 AST elevations. 17% of patients treated with Jakafi and <1% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was <1% for Jakafi with no Grade 3 or 4 cholesterol elevations. Clinical Trial Experience in Polycythemia Vera In a randomized, open-label, active-controlled study, 110 patients with PV resistant to or intolerant of hydroxyurea received Jakafi and 111 patients received best available therapy [see Clinical Studies (14.2) in Full Prescribing Information]. The most frequent adverse drug reaction was anemia. Table 3 presents the most frequent non-hematologic treatment emergent adverse events occurring up to Week 32. Discontinuation for adverse events, regardless of causality, was observed in 4% of patients treated with Jakafi.

45 Table 3: Polycythemia Vera: Treatment Emergent Adverse Events Occurring in 6% of Patients on Jakafi in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment Adverse Events All Grades a (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Headache 16 <1 19 <1 Abdominal Pain b 15 <1 15 <1 Diarrhea <1 Dizziness c Fatigue Pruritus 14 < Dyspnea d Muscle Spasms 12 <1 5 0 Nasopharyngitis Constipation Cough Edema e Arthralgia <1 Asthenia Epistaxis Herpes Zoster f 6 <1 0 0 Nausea a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes abdominal pain, abdominal pain lower, and abdominal pain upper c includes dizziness and vertigo d includes dyspnea and dyspnea exertional e includes edema and peripheral edema f includes herpes zoster and post-herpetic neuralgia Other clinically important treatment emergent adverse events observed in less than 6% of patients treated with Jakafi were: Weight gain, hypertension, and urinary tract infections. Clinically relevant laboratory abnormalities are shown in Table 4. Table 4: Polycythemia Vera: Selected Laboratory Abnormalities in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment a Laboratory Parameter Hematology All Grades b (%) Jakafi (N=110) Jakafi (N=110) Grade 3 (%) Grade 4 (%) All Grades (%) Best Available Therapy (N=111) Grade 3 (%) Grade 4 (%) Anemia 72 <1 < Thrombocytopenia 27 5 < <1 Neutropenia 3 0 <1 10 <1 0 Chemistry Hypercholesterolemia Elevated ALT 25 < Elevated AST <1 0 Hypertriglyceridemia a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 Best Available Therapy (N=111) DRUG INTERACTIONS Fluconazole Concomitant administration of Jakafi with fluconazole doses greater than 200 mg daily may increase ruxolitinib exposure due to inhibition of both the CYP3A4 and CYP2C9 metabolic pathways [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Increased exposure may increase the risk of exposure-related adverse reactions. Avoid the concomitant use of Jakafi with fluconazole doses of greater than 200 mg daily [see Dosage and Administration (2.3) in Full Prescribing Information]. Strong CYP3A4 inhibitors Concomitant administration of Jakafi with strong CYP3A4 inhibitors increases ruxolitinib exposure [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Increased exposure may increase the risk of exposure-related adverse reactions. Consider dose reduction when administering Jakafi with strong CYP3A4 inhibitors [see Dosage and Administration (2.3) in Full Prescribing Information]. Strong CYP3A4 inducers Concomitant administration of Jakafi with strong CYP3A4 inducers may decrease ruxolitinib exposure [see Clinical Pharmacology (12.3) in Full Prescribing Information]. No dose adjustment is recommended; however, monitor patients frequently and adjust the Jakafi dose based on safety and efficacy [see Clinical Pharmacology (12.3) in Full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Risk Summary When pregnant rats and rabbits were administered ruxolitinib during the period of organogenesis adverse developmental outcomes occurred at doses associated with maternal toxicity (see Data). There are no studies with the use of Jakafi in pregnant women to inform drug-associated risks. The background risk of major birth defects and miscarriage for the indicated populations is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk in the U.S. general population of major birth defects is 2% to 4% and miscarriage is 15% to 20% of clinically recognized pregnancies. Data: Animal Data Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There were no treatment-related malformations. Adverse developmental outcomes, such as decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Lactation: Risk Summary No data are available regarding the presence of ruxolitinib in human milk, the effects on the breast fed infant, or the effects on milk production. Ruxolitinib and/or its metabolites were present in the milk of lactating rats (see Data). Because many drugs are present in human milk and because of the potential for thrombocytopenia and anemia shown for Jakafi in human studies, discontinue breastfeeding during treatment with Jakafi and for two weeks after the final dose. Data: Animal Data Lactating rats were administered a single dose of [ 14 C]-labeled ruxolitinib (30 mg/kg) on postnatal Day 10, after which plasma and milk samples were collected for up to 24 hours. The AUC for total radioactivity in milk was approximately 13-fold the maternal plasma AUC. Additional analysis showed the presence of ruxolitinib and several of its metabolites in milk, all at levels higher than those in maternal plasma. Pediatric Use The safety and effectiveness of Jakafi in pediatric patients have not been established. Jakafi was evaluated in a single-arm, dose-escalation study (NCT ) in 27 pediatric patients with relapsed or refractory solid tumors (Cohort A) and 20 with leukemias or myeloproliferative neoplasms (Cohort B). The patients had a median age of 14 years (range, 2 to 21 years) and included 18 children (age 2 to < 12 years), and 14 adolescents (age 12 to <17 years). The dose levels tested were 15, 21, 29, 39, or 50 mg/m 2 twice daily in 28-day cycles with up to 6 patients per dose group. Overall, 38 (81%) patients were treated with no more than a single cycle of Jakafi, while 3, 1, 2, and 3 patients received 2, 3, 4, and 5 or more cycles, respectively. A protocol-defined maximal tolerated dose was not observed, but since few patients were treated for multiple cycles, tolerability with continued use was not assessed adequately to establish a recommended Phase 2 dose. The safety profile in children was similar to that seen in adults. Geriatric Use Of the total number of patients with MF in clinical studies with Jakafi, 52% were 65 years and older, while 15% were 75 years and older. No overall differences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment Reduce the Jakafi dosage when administering Jakafi to patients with MF and moderate (CLcr 30 ml/min to 59 ml/min as estimated using Cockcroft-Gault) or severe renal impairment (CLcr 15mL/min to 29 ml/min) with a platelet count between 50 X 10 9 /L and 150 X 10 9 /L [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in Full Prescribing Information]. Reduce the Jakafi dosage for patients with PV and moderate (CLcr 30 to 59 ml/min) or severe renal impairment (CLcr 15 to 29 ml/min) [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in Full Prescribing Information]. Reduce the Jakafi dosage for all patients with ESRD on dialysis [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in Full Prescribing Information]. Hepatic Impairment Reduce the Jakafi dosage when administering Jakafi to patients with MF and any degree of hepatic impairment (Child-Pugh Class A, B and C) and with a platelet count between 50 X 10 9 /L and 150 X 10 9 /L [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in Full Prescribing Information]. Reduce the Jakafi dosage for patients with PV and hepatic impairment (Child-Pugh Class A, B and C) [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in Full Prescribing Information]. OVERDOSAGE There is no known antidote for overdoses with Jakafi. Single doses up to 200 mg have been given with acceptable acute tolerability. Higher than recommended repeat doses are associated with increased myelosuppression including leukopenia, anemia and thrombocytopenia. Appropriate supportive treatment should be given. Hemodialysis is not expected to enhance the elimination of Jakafi. Jakafi is a registered trademark of Incyte. All rights reserved. U.S. Patent Nos ; ; ; ; ; Incyte Corporation. All rights reserved. Revised: December 2017 RUX-2429

46 2019 Spring Managed Care Forum Rosen Shingle Creek Orlando, FL SAVE THE DATE! April 25-26, 2019 Hotel photos: Rosen Shingle Creek d

47 What s New in the Evolving Management of Type 2 Diabetes: Individualizing Therapy with Novel Treatment Options Carol H. Wysham, MD For a CME/CEU version of this article please go to and then click the activity title. Summary Therapy for type 2 diabetes mellitus (T2DM) is evolving to focus on underlying pathophysiologic defects and benefits in reducing macrovascular consequences while minimizing adverse effects. Two newer classes of agents (GLP-1 RA and SGLT- 2 inhibitors) have many advantages over other older agents and are being increasingly used earlier in therapy and in more patients. Key Points Personalized medicine using genetic markers is in the very early stages for T2DM. Newer studies suggest cardiovascular and renal benefit of GLP-1 RA and SGLT-2 inhibitors, compared with other agents. GLP-1 RA and SGLT-2 inhibitors have significant benefits over other classes of medication. IN 2017, THE CENTERS FOR DISEASE CONtrol and Prevention (CDC) estimated that 30.3 million people, or 9.4 percent of adults in the United States (U. S), had diabetes mellitus; the majority of which have type 2 disease (T2DM). 1 The rate in those over the age of 65 is 25 percent; however, there is an increasing rate of this disease in younger patients (even in their teens), which is concerning given that these patients seem to develop complications of the disease faster. The long-term micro and macrovascular complications of the disease are well known, but they are reduced with good glycemic control (Exhibit 1). 2 For every 1 percent someone can reduce their A1C (and keep it down), they reduce their risk of complications by 37 percent. The reduction in complications with therapy has primarily been in microvascular disease, but macrovascular complications are really what cause deaths in T2DM. Peripheral vascular disease (PV) is the number one presenting vascular disease in T2DM patients, with heart failure number two. Some of the newer therapies have been shown to reduce macrovascular complications and will be discussed later. Controlling blood pressure and lipids is also important in reducing risk of macrovascular complications. Because of therapy improvements, patients are living many years with T2DM without complications. Thus, we are able to change the natural history of the disease, but it is hard to do within the U.S. health care system. In Germany, all therapies for diabetes are covered with no copay, and their outcomes are much better than those in the U.S. Many of our patients with T2DM are unable to afford medications and monitoring. The thought that if the patient would just do better with diet and exercise they would not need medicine is a fallacy because of the progressive nature of Vol. 21, No. 4 Journal of Managed Care Medicine 47

48 Exhibit 1: Long-Term Complications of Diabetes 2 Leading cause of blindness in working age adults Diabetic Retinopathy Stroke 2-fold to 4-fold increase in cardiovascular events and mortality Myocardial Infarction Heart Failure Atrial Fibrillation Diabetic Nephropathy Leading cause of end-stage renal disease Diabetic Neuropathy Leading cause of nontraumatic lower extremity amputations Exhibit 2: SNP Variants with Predictive Value for Therapeutics/Complications Predicts response to diet/exercise FTO respond better to high protein diet TCF7L2 respond better to low fat diet ISIG2 lower response to resistance exercise in males Predicts response to medication HNF1A MODY high response to SU Loss of function CYP2Cp increase SU efficacy OCT1 variants associated with decreased efficacy and tolerability of metformin TCF7L2 variants associated with decreased response to DPP-4i and GLP-1 RA Risk for complications Haptoglobin variants increased CVD risk MTHFR677C/T modest increase risk for nephropathy and retinopathy SU = sulfonylurea DPP-4i = dipeptidyl peptidase-4 inhibitor GLP-1 RA = glucagon like peptide one receptor agonist CVD = cardiovascular disease the disease. At the time of diagnosis, patients have lost 35 to 40 percent of β-cell function already. Diet and exercise are complementary to medications, but they cannot replace them over the long run. Glycemic control will deteriorate if therapy is not altered over time to account for progressive β-cell dysfunction. After about three years on single-agent sulfonylurea, glucose will begin to increase and A1C will return to baseline if the dose or drug is not adjusted. 3 Metformin remains effective as monotherapy for six or seven years. Diabetes is a much more heterogeneous disease than the present subdivision into types 1 and 2 assumes. 4 These two divisions probably represent extremes on a range of diabetic disorders; thus, clinical features vary markedly among patients. Currently, 48 Journal of Managed Care Medicine Vol. 21, No. 4

49 Exhibit 3: Pathophysiologic Defects in T2DM and Effect of Medications Insulin Sulfonylureas Megltinides GLP-1 RA DPP-4 inhibitors Islet β-cell GLP-1 RA DPP-4 inhibitors Decreased Incretin Effect Insulin TZDs GLP-1 RA DPP-4 inhibitors Islet α-cell Impaired Insulin Secretion Hyperglycemia Increased Lipolysis SGLT-2 inhibitors Increased Glucagon Secretion Increased Glucose Reabsorption Metformin Insulin TZD GLP-1RA Increased Hepatic glucose production Neurotransmitter Dysfunction Bromocriptine GLP-1 RA Insulin TZDs Decreased Glucose Uptake DPP-4 = dipeptidyl peptidase-4 GLP-1 RA = glucagon like peptide one receptor agonist TZD = thiazolidinedione SGLT-2 = serum glucose cotransporter two therapy decisions can only be based upon medication attributes and patient phenotype; however, personalized medicine is based on the identification of specific genetic markers. Numerous single nucleotide polymorphisms (SNPs) have been identified that are associated with increased risk for diabetes mellitus. For example, TCF7L2 encodes for enteroendocrine transcription factor, which regulates peptide hormone made by enteroendocrine cells (glucagon-like peptide 1). Some SNP variants have some predictive value for therapeutics/complications (Exhibit 2). The only one currently used in clinical practice is HNF1A, which increases risk for Maturity-Onset Diabetes of the Young (MODY). Those with MODY respond dramatically for many years to very small doses of sulfonylureas. MODY is typically diagnosed before 30 years of age and is often misdiagnosed as type 1 diabetes mellitus. This testing should be considered in patients with family histories of two or three generations of diabetes diagnosed at a young age. Pathophysiologic defects in numerous body organs are involved in the development of hyperglycemia, fatty liver, and lipid disorders in T2DM. Exhibit 3 shows each of the involved organs and which medications impact each organ. The American Diabetes Association and American College of Clinical Endocrinologist management guidelines recommend diet, exercise, diabetes education, and metformin as the foundation for treatment. 5,6 Metformin, if tolerated, is continued even when other agents are added. Some patients will have primary or secondary metformin failure and will require alternative therapies. Thiazolidinediones (TZD), sulfonylureas (SU), glucagon-like peptide one receptor agonists (GLP-1 RAs), dipeptidyl peptidase-4 (DPP-4) inhibitors, serum glucose cotransporters two (SGLT-2) inhibitors, or insulin are all options to add to metformin if hemoglobin A1C goals are not met on monotherapy. As a thirdline treatment, an agent/class not previously used can be added to the regimen. The only combination which should not be used together is a DPP-4 inhibitor and a GLP-1 RA because their mechanisms of action are essentially the same. Long term, many patients will need basal insulin and likely a GLP-1 RA in combination. Second- and third-line agents after metformin can Vol. 21, No. 4 Journal of Managed Care Medicine 49

50 Exhibit 4: Benefits of Weight Loss in T2DM 7-12 Progression from prediabetes to diabetes Measures of glycemia Triglycerides and HDL cholesterol Systolic and diastolic blood pressure Hepatic steatosis Measures of feeling and function Symptoms of urinary stress incontinence Measures of sexual function Quality of life measures Apnea-hypopnea index Reduction in CV events, mortality, remission of T2DM -3.0% -5.0% -10.0% -15.0% Exhibit 5: Comparing GLP-1 RA and SGLT-2 inhibitors GLP-1 RA Mode of Action Increases insulin secretion (glucose dependent) Decreases glucagon secretion (glucose dependent) Suppresses appetite Slows gastric emptying (short acting) Perks Weight loss Low risk for hypoglycemia Lower blood pressure Improved lipid profile Improves fatty liver Reduction in CV events (liraglutide, semaglutide) Precautions Expensive Gastrointestinal side effects Volume depletion (acute kidney injury not seen in CVOT trials) Pancreatitis (not seen in CVOT trials) SGLT-2 Inhibitors Mode of Action Inhibit reabsorption of glucose in the proximal tubule Perks Low rate of hypoglycemia Weight loss Lower blood pressure Reduced risk for hospitalization for HF (canagliflozin, empagliflozin) and death from CVD (empagliflozin) Slowed progression of nephropathy (both) Precautions Volume depletion (especially in elderly, acute kidney injury not seen in CVOT trials) Genital infections? Fractures and amputations (canagliflozin) CVOT = cardiovascular outcomes trials HF = heart failure CVD - cardiovascular disease be selected based on the likely adverse effects (hypoglycemia, weight gain, etc.) and concomitant conditions which may contraindicate or be benefited by a specific agent. For example, SGLT-2-inhibitors, GLP-1 RAs, and pioglitazone have been shown to provide benefit in those with fatty liver disease. Other clinical considerations when choosing therapy include abilities/adherence/motivation, age, disease duration, ease of use, accessibility/resources, and patient preferences, needs, and values. Weight loss and especially avoidance of additional weight gain is important in most patients with 50 Journal of Managed Care Medicine Vol. 21, No. 4

51 Exhibit 6: Approved Antihyperglycemic Medications with Proven Benefit on Cardiovascular Outcomes in Prospective Randomized Controlled Trials Empagliflozin (EMPA-REG) Rate per 100 Patient-Years RR: -14% EMPA RR: -35% PBO RR: -38% RR: -32% Liraglutide (LEADER) Rate per 100 Patient-Years RR: -13% LIRA PBO RR: -15% RR: -13% NS RR: -22% MACE HF Hospitalization CV Mortality All-cause Mortality Canagliflozin (CANVAS) Rate per 100 Patient-Years RR: -14% CANA RR: -36% PBO RR: -9% NS RR: -11%NS T2DM. Weight loss improves insulin sensitivity, reduces hepatic glucose production, decreases lipolysis, and decreases fat in liver. A 5 percent loss of baseline weight is beneficial in improving glycemic control. Additional weight loss is even more beneficial (Exhibit 4) Modest weight loss is associated with use of GLP-1 RAs and SGLT-2 inhibitors, whereas weight gain can occur with insulin, SU, and TZD. The DPP-4 inhibitors are considered weight neutral. Given the inherent issues with appetite control in T2DM which contribute to weight issues, some patients may actually need weight loss medications. Sulfonylureas have poor durability of efficacy, risk for hypoglycemia, risk for weight gain, and have no effects on comorbidities of T2DM. Insulin is poorly accepted by patients and can lead to weight gain and hypoglycemia. It is more difficult for providers to prescribe, and there tends to be poor patient adherence. Additionally, insulin therapy has not been shown to have any effect on the development of macrovascular comorbidities of T2DM. In one trial, only 27 percent of patients on basal insulin achieved A1C less than 7 percent. 13 As data on more and more benefits of using the GLP-1 RAs and the SGLT-2 inhibitors have accumulated, the use of these agents has increased. Exhibit 5 compares these two classes. GLP-1 RAs (liraglutide, semaglutide) and SGLT-2 inhibitors (canagliflozin, empagliflozin) have shown CVD benefit Exhibit 6 shows the results for canagliflozin, empagliflozin, and liraglutide Two other GLP-1 RA trials were neutral, and additional trials with canagliflozin and dapagliflozin are ongoing. The CVD benefits are truly needed in patients with T2DM. The GLP-1 RAs have been compared to basal insulin and are an option instead of starting basal insulin because they are at least as good if not better for reducing A1C. 18 GLP-1 RA can also be added to basal insulin. They have complementary actions and the GLP-1 RA can mitigate the weight gain from insulin. Fixed-dose combinations with basal and GLP-1 RAs are now available (insulin glargine/ lixisenatide, insulin degludec/liraglutide), and they are injected once daily. GLP-1 RA and SGLT2 inhibitor combinations address almost all the defects in T2DM. The combination has been shown to be effective and safe. 19,20 The weight loss and blood pressure reduction are additive with these two classes. Heart failure (HF) is a common complication of T2DM. TZDs are associated with increased risk and metformin may be protective. 21 DPP-4 inhibitors may be associated with a slight increase in risk for patients with established CVD. GLP-1 RAs appear Vol. 21, No. 4 Journal of Managed Care Medicine 51

52 to be neutral and the SGLT-2 inhibitors reduce hospitalizations from HF. Treatment with insulin is associated with increased risk in epidemiologic studies but this may be a confounding effects of insulin therapy with long duration of diabetes. Overall, the advantages of GLP-1 RAs and SGLT- 2 inhibitors in treatment of T2DM are the ability to meet patient values by improved glucose control, decreased risk for weight gain, decreased risk for hypoglycemia, and decreased risk of CVD. They require minimal (or no) titration, decrease non-pharmacy health care expenditures (decreased emergency department visits, CVD, advancing renal disease, and fatty liver), and potential decreased progression of disease, which would decrease adverse clinical complications due to clinical inertia. Conclusion The main objective of personalized therapy in diabetes is matching a patient s phenotype to predict an effective, sustained, and safe therapy. Increasingly, we are able to select medications according to a patient s clinical attributes and values, presence of comorbidities, and relative risk for hypoglycemia and weight gain. With few exceptions, we are currently unable to select optimal therapy based upon genetic variants. Carol H. Wysham, MD, is Clinical Professor of Medicine at the University of Washington Rockwood Clinic in Spokane, WA. References 1. Centers for Disease Control. National Diabetes Statistics Report, Estimates of Diabetes and Its Burden in the United States. Available at gov. Accessed 7/28/ National Diabetes Information Clearinghouse. Diabetes. Available at www. niddk.nih.gov/health/diabetes/pubs/dmstats/dmstats.htm. Accessed 7/28/ DeFronzo RA, Eldor R, Abdul-Ghani M. Pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes. Diabetes Care. 2013;36 Suppl 2:S Tuomi T, Santoro N, Caprio S, et al. The many faces of diabetes: a disease with increasing heterogeneity. Lancet. 2014;383(9922): American Diabetes Association. Standards of Medical Care in Diabetes Diabetes Care. 2018;41(Suppl 1):S1-S Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE/ACE comprehensive type 2 diabetes management algorithm Endocr Pract.2016;22: Cefalu WT, Bray GA, Home PD, et al. Advances in the science, treatment, and prevention of the disease of obesity: reflections from a diabetes care editors expert forum. Diabetes Care. 2015;38(8): Lazo M, Solga SF, Horska A, et al. Effect of a 12-month intensive lifestyle intervention on hepatic steatosis in adults with type 2 diabetes. Diabetes Care. 2010;33(10): Wing RR, Bond DS, Gendrano IN 3rd, et al. Effect of intensive lifestyle intervention on sexual dysfunction in women with type 2 diabetes: results from an ancillary Look AHEAD study. Diabetes Care. 2013;36(10): Kolotkin RL, Crosby RD, Williams GR, et al. The relationship between health-related quality of life and weight loss. Obes Res. 2001;9(9): Sjöström L, Peltonen M, Jacobson P, et al. Bariatric surgery and long-term cardiovascular events. JAMA. 2012;307(1): Sjöström L, Peltonen M, Jacobson P1, et al. Association of bariatric surgery with long-term remission of type 2 diabetes and with microvascular and macrovascular complications. JAMA. 2014;311(22): Dalal MR, Grabner M, Bonine N, et al. Are patients on basal insulin attaining glycemic targets? Characteristics and goal achievement of patients with type 2 diabetes mellitus treated with basal insulin and physician-perceived barriers to achieving glycemic targets. Diabetes Res Clin Pract. 2016;121: Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22): Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4): Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7): Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19): Buse JB, Peters A, Russell-Jones D, et al. Is insulin the most effective injectable antihyperglycemic therapy? Diabetes Obes Metab. 2015;17(2): Frías JP, Guja C, Hardy E, Ahmed A4, et al. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURA- TION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2016;4(12): Martinez RA, Al-Gburi K, Al Jobori H, et al. Effect of combination SGLT2i and GLP-1RA therapy on glycemic control, body weight, and beta-cell function in type 2 diabetic (t2d) subjects. Poster 167-LB. Presented at 77th Annual ADA Scientific Meeting, San Diego, CA Gilbert RE, Krum H. Heart failure in diabetes: effects of anti-hyperglycemic drug therapy. Lancet. 2015;385(9982): Journal of Managed Care Medicine Vol. 21, No. 4

53 Powerful1 migraine relief made simple 2,3 ZEMBRACE SymTouch may be an appropriate option for your patients who experience: migraine with nausea rapid onset migraine morning migraine ZEMBRACE SymTouch is a prefilled 3 mg SUMATRIPTAN AUTOINJECTOR 2 Features a discreet, compact design with a SIMPLE TWO-STEP INJECTION PROCESS a,1,4 Contains a thin-walled, CONCEALED, 29-gauge needle the SMALLEST NEEDLE IN A SUMATRIPTAN AUTOINJECTOR 5,6 With sumatriptan 3 mg, 17% of patients felt pain relief in AS LITTLE AS 10 MINUTES and 60% of patients felt pain relief within 2 hours, compared with 5% and 21% for placebo, respectively 2 a Please see complete Instructions for Use on ZEMBRACE.com. E.com. Indication and Usage ZEMBRACE SymTouch is indicated for the acute treatment of migraine with or without aura in adults. Limitations of Use: Use only if a clear diagnosis of migraine has been established. If a patient has no response to the first migraine attack treated with ZEMBRACE SymTouch, reconsider the diagnosis before ZEMBRACE SymTouch is administered to treat any subsequent attacks. ZEMBRACE SymTouch is not indicated for the prevention of migraine attacks. Important Safety Information ZEMBRACE SymTouch is contraindicated in patients with: Ischemic Coronary Artery Disease (CAD) or coronary artery vasospasm (including Prinzmetal s angina), Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders Uncontrolled hypertension, history of stroke or transient ischemic attack (TIA) or history of hemiplegic or basilar migraine Peripheral vascular disease Ischemic bowel disease Recent (i.e., within 24 hours) use of ergotamine-containing medication, ergot derivatives, or another 5-HT 1 agonist Concurrent or recent (within 2 weeks) use of an MAO-A inhibitor Known hypersensitivity to sumatriptan Severe hepatic impairment There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of sumatriptan injection. Some of these reactions occurred in patients without known CAD. 5-HT 1 agonists, including ZEMBRACE SymTouch, may cause coronary artery vasospasm. Life-threatening disturbances of cardiac rhythm leading to death in some cases, have been reported within a few hours following the administration of 5-HT 1 agonists. Cerebrovascular events including cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT 1 agonists, and some have resulted in fatalities. Discontinue ZEMBRACE SymTouch if any of these events occur. Perform a cardiovascular evaluation in triptan-naive patients who have multiple cardiovascular risk factors prior to receiving ZEMBRACE SymTouch. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of ZEMBRACE SymTouch in a medically supervised setting and consider periodic follow up. Sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw commonly occur after treatment with sumatriptan injection and are usually non-cardiac in origin. ZEMBRACE SymTouch may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction, splenic infarction, and Raynaud s syndrome. Overuse of acute migraine drugs may lead to exacerbation of headache (medication overuse headache). Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms may be necessary. Serotonin syndrome may occur with ZEMBRACE SymTouch, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors. Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT 1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with ZEMBRACE SymTouch. Discontinue ZEMBRACE SymTouch if serotonin syndrome is suspected or hypertensive crisis is observed. Seizures have been reported following administration of sumatriptan. Some have occurred in patients with either a history of seizures or concurrent conditions predisposing to seizures. ZEMBRACE SymTouch should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold. Most common adverse reactions ( 5% and > placebo) were injection site reactions, tingling, dizziness/vertigo, warm/hot sensation, burning sensation, feeling of heaviness, pressure sensation, flushing, feeling of tightness, and numbness. These are not all the side effects associated with ZEMBRACE SymTouch. Advise the patient to read the FDA-approved patient labeling. Please see Patient Information, Instructions For Use and Full Prescribing Information for ZEMBRACE SymTouch. You are encouraged to report negative side effects of prescription drugs. To report SUSPECTED SIDE EFFECTS, call Promius Pharma at or contact the FDA at FDA-1088 ( ) or online at Please see Brief Summary of Prescribing Information on the adjacent page. References: 1. Derry CJ, Derry S, Moore RA. Sumatriptan (all routes of administration) for acute migraine attacks in adults - overview of Cochrane reviews. The Cochrane database of systematic reviews. 2014;5:Cd ZEMBRACE SymTouch Prescribing Information, Promius Pharma, March Brand-Schieber E, Munjal S, Kumar R, Andre AD, Valladao W, Ramirez M. Human factors validation study of 3 mg sumatriptan autoinjector, for migraine patients. Med Devices (Auckl). 2016;9: ZEMBRACE SymTouch Instructions for Use. Promius Pharma, March US Food and Drug Administration NDA # Dr. Reddy's Laboratories. Princeton, NJ: Jan Confirmation of Outside Diameter (OD) of Sumatriptan Autoinjector Pre-filled Syringes (PFS). Promius Pharma, Mar ZEMBRACE and SymTouch are registered trademarks of Dr. Reddy's Laboratories, LTD Promius Pharma, LLC. ZEM March 2018

54 Rx Only BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION This brief summary does not include all the information needed to use ZEMBRACE SymTouch safely and effectively. Please consult Full Prescribing Information. INDICATIONS AND USAGE ZEMBRACE SymTouch is indicated for the acute treatment of migraine with or without aura in adults. Limitations of Use: Use only if a clear diagnosis of migraine has been established. If a patient has no response to the first migraine attack treated with ZEMBRACE SymTouch, reconsider the diagnosis before ZEMBRACE SymTouch is administered to treat any subsequent attacks. ZEMBRACE SymTouch injection is not indicated for the prevention of migraine attacks. CONTRAINDICATIONS ZEMBRACE SymTouch is contraindicated in patients with: Ischemic Coronary Artery Disease (CAD) (angina pectoris, history of myocardial infarction, or documented silent ischemia) or coronary artery vasospasm, including Prinzmetal s angina. Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders. History of stroke or transient ischemic attack (TIA) or history of hemiplegic or basilar migraine because these patients are at a higher risk of stroke. Peripheral vascular disease Ischemic bowel disease Uncontrolled hypertension Recent (i.e., within 24 hours) use of ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or methysergide), or another 5-hydroxytryptamine1 (5-HT 1 ) agonist Concurrent administration of an MAO-A inhibitor or recent (within 2 weeks) use of an MAO-A inhibitor Known hypersensitivity to sumatriptan (angioedema and anaphylaxis seen) Severe hepatic impairment. WARNINGS AND PRECAUTIONS Myocardial Ischemia, Myocardial Infarction, and Prinzmetal s Angina The use of ZEMBRACE SymTouch injection is contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of sumatriptan injection. Some of these reactions occurred in patients without known CAD. 5-HT 1 agonists, including ZEMBRACE SymTouch injection, may cause coronary artery vasospasm (Prinzmetal s angina), even in patients without a history of CAD. Perform a cardiovascular evaluation in triptan-naive patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving ZEMBRACE SymTouch injection. If there is evidence of CAD or coronary artery vasospasm, ZEMBRACE SymTouch injection is contraindicated. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of ZEMBRACE SymTouch injection in a medically supervised setting and performing an electrocardiogram (ECG) immediately following ZEMBRACE SymTouch injection. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of ZEMBRACE SymTouch injection. Arrhythmias Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT 1 agonists. Discontinue ZEMBRACE SymTouch injection if these disturbances occur. ZEMBRACE SymTouch injection is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders. Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure Sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw commonly occur after treatment with sumatriptan injection and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of ZEMBRACE SymTouch injection is contraindicated in patients shown to have CAD and those with Prinzmetal s variant angina. Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT 1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT 1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA). Discontinue ZEMBRACE SymTouch injection if a cerebrovascular event occurs. Before treating headaches in patients not previously diagnosed with migraine or in patients who present with atypical symptoms, exclude other potentially serious neurological conditions. ZEMBRACE SymTouch injection is contraindicated in patients with a history of stroke or TIA. Other Vasospasm Reactions ZEMBRACE SymTouch injection may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud s syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT 1 agonist, rule out a vasospastic reaction before receiving additional ZEMBRACE SymTouch injections. Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT 1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT 1 agonists have not been clearly established. Medication Overuse Headache Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches, or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary. Serotonin Syndrome Serotonin syndrome may occur with ZEMBRACE SymTouch injection, particularly during co- administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue ZEMBRACE SymTouch injection if serotonin syndrome is suspected. Increase in Blood Pressure Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT 1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with ZEMBRACE SymTouch. ZEMBRACE SymTouch injection is contraindicated in patients with uncontrolled hypertension. Anaphylactic Reactions Anaphylactic reactions have occurred in patients receiving sumatriptan. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. ZEMBRACE SymTouch injection is contraindicated in patients with a history of hypersensitivity reaction to sumatriptan. Seizures Seizures have been reported following administration of sumatriptan. Some have occurred in patients with either a history of seizures or concurrent conditions predisposing to seizures. There are also reports in patients where no such predisposing factors are apparent. ZEMBRACE SymTouch injection should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Table 1 lists adverse reactions that occurred in 2 US placebo-controlled clinical trials in migraine subjects (Studies 2 and 3), following either a single 6-mg dose of sumatriptan injection or placebo. Only reactions that occurred at a frequency of 2% or more in groups treated with sumatriptan injection 6 mg and that occurred at a frequency greater than the placebo group are included in Table 1. Table 1: Adverse Reactions in Pooled Placebo-Controlled Trials in Patients with Migraine (Studies 2 and 3) Adverse Reaction Atypical sensations Tingling Warm/hot sensation Burning sensation Feeling of heaviness Pressure sensation Feeling of tightness Numbness Feeling strange Tight feeling in head Cardiovascular Flushing Chest discomfort Tightness in chest Pressure in chest Ear, nose, and throat Throat discomfort Discomfort: nasal cavity/sinuses Percent of Subjects Reporting Sumatriptan Injection 6 mg Subcutaneous (n = 547) Placebo (n = 370) <1 1 2 <1 2 <1 <1 2 1 <1 <1 <1 <1 Injection site reaction a Miscellaneous Jaw discomfort 2 0 Musculoskeletal Weakness Neck pain/stiffness Myalgia <1 <1 <1 Adverse Reaction Neurological Dizziness/vertigo Drowsiness/ sedation Headache Percent of Subjects Reporting Sumatriptan Injection 6 mg Subcutaneous (n = 547) Placebo (n = 370) Postmarketing Experience The following adverse reactions have been identified during postapproval use of sumatriptan tablets, sumatriptan nasal spray, and sumatriptan injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular Hypotension, palpitations Neurological Dystonia, tremor DRUG INTERACTIONS Ergot-Containing Drugs Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and ZEMBRACE SymTouch within 24 hours of each other is contraindicated. Monoamine Oxidase-A Inhibitors MAO-A inhibitors increase systemic exposure by 2-fold. Therefore, the use of ZEMBRACE SymTouch injection in patients receiving MAO-A inhibitors is contraindicated. Other 5-HT 1 Agonists Because their vasospastic effects may be additive, coadministration of ZEMBRACE SymTouch injection and other 5-HT 1 agonists (e.g., triptans) within 24 hours of each other is contraindicated. Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome Cases of serotonin syndrome have been reported during coadministration of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors. USE IN SPECIFIC POPULATIONS PREGNANCY Pregnancy Category C There are no adequate and well-controlled trials of sumatriptan injection in pregnant women. ZEMBRACE SymTouch injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. NURSING MOTHERS Sumatriptan is excreted in human milk following subcutaneous administration. Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with ZEMBRACE SymTouch injection. PEDIATRIC USE Safety and effectiveness in pediatric patients have not been established. ZEMBRACE SymTouch injection is not recommended for use in patients younger than 18 years of age. GERIATRIC USE Clinical trials of sumatriptan injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. OVERDOSAGE Coronary vasospasm was observed after intravenous administration of sumatriptan injection. The elimination half-life of sumatriptan is about 2 hours, and therefore monitoring of patients after overdose with ZEMBRACE SymTouch injection should continue for at least 10 hours or while symptoms or signs persist. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of sumatriptan. ZEMBRACE and SymTouch are registered trademarks of Dr. Reddy s Laboratories Limited Manufactured for: Dr. Reddy s Laboratories Limited by Ajinomoto Althea Inc., San Diego, CA Distributed by: Promius Pharma, LLC, Princeton, NJ Based on PI , Issued March <1 Skin Sweating 2 1 a Includes injection site pain, stinging/burning, swelling, erythema, bruising, bleeding

55 Management Insights for Optimizing Outcomes in the Treatment of Hemophilia Mark T. Reding, MD For a CME/CEU version of this article please go to and then click the activity title. Summary Optimizing outcomes for those with hemophilia requires using appropriate prophylactic treatments for the patient s lifetime, while supporting their adherence with this therapy. Various improvements in hemophilia treatment have been developed to address the major unmet needs in this devastating disease. Patients with this disease, who are started on therapy as children, are now living normal life spans with minimal disease consequences. Key Points Hemophilic arthropathy is currently the most significant complication of hemophilia. Inhibitor development is the most serious complication of hemophilia treatment. Strict adherence to long-term prophylaxis is the only way to prevent hemophilic arthropathy and its devastating consequences. Extended half-life factor products can improve outcomes in certain patients. A new therapy for hemophilia A patients with inhibitors is now available, which should improve outcomes and is likely to be cost effective in this population. HEMOPHILIA IS A CONGENITAL BLEEDING disorder due to deficiency or absence of a coagulation protein. Exhibit 1 shows the difference between hemophilia A and B. These two clinical phenotypes are indistinguishable, but they must be distinguished by laboratory testing in order to choose the correct treatment. There are approximately 20,000 hemophiliacs in the United States (U.S.) and 500,000 hemophiliacs worldwide. Hemophilia affects all racial, ethnic, and socioeconomic groups. The severity of bleeding tendency in a given patient depends on the factor level present. Those with mild hemophilia (> 5% factor level) bleed only after severe injury, trauma, or surgery and may not be diagnosed until adulthood. Those with 1 to 5 percent factor levels have moderate disease and will bleed after injury or surgery and may occasionally have spontaneous bleeding. Frequent spontaneous bleeding occurs in those with severe hemophilia (<1% factor levels). Severe hemophilia is usually diagnosed at birth or in early childhood and approximately two-thirds of all patients have severe disease. Complications of hemophilia include joint bleeds (hemarthrosis), deep muscle bleeds, and intracranial bleeds. Blood in the joint space starts an inflammatory reaction that leads to synovitis and joint damage. Joint bleeds are very painful and recurrent bleeding into a joint results in continued joint damage, destruction, and eventually disability. Hemophilic arthropathy is currently the most significant complication of hemophilia. Deep muscle bleeds can occur spontaneously and can be life threatening. Intracranial bleeds are relatively rare and mostly occur with falls. The treatment of hemophilia is factor replacement therapy. Adequate factor replacement, given by intravenous infusion, can prevent the development of arthropathy and the other complications. Plasmaderived concentrates were first developed in the 1960s. HIV contaminated factors in the 1980s led to devastating rates of AIDS in those with hemophilia. The AIDS epidemic led to the development of recombinant factor products being developed in the 1990s. Each new generation of recombinant fac- Vol. 21, No. 4 Journal of Managed Care Medicine 55

56 Exhibit 1: Hemophilia A and B Hemophilia A Factor VIII deficiency Classical Hemophilia 1 in 5,000-10,000 male births 80% of total cases Sontaneous mutations (no family history) = 30% Hemophilia B Factor IX deficiency Christmas disease 1 in 30,000 male births 20% of total cases Spontaneous mutations = 20% Exhibit 2: PK in Hemophilia Patient 1: short half-life Patient 2: long half-life Log FVIII IU/dL 10 Diffrence in FVIII level at 48 hours Difference in time to C min Time (hours) tor products has improved the removal of human and animal proteins and decreased the infusion volumes. The fourth-generation products are possibly less immunogenic because they are produced from human cell lines instead of from Chinese hamster ovary cell lines. Each of the standard half-life recombinant factor products has equivalent efficacy and the same dosing schedules. Extended half-life products are discussed later. The two options for factor replacement are on demand or prophylactic. On demand is treatment of bleeds when they occur with factor replacement. This is good at stopping bleeds after they start, but does not prevent bleeds. Prophylactic factor replacement is regular administration of factor to prevent bleeds from occurring, with a goal of no bleeding. Prophylaxis was pioneered in Sweden (1958) and has been the standard of care in the U.S. since the 1990s. The benefits of prophylactic administration includes a proven decrease in bleeds, prevention of joint damage, improved functional status and quality of life, possible delay of arthropathy progression if already present, and protection from traumatic and unexpected bleeds. Although factor replacement is expensive, the costs of not doing prophylaxis are much more, especially in terms of disability costs. Children with hemophilia today are started on prophylaxis at a very young age, are maintaining normal joints, living a normal life span, and many have never had a single bleed. Problems with standard half-life prophylactic factor replacement includes the cost, frequent intravenous infusions (3 to 4 times per week), venous access, peaks and troughs in factor level, and maintaining adherence long term. 1 Large inter-patient PK variability with the shorter acting factors commonly occurs (Exhibit 2). 2 Young adults are the one population with especially difficult adherence issues. 56 Journal of Managed Care Medicine Vol. 21, No. 4

57 Exhibit 3: EHL Factor Products: Current Status Drug Approval rfix-fc (Alprolix ) March 2014 rfviii-fc (Eloctate ) June 2014 rfviii-peg (Adynovate ) November 2015 rfix-alb (Idelvion ) March 2016 N9-GlycoPEG (Rebinyn ) May 2017 rfviii-peg (BAY ) Expected 2018 Another problem with factor replacement is the development of inhibitors. When treated with factor replacement, the immune systems of some hemophilia patients react to exogenous factor VIII or factor IX as a foreign protein and produce antibodies (inhibitors) directed against the factor which neutralize their procoagulant effect and render standard treatment useless. Development of inhibitors is currently the most serious complication of factor replacement therapy. Inhibitors are typically seen in those with severe hemophilia (hemophilia A ~30%, hemophilia B < 5%). It may occur in those with mild or moderate hemophilia after intense factor exposure related to trauma or surgery. It was previously thought that almost all inhibitors in those with severe hemophilia A developed after only a few exposures to factor replacement; however, it is now known that inhibitors arise throughout life, with a bimodal risk (< 5 years, > 60 years). 3 Genetic markers have been discovered that increase risk for developing inhibitors, and it is becoming more common to conduct genetic testing to avoid using factor replacement in those with the markers unless absolutely necessary. The end result of inhibitors is bleeding is more difficult to control, devastating joint disease and disability occur because bleeding is not well controlled, and therapy is even more expensive because alternative therapies must be used. Because standard factor replacement therapy is not possible in those with hemophilia and inhibitors, bypass agents, recombinant activated factor VII (rfvi- Ia) and activated prothrombin complex concentrate (apcc), have to be used. The major problems with these agents are that the missing factors are not being replaced, and there is a high degree of variability in response with on-demand use. The bypass agents are only 75 to 90 percent effective in stopping acute bleeds. Prophylaxis, which is the only apcc approved, is less effective than standard factor replacement and causes a high patient burden due to frequent large infusion volume. Additionally, there is no established routine method of lab monitoring for the bypass agents, and they carry a significant risk of thrombosis. Immune tolerance therapy is another option for children with inhibitors, but it is only approximately 70 percent successful. Similar to allergy shots, the patient is exposed to daily doses of factor to promote tolerance by the immune system along with highdose bypass agents for prophylaxis. This approach is very expensive, at approximately $1 million; however, continuing to have inhibitors is also expensive and devastating. In non-inhibitor patients, reducing the burden of prophylaxis and maintaining adherence over decades are major unmet needs. In inhibitor patients, effective prophylaxis and more consistent bleed management are needed. Major steps toward optimizing outcomes are extended half-life (EHL) factor products, personalized prophylaxis, a new therapy for selected patients with inhibitors, and emerging therapies. Extended half-life (EHL) factor products have been modified in various ways to prolong the halflife (Exhibit 3). Factor VIII EHL products can be dosed every three to seven days, compared with every two- to three-day dosing with standard half-life products. There is a huge biological barrier to extending the half-life of factor VIII because its halflife is dependent on that of von Willebrand factor. Factor IX EHL products have a much more dramatic extension of dosing intervals: once every one to two weeks, compared with once or twice per week. This is game changing for the patients with factor IX deficiency, and some patients are able to extend their dosing out to every 21 days. Unlike standard half-life factor products, EHL products are not interchange- Vol. 21, No. 4 Journal of Managed Care Medicine 57

58 Exhibit 4: Case Examples Clinical History WAPPS- Hemo Outcome Clinical History WAPPS- Hemo Outcome 32-year-old man, severe hemophelia A Prophylaxis 3 times per week with rfviii, struggles with adherence Determined to switch to EHL product so I can treat weekly Team concerned because he is still having breakthrough bleeds (? adherence vs. pharmacokinetics) Half-life = 13.5 hours (on EHL product) Time to 5% = 40 hours Time to 2% = hours Time to 1% = 77 hours Based on WAPPS-Hemo data, needs every 72 hours dosing Extended dosing intervals are not a good option Focus efforts on improving and maintaining adherence 32-year-old man, severe hemophelia A Has only used prophylaxis for defined periods (e.g. after knee replacements), but now motivated by fewer bleeds and less pain during prophylaxis Apprehensive about maintaining adherence long-term Standard rfviii: EHL FVIII Product: Half-life = 17 hours Half-life = 22 hours Time to 5% = 59 hours Time to 5% = 97 hours Time to 2% = 81.5 hours Time to 2% = 132 hours Time to 1% = hours Time to 1% = 167 hours Start long-term prophylaxis with EHL product every 7 days Good adherence No documented bleeds in >12 months able, have clinically meaningful pharmacokinetic differences, and have more complex and varied dosing schedules. The EHL products are effective and safe, produce a high degree of patient satisfaction, and have improved adherence, compared with standard half-life products. They are a good choice for many, but not all patients. Variables that affect decision making to choose an EHL product compared with standard factor products include age, adherence, venous access, activity type and pattern, pharmacokinetics, bleeding phenotype, and joint status. The pharmacokinetics of factor replacement are crucial for designing an optimal prophylactic regimen which will ultimately improve outcomes while minimizing costs. As discussed previously, some patients will have very short half-lives for factors and others will metabolize them slower. Classic pharmacokinetic study design is to give a single dose of factor to a small number of subjects and obtain blood samples at multiple time points over 48 to 72 hours. The average values for the population are determined and applied to all subsequent populations. This approach is logistically difficult and there is a high-degree of inter-subject variability, but it is good for studying characteristics of a drug, but not good for tailoring treatment for specific patients. Population pharmacokinetic studies, which were first used in hemophilia in the mid-1980s, use a model based on combining data from many pharmacokinetic curves created by the use of classic sampling techniques. Robust population modeling allows for the accurate determination of the profile for individual patients with a small number of data points. 2,4 Computerized modeling programs can use one or three data points from an individual to predict that patient s elimination profile for personalizing factor replacement dosing intervals. The Web-Accessible Population Pharmacokinetic Service Hemophilia (www. wapps-hemo.org) is one example. This is a multi-center prospective project using a web-accessible platform developed and run by the Health Information Research Unit at McMaster University. The specific ob- 58 Journal of Managed Care Medicine Vol. 21, No. 4

59 jectives of this service are to collect individual classical pharmacokinetic data from independent investigators and factor concentrate manufacturers, create and make available population pharmacokinetic models for each factor concentrate, develop web-based application to use those models to calculate pharmacokinetic parameters for individual patients, and determine the potential value of this service for clinicians. 5 An option for improving care in inhibitor patients is now available. Emicizumab-kxwh (Hemlibra ) was FDA approved in November of 2107 for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A with factor VIII inhibitors. Emicizumab-kxwh is a bispecific humanized monoclonal antibody that restores the function of missing activated FVIII by bridging activated FIX and FX to facilitate effective hemostasis in patients with hemophilia A. 6 It has been studied in adults and children with and without inhibitors; thus, FDA approval for non-inhibitor hemophilia A patients is likely to occur in In a trial of emicizumab-kxwh prophylaxis versus no prophylaxis in 109 adult and adolescent males (aged 12 to 75 years) with hemophilia A with FVIII inhibitors, the annualized bleeding rate (ABR) requiring treatment with coagulation factors was 2.9 compared with 23.3 for patients not receiving prophylaxis corresponding to an 87 percent reduction in ABR. 7 In addition, improvements in patient-reported hemophilia-related symptoms and physical functioning in patients receiving emicizumab-kxwh prophylaxis were observed. Cases of thrombotic microangiopathy and thrombotic events were reported when a cumulative amount of >100 U/kg/24 hours of apcc was administered for 24 hours or more to patients receiving emicizumab-kxwh prophylaxis; the product labeling contains a boxed warning to monitor for these adverse events when apcc is administered. The recommended dose of emicizumab-kxwh is 3 mg/kg by subcutaneous injection once weekly for the first four weeks, followed by 1.5 mg/kg once weekly. Subcutaneous injection is an improvement over intravenous infusion of the factor products and should improve patient acceptance and adherence. This agent is the first viable therapy for those with hemophilia A and inhibitors. An Institute for Clinical and Economic Review (ICER) report concluded that emicizumab-kxwh is cost effective in the hemophilia A with inhibitors population, despite its price of $482,000 for the first year and $448,000 after that. 8 The agency estimated that the medication would reduce the health care budget in the U.S. by $720,000 per patient annually for children under the age of 12, and by $1.85 million a year for people over the age of 12. Additional options for treatment are under investigation. Fitusiran and at least three tissue factor pathway inhibitors (TFPIs) are also under study in hemophilia A and B, with and without inhibitors. Fitusiran lowers antithrombin levels, which inhibits blood clotting, while increasing production of thrombin to aid clotting. It would be used as prophylaxis and would likely be dosed monthly. TFPI binds to factor Xa and, in this combination, binds to and inhibits tissue factor/factor VIIa complex 2 and 3; blocking TFPI would aid coagulation. These agents likely will not reach the market until 2020 or later. Conclusion Aside from development of inhibitors, hemophilic arthropathy is currently the most significant complication of hemophilia. Strict adherence to long-term prophylaxis is the only way to prevent hemophilic arthropathy and its devastating consequences. New and emerging treatments are beginning to address many of the barriers to effective prophylaxis, and offer hope to those with inhibitors. Optimal use of these new treatments and tools for personalized prophylaxis has made clinical decision making much more complex. The resources and expertise necessary for optimal management of hemophilia in the current era do not exist outside of a hemophilia treatment center. Managed care should expect continued and substantial evolution in the management of hemophilia over the next several years. Mark T. Reding, MD, is an Associate Professor of Medicine in the Division of Hematology, Oncology, and Transplantation and Director, Center for Bleeding and Clotting Disorders at the University of Minnesota Medical Center in Minneapolis, MN. References 1. Mahdi AJ, Obaji SG, Collins PW. Role of enhanced half-life factor VIII and IX in the treatment of haemophilia. Br J Haematol. 2015;169(6): Morfini M. The history of clotting factor concentrates pharmacokinetics. J Clin Med. 2017;6(3). pii: E Hay CR, Palmer B, Chalmers E, et al. Incidence of factor VIII inhibitors throughout life in severe hemophilia A in the United Kingdom. Blood. 2011;117(23): Berntorp E. If you know you will also see: population pharmacokinetics is the way to personalize and optimize prophylaxis in hemophilia. J Thromb Haemost. 2017;15(6): Iorio A, Keepanasseril A, Foster G, et al. Development of a web-accessible population pharmacokinetic service-hemophilia (WAPPS-HEMO): study protocol. JMIR Res Protoc. 2016;5(4):e Scott LJ, Kim ES. Emicizumab-kxwh: First global approval. Drugs. 2018;78(2): Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med. 2017;377(9): Institute for Clinical and Economic Review. Hemophilia Final Evidence Report. Available at Hemophilia_Final_Evidence_Report_ pdf. Accessed 7/30/18. Vol. 21, No. 4 Journal of Managed Care Medicine 59

60 The Future Management of IPF: Advanced Diagnostic and Treatment Strategies Charles Vega, MD, FAAFP For a CME/CEU version of this article please go to and then click the activity title. Summary Idiopathic pulmonary fibrosis (IPF) is a rare, progressive, and fatal lung disease. Treatments which slow the progression of lung dysfunction are now available, and one of these can reduce mortality related to the disease. Lung transplant is the curative option for IPF. Key Points IPF is a progressive and fatal lung disease. Treating GERD is important in those with symptoms and IPF. Pirfenidone and nintedanib are effective and relatively safe agents. Pirfenidone can reduce mortality. Lung transplantation is a curative treatment. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS a progressive and fatal lung disease with inevitable loss of lung function. This is a very symptomatic disease that is scary and petrifying for patients. It can take six to 12 months to receive a diagnosis because the symptoms tend to be common to many different lung diseases. IPF has an estimated prevalence of 13 to 20 per 100,000 people worldwide. Approximately 100,000 people are affected in the United States (U.S.), and 30,000 to 40,000 new cases are diagnosed each year. 1 Patients may not have many symptoms early in the disease process and will just complain of being increasingly short of breath with minimal activity over time. Chronic obstructive pulmonary disease, asthma, and heart failure will typically be ruled out as the cause of shortness of breath before IPF is even thought about, which can lead to diagnosis delay. IPF can be suspected based on age and symptoms of dyspnea and cough. Patient history of smoking, chronic exposures, lung infections, and symptoms suggestive of other lung diseases can help rule out IPF. Physical examination is of limited utility in the diagnosis of IPF. Fine bibasilar inspiratory crackles (Velcro crackles) and clubbing of the digits (20 to 50% of patients) are the few physical clues. There is no strong evidence to support specific serological testing for IPF diagnosis including rheumatoid factor (RF) and antinuclear antibodies (ANA) to rule out autoimmune diseases and matrix metalloproteinase. Spirometry is useful for showing that the issue is definitely with the lungs. Chest X-rays and echocardiograms are not very helpful for diagnosing IPF, but they will help rule out heart failure. CT scan is especially useful in making the diagnosis. Interstitial lung disease on CT scan combined with age 70 and older has a 95 percent pretest positive predictive value for IPF. 2 Histopathology of lung biopsy specimens is the best way to diagnose IPF, but it may not be necessary in the situation where all the other evidence supports the IPF diagnosis. Video-assisted thoracic 60 Journal of Managed Care Medicine Vol. 21, No. 4

61 Exhibit 1: FVC Results from Pirfenidone ASCEND Trial FVC decline or death No change in FVC 0 Pirfenidone Placebo FVC = forced vital capacity surgery is preferred for obtaining specimens and multiple biopsy sites are preferred. 2 Histopathologically, IPF is demonstrated by honeycombing, fibrotic foci, and dense fibrosis. Unfortunately, significant rates of mortality can occur with lung biopsy. Risk factors for death include a nonelective procedure, male gender, and open surgery. 3 Because of the risk of a biopsy, it may not be necessary to make the diagnosis, but the implications of not having a tissuebased diagnosis to qualify for the various treatments will have to be considered. Recommended baseline testing in IPF includes spirometry, single breath diffusing capacity for carbon monoxide (DLCO), resting oxygen saturation, six-minute walk test distance, and oxygen saturation. 4 These tests should be repeated every six months to track the course of the disease. The natural history of IPF is variable. Classic life expectancy has been three to five years after diagnosis. Negative prognostic factors include age 70 years or more, pulmonary hypertension, concurrent coronary artery disease or gastroesophageal reflux disease (GERD), forced vital capacity (FVC) < 65 percent predicted, DLCO < 35 percent predicted, six-minute walk < 250 meters, hypoxemia, and usual interstitial pneumonia (UIP) pattern on CT scan. Management of comorbid illness is important in IPF. Pulmonary hypertension occurs in 30 to 50 percent of those with IPF. The selective endothelin receptor antagonist ambrisentan is not recommended for pulmonary hypertension treatment in IPF because it causes a twofold increase in mortality and acceleration of lung dysfunction. 5 Other FDA approved agents, including sildenafil, can be used to treat the pulmonary hypertension. Sildenafil has no impact on mortality, exacerbation, pulmonary testing, and exercise tolerance, but it can improve quality of life. Treating gastroesophageal reflux disease (GERD) is associated with positive outcomes and may reduce progressive decline in FVC. 6 Having a diagnosis of GERD increases risk of mortality and receiving acid suppression medication or having a Nissen fundoplication procedure reduces risk. 6 Several agents which have been used over the years to treat IPF are no longer recommended. Warfarin, prednisone, azathioprine, and N-acetyl cysteine (NAC) should also be avoided because of increased mortality risk. 5 Until clinicians and researchers better understand the pathophysiology of IPF it is hard to develop good targeted therapy. Activation of cell-signaling pathways through tyrosine kinases such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) has been implicated in the pathogenesis of the disease. Two agents specifically for IPF are now FDA approved (pirfenidone and nintedanib) and more are under development. Pirfenidone (Esbriet ) is an oral drug with antiinflammatory, anti-fibrotic, and antioxidant effects. It blocks PDGF and reduces fibroblast proliferation. The usual dose is 801 mg three times a day and costs approximately $12,000 per month. Clinical trials have shown lung function, mortality, and physical function (six-minute walk) benefit of pirfenidone with minimal adverse effects. 7,8 Exhibit 1 shows data on two of the outcomes measures in one trial. 7 In another trial, in the pirfenidone group, as com- Vol. 21, No. 4 Journal of Managed Care Medicine 61

62 Exhibit 2 FVC Benefits of Nintedanib 9 FVC decline Nintedanib Placebo FVC = forced vital capacity pared with the placebo group, there was a relative reduction of 47.9 percent in the proportion of patients who had an absolute decline of 10 percentage points or more in the percentage of the predicted FVC or who died. 8 There was also a relative increase of percent in the proportion of patients with no decline in FVC; a reduced decline in the sixminute walk distance, and improved progressionfree survival with pirfenidone treatment. 8 Combining the two Phase III trials, mortality due to IPF was reduced 68 percent with pirfenidone treatment, compared with placebo. The most common adverse effects of pirfenidone are nausea, dyspepsia, vomiting, anorexia, rash, photosensitivity, and dizziness. Increases in liver function tests can also occur and should be monitored for. Taking the medication with food can help prevent the gastrointestinal adverse effects. Overall, it is a well-tolerated agent. Nintedanib (Ofev ) is an oral tyrosine kinase inhibitor that targets VEGF, FGF, and PDGF. The usual dose is 150 mg twice a day, and the cost is approximately the same as pirfenidone. In a one-year trial comparing nintedanib to placebo, there was a 68.4 percent reduction in the rate of loss function as measured by FVC (Exhibit 2). 9 There was also a lower incidence of acute exacerbations compared with placebo (2.4 vs per 100 patient-years, P = 0.02) and a small improvement in quality of life with nintedanib treatment. 9 There were no significant mortality benefits in this trial. In two other one-year trials, there was a slowing in the FVC annual rate of change (~100 ml benefit). 10 One of the trials found a significant benefit in time to the first exacerbation, while there was no significant difference in the other trial. No benefit on quality of life or mortality were seen in these two trials. 10 Diarrhea, nausea, and vomiting are very common with nintedanib. Study withdrawal due to an adverse event occurred in 19 percent of those on nintedanib and 13 percent on placebo. Withdrawal specifically due to gastrointestinal issues was 7 percent versus 1 percent, respectively. Increased liver function tests (5% vs <1%) and heart attack (1.5% vs 0.5%) occurred more commonly in the nintedanib-treated patients. 10 The ultimate treatment for IPF is lung transplant. Clinicians should consider referral for transplant evaluation at the time of diagnosis. The Lung Allocation Score for selecting transplant recipients does prioritize IPF. In 2011, the average wait for a transplant for those with IPF was 2.1 months. 11 A retrospective cohort study of 4,134 patients with IPF who received a lung transplant found a 66.6 percent survival and 2.8 percent re-transplant rate over a median follow-up of two years. 12 A double-lung transplant is associated with better graft survival in patients with IPF than a single lung transplant. Conclusion Idiopathic pulmonary fibrosis is a devastating disease; however, there are oral treatments which can slow the progression of lung function decline and, for those who qualify, transplant can cure the disease. Early diagnosis is important for catching the disease when its natural history can be changed. Charles Vega, MD, FAAFP, is a Health Sciences Clinical Professor, UC Irvine Department of Family Medicine, Associate Dean 62 Journal of Managed Care Medicine Vol. 21, No. 4

63 for Diversity and Inclusion, UC Irvine School of Medicine and Executive Director, UC Irvine Program in Medical Education for the Latino Community, UC Irvine School of Medicine, Irvine, CA. References 1. U.S. National Library of Medicine. Genetics Home Reference. Idiopathic pulmonary fibrosis. Available at Accessed 7/21/ Martinez FJ, Chisholm A, Collard HR, et al. The diagnosis of idiopathic pulmonary fibrosis: current and future approaches. Lancet Respir Med. 2017;5(1): Hutchinson JP, Fogarty AW, McKeever TM, Hubbard RB. In -Hospital Mortality after Surgical Lung Biopsy for Interstitial Lung Disease in the United States to Am J Respir Crit Care Med. 2016;193(10): Meyer KC. Pulmonary fibrosis, part I: epidemiology, pathogenesis, and diagnosis. Expert Rev Respir Med. 2017;11(5): Raghu G, Rochwerg B, Zhang Y, et al. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline. Am J Respir Crit Care Med. 2015;192(2):e Lee JS, Collard HR, Anstrom KJ, et al. Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials. Lancet Respir Med. 2013;1(5): Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011;377(9779): King TE Jr, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22): Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 2011;365(12): Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22): Raghu G, Richeldi L. Current approaches to the management of idiopathic pulmonary fibrosis. Respir Med. 2017;129: Schaffer JM, Singh SK, Reitz BA, et al. Single- vs double-lung transplantation in patients with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis since the implementation of lung allocation based on medical need. JAMA. 2015;313(9): Certification Creates Confidence in nurses and their patients Certified Managed Care Nurses (CMCNs) have shown they ve got the skills to advocate for members and guide them through the care continuum. Does your staff have the know-how? Prove it to the world..org Vol. 21, No. 4 Journal of Managed Care Medicine 63

64 Payer Challenges and Issues in the Management of OAB: Improving Patient Outcomes with Optimal Cost and Treatment Strategies Craig V. Comiter, MD, PhD For a CME/CEU version of this article please go to and then click the activity title. Summary Overactive bladder (OAB) is a very common condition with significant health-related costs. There are effective treatments available, ranging from behavioral interventions for mild symptoms to surgery for uncontrolled symptoms. Each of the available treatments has advantages and disadvantages which must be considered in selecting therapy. Key Points Urgency, frequency, and urinary urge incontinence are the symptoms of OAB. Conditions and medications that mimic or worsen the syndrome need to be ruled out. Therapy includes behavioral interventions, pharmacotherapy, chemodenervation, neurostimulation, and surgery. Mirabegron is a good choice for many elderly patients because it causes fewer adverse effects while still being very efficacious. Neurostimulation is cost effective over time, compared to medication or chemodenervation. BLADDER EMPTYING SYNDROMES CAN be characterized as the inability to store urine appropriately or the inability to empty the bladder, which can be due to the bladder itself or the bladder outlet. Normal bladder storage is done at low pressure to keep the kidneys safe, with no unpleasant sensation or unstable contractions. Normal bladder emptying occurs when the detrusor muscle contracts and the external sphincter relaxes. Overactive bladder (OAB) is a bladder storage issue where the detrusor muscle contracts inappropriately in response to small volumes of urine. The OAB symptom complex is characterized by urgency, frequency, and a large amount of urinary leakage in patients who have episodes of urinary urge incontinence (UUI). An inability to store urine can be neurogenic, myogenic, or pelvic floor related. Reduction in peripheral or central neurologic inhibition, enhancement of excitatory transmission in the micturition reflex pathway, increased primary afferent input from the lower urinary tract, or emergence of bladder reflexes that are resistant to central inhibition are all neurogenic mechanisms of OAB. Suprapontine and spinal cord lesions are neurogenic causes of OAB. Myogenic mechanisms for OAB occur because of changes in electrical conductivity within the bladder muscles. Changes in the electric coupling between muscle cells may lead to uncontrolled spread of muscle contraction over the whole bladder (urgency, incontinence). Pelvic floor dysfunction contributes to OAB. Urgency and UUI occur due to combined defects in the bladder and pelvic floor. Patients with weak pelvic floor muscles cannot overcome the urgency by tightening the urinary sphincter. The overall prevalence of OAB is 16.6 percent and increases with age in both men and women (Exhibit 1). 1 The prevalence exceeds 30 percent among indi- 64 Journal of Managed Care Medicine Vol. 21, No. 4

65 Exhibit 1: Prevalence of OAB by Age 1 Prevalence (percent) Men Women 0 < Age (years) Exhibit 2: Costs Associated with OAB Comorbidities 4 $1,000 $900 Cost per Patient $800 $700 $600 $500 $400 $300 11,556 adult patients with OAB, 11,556 controls, matched on propensity score P < $200 $100 $0 Vulvovaginitis Skin infections Depression UTIs Falls and Fractures Overactive bladder Control viduals older than 65 years of age. The prevalence of OAB in men and women is surprisingly similar across age groups. However, in contrast to OAB without incontinence, OAB with incontinence is more common in women than in men at all ages, especially in the elderly. OAB is more common than hypertension, heart disease, asthma, or diabetes. 2 The total costs of OAB with UUI have been estimated to be $66 billion (2007). 3 This is projected to increase to $83 billion by The annual spending for patients with OAB is fivefold higher compared to patients without the condition. Among community residents, the majority of costs related to OAB are treatment and managing the health-related consequences. Exhibit 2 shows the costs of OAB comorbidities. 4 The initial evaluation of a patient with suspected OAB will include a patient history detailing the urinary complaints, duration of symptoms, most bothersome symptoms, triggering factors or events (cough, sneeze), and the irritants of the bladder or lifestyle that contribute to the problem. A voiding diary can be helpful in objectively documenting the number of episodes that occur daily. Other contributors to the bladder issues including medications, prior surgeries (spinal, pelvic), bowel disor- Vol. 21, No. 4 Journal of Managed Care Medicine 65

66 ders (irritable/inflammatory bowel syndrome), and dementia should be identified. Medications, which can contribute to lower urinary tract dysfunction, include diuretics, antidepressants, alpha-agonists, alpha-antagonists, beta blockers, sedatives, anticholinergics, and analgesics. Medications can impact fluid output, bladder contractility, and urinary outlet response. Effects of urinary issues on quality of life are very important to identify; incontinence has a major impact on social functioning. Beyond medications, various other diseases and conditions as a cause of the urinary symptoms need to be ruled out during the evaluation. Local pathology including infection, bladder stones, bladder tumors, interstitial cystitis, and outlet obstruction; metabolic factors including diabetes and polydipsia; pregnancy; and psychological factors can cause similar symptoms. Also, reversible causes of urinary incontinence, if it is present, must also be ruled out; these include delirium, infection, atrophic vaginitis, medications, benign prostatic hyperplasia, diabetes insipidus, restricted mobility, and stool impaction. Treatments for OAB, with and without incontinence, include behavior modification, pharmaceuticals, chemodenervation, neuromodulation, and surgery. Behavior modification can help patients overcome the urge to urinate. Fluid and dietary modifications, scheduled (timed) voiding, bladder retraining drills, and pelvic floor re-education and exercise can all be helpful and are typically the first step in treatment. The combination of behavioral modification and medications is more effective than either treatment alone. 5 Antimuscarinic agents (oxybutynin, tolterodine, trospium, solifenacin, darifenacin, and fesoterodine) have been the mainstay for treating OAB. OAB symptoms are relieved by antimuscarinic agents by inhibition of involuntary bladder contractions and increased bladder capacity. Treatment with these agents can be limited by side effects, such as dry mouth, constipation, and central nervous system (CNS) effects. Antimuscarinics have the potential to cause significant CNS impairment, including memory deficits which may be irreversible, sleep disruption, confusion, and hallucinations. The extent of CNS effects is determined by the integrity of the bloodbrain barrier (BBB), the drug s ability to cross the BBB, and the drug s ability to block M1 receptors in the brain. An older patient s underlying cardiac health also needs to be considered when selecting an agent for treating OAB. There are changes in cardiac function with age and decreased drug metabolism which can affect medication safety and efficacy. Polypharmacy is also common in the elderly, which increases the risk of drug-drug interactions. Antimuscarinic therapy may impact heart rate and QT interval. Clinical and electrocardiographic monitoring may be necessary in selected populations, such as patients aged > 80 years, and those with coronary heart disease or heart failure. Persistence with antimuscarinic therapy for OAB is not optimal. In one study, 18.2 percent of prescriptions for these agents were not filled at the time of initial prescribing. 6 In another claims- based trial, there was a 30.3 percent overall persistence rate. The rate is higher (35.2%) with extended-release products, compared with immediate-release products that have to be dosed more frequently (23.5%). 7 Another trial in a Medicaid population found that only 32 percent of those taking oxybutynin immediate release and 44 percent of those taking either tolterodine or oxybutynin extended release remained adherent past 30 days. 8 Of those remaining on medication after 30 days, the risk of nonadherence was higher for oxybutynin ER than for tolterodine ER. 7 It is not known if lack of efficacy or adverse effects led to the low persistence rates in these trials. These findings highlight the need for medication counseling by health care providers about how to manage adverse effects, what kind of efficacy to expect, and when to expect the onset of efficacy. Mirabegron (Myrbetriq ) is a selective beta-3 adrenoceptor agonist that activates beta-3 adrenoceptors on the detrusor muscle of the bladder to facilitate filling of the bladder and improved storage. In a review of 44 trials of antimuscarinic agents and mirabegron, mirabegron 50 mg was as efficacious as antimuscarinics with respect to reducing frequency and UUI. 9,10 The exception was solifenacin 10 mg, which is more efficacious than mirabegron 50 mg. Mirabegron has a different adverse effect profile than antimuscarinic therapy. It causes dry mouth at a rate similar to placebo and significantly lower than all antimuscarinics. This agent does not have anticholinergic activity and thus is unlikely to cause constipation or CNS adverse effects. There are no clinically significant effects on blood pressure or heart rate at therapeutic doses amongst patients 65 years and older. 11 In a prospective, randomized trial comparing mirabegron and solifenacin, the 12-month persistence rate was 12.2 percent in the mirabegron group versus 20.1 percent in the solifenacin group, which was reported as not statistically significantly different. 12 Discontinuation due to side-effects was significantly more frequent in the solifenacin group than the mirabegron group (27.3 vs. 7.9%, P < 0.05). In contrast, discontinuation due to lack of efficacy was 66 Journal of Managed Care Medicine Vol. 21, No. 4

67 significantly more frequent in the mirabegron group than the solifenacin group (36.8 vs. 5.6%, P < 0.05). In a Markov state-transition model of cost effectiveness for U.S. commercial health plans and Medicare Advantage, mirabegron was the most clinically effective, whereas oxybutynin had the least expensive acquisition cost. Mirabegron was the most costeffective pharmacologic treatment for OAB from U.S. commercial health plan and Medicare perspectives because of fewer adverse effects, comorbidities, and better persistence. Tolterodine immediate release was also on the cost-effectiveness frontier. Costs per quality of life year (QALY) were $59,690 for mirabegron and $66,347 for tolterodine. Other antimuscarinics were less cost effective, compared to tolterodine and mirabegron. Chemodenervation with botulinum toxin injection into the bladder muscle is another treatment option. It works by inhibiting neurotransmitter release from efferent and afferent nerve terminals and inhibition of ATP, neurotrophins, and nitric oxide from the urothelium. 14 Botulinum toxin is given as 30 one milliliter injections of onabotulinumtoxina spread approximately 1 cm apart around the urothelium into the detrusor muscle. This treatment reduces UUI episodes by 35.9 percent, micturition episodes by 17.3 percent, urgency by 27.2 percent, and nocturia by 18.4 percent. 15,16 Thirty percent of patients in the trials actually had a 100 percent response. The beneficial effects on OAB wear off after about six months and treatment has to be repeated. A risk of this treatment is urinary retention; however, the risk is acceptably low (6.5%). Botox is cost effective in patients with UUI who are refractory to anticholinergic agents. 17 When medication and behavioral interventions fail, neuromodulation is another treatment option. With neuromodulation, electrical stimulation is used to target specific nerves that control bladder functions. The mechanism of action is not completely understood but may be a direct effect on the bladder or a central effect on micturition centers of brain. 18 Neurostimulation of the sacral, tibial, and pudendal nerve has been shown to have a longterm, sustained effect on OAB symptoms. With sacral nerve stimulation (SNS), 50 to 60 percent of patients will have a greater than 50 percent improvement in UUI and 40 to 50 percent will have greater than 50 percent improvement in frequency. 19 Because the stimulator is permanently implanted, surgical adverse effects including lead migration (3.4%), infection (3.4%); and need for re-operation (3.9%) can occur. Posterior tibial nerve stimulation (PTNS) is less invasive than SNS because the stimulator is not permanently implanted, but it is less effective than SNS. PTNS sessions are conducted in the physician s office for 30 minutes once a week for 10 to 12 weeks. How often to repeat the procedure is unknown; however, a 14-week tapering protocol (every 2 weeks for 2 treatments, then every 3 weeks times 2, and every 4 weeks times 1) and then giving treatment as needed to control symptoms was used in one published clinical trial. 20 Overall, 77 percent of subjects in this trial had moderate to marked subjective improvement. 20 When comparing neurostimulation to medications, SNS is more effective (subjective response 86 % vs 44%, objective response 61% vs 42%) and safer (27.3% vs 30% with adverse effects). 21 PTNS is equally effective objectively to tolterodine, but it was rated as more effective by patients with a similar rate of adverse effects. 22 Cost benefit analyses of SNS have been done. In a trial of 65 patients receiving SNS, outpatient visits for urinary symptoms decreased over the 12 months after placement, with a 73 percent reduction in average yearly office visit expenses. 23 There was a 92 percent reduction in diagnostic and therapeutic procedures ($733 to $59) and a 30 percent decrease in drug costs ($693 to $483). Thus post SNM, voiding-related health care costs are reduced. In a Canadian analysis, there was a significant increase in QALY for SNS, compared to Botox or medications. 24 SNS was also less costly over time than either Botox or medications. The difference in the cost of SNS compared to Botox was more expensive at year one ($7,237) because of the upfront surgical costs but was less expensive by $9,402 by year ten. Compared to medications, SNS cost $8,878 more in year one, but was $11,447 less by year ten. This analysis concluded that SNM was cost effective in refractory OAB, compared to Botox or medications. A UK study found SNM cost effective, compared to Botox by year four of treatment. 25 A treatment of last resort is enterocystoplasty or bladder augmentation. With this procedure, a piece of the bowel is used to enlarge the size of the bladder. There is about a 15 percent risk of retention after this procedure because the original continuous nature of the bladder muscle is interrupted. Surgery would be indicated when all other treatment options have been exhausted or the patient has major health issues related to incontinence, such as skin breakdown or ulcers. Conclusion Behavior modification, medications, chemodenervation, neuromodulation, and surgery are all effective in treating OAB. Each has advantages and disadvantages which must be considered when se- Vol. 21, No. 4 Journal of Managed Care Medicine 67

68 lecting therapy. The typical path is to start with behavior modification, with or without medications, and then move to more aggressive therapy if that fails. Mirabegron is a good choice for many elderly patients because it causes fewer adverse effects, while still being very efficacious. Craig V. Comiter, MD, PhD, is an Associate Professor in the Department of Urology and the Department of Obstetrics and Gynecology at Stanford University School of Medicine, Stanford, CA. References 1. Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003;20: Adams PF, Hendershot GE, Marano MA. Current estimates from the National Health Interview Survey, National Center for Health Statistics. Vital Health Statistics ; No. 200: Coyne KS, Wein A, Nicholson S, et al. Economic burden of urgency urinary incontinence in the United States: a systematic review. J Manag Care Pharm. 2014;20(2): Darkow T, Fontes CL, Williamson TE. Costs associated with the management of overactive bladder and related comorbidities. Pharmacotherapy. 2005;25(4): Burgio KL, Locher JL, Goode PS. Combined behavioral and drug therapy for urge incontinence in older women. J Am Geriatr Soc. 2000;48(4): Rashid N, Vassilakis M, Lin KJ, et al. Primary Nonadherence to Overactive Bladder Medications in an Integrated Managed Care Health Care System. J Manag Care Spec Pharm. 2017;23(4): D Souza AO, Smith MJ, Miller LA, et al. Persistence, adherence, and switch rates among extended-release and immediate-release overactive bladder medications in a regional managed care plan. J Manag Care Pharm. 2008;14(3): Shaya FT, Blume S, Gu A, et al. Persistence with overactive bladder pharmacotherapy in a Medicaid population. Am J Manag Care Jul;11(4 Suppl):S Maman K, Aballea S, Nazir J, et al. Comparative efficacy and safety of medical treatments for the management of overactive bladder: a systematic literature review and mixed treatment comparison. Eur Urol. 2014;65(4): Thiagamoorthy G, Kotes S, Zacchè M, Cardozo L. The efficacy and tolerability of mirabegron, a β3 adrenoceptor agonist, in patients with symptoms of overactive bladder. Ther Adv Urol. 2016;8(1): Wagg A, Nitti VW, Kelleher C, et al. Oral pharmacotherapy for overactive bladder in older patients: mirabegron as a potential alternative to antimuscarinics. Curr Med Res Opin. 2016;32(4): Kinjo M, Sekiguchi Y, Yoshimura Y, Nutahara K Long-term persistence with mirabegron versus solifenacin in women with overactive bladder: prospective, randomized trial. Low Urin Tract Symptoms. 2018;10(2): Wielage RC, Perk S, Campbell NL, et al. Mirabegron for the treatment of overactive bladder: cost-effectiveness from U.S. commercial health-plan and Medicare Advantage perspectives. J Med Econ. 2016;19(12): Smith CP, Gangitano DA, Munoz A, et al. Botulinum toxin type A normalizes alterations in urothelial ATP and NO release induced by chronic spinal cord injury. Neurochem Int. 2008;52(6): Nitti VW, Dmochowski R, Herschorn S, et al. Onabotulinum toxin A for the treatment of patients with overactive bladder and urinary incontinence: results of a phase 3, randomized, placebo controlled trial. J Urol. 2013;189(6): Chapple C, Sievert KD, MacDiarmid S, et al. Onabotulinum toxin A 100 U significantly improves all idiopathic overactive bladder symptoms and quality of life in patients with overactive bladder and urinary incontinence: a randomised, double-blind, placebo-controlled trial. Eur Urol. 2013;64(2): Carlson JJ, Hansen RN, Dmochowski RR, et al. Estimating the cost-effectiveness of onabotulinum toxin A for neurogenic detrusor overactivity in the United States. Clin Ther. 2013;35(4): van der Pal F, Heesakkers JP, Bemelmans BL. Current opinion on the working mechanisms of neuromodulation in the treatment of lower urinary tract dysfunction. Curr Opin Urol. 2006;16(4): Siddiqui NY, Wu JM, Amundsen CL. Efficacy and adverse events of sacral nerve stimulation for overactive bladder: A systematic review. Neurourol Urodyn. 2010;29 Suppl 1:S Peters KM, Carrico DJ, Wooldridge LS, et al. Percutaneous tibial nerve stimulation for the long-term treatment of overactive bladder: 3-year results of the STEP study. J Urol. 2013;189(6): Siegel S, Noblett K, Mangel J, et al. Results of a prospective, randomized, multicenter study evaluating sacral neuromodulation with InterStim therapy compared to standard medical therapy at 6-months in subjects with mild symptoms of overactive bladder. Neurourol Urodyn. 2015;34(3): Peters KM, Macdiarmid SA, Wooldridge LS, et al. Randomized trial of percutaneous tibial nerve stimulation versus extended-release tolterodine: results from the overactive bladder innovative therapy trial. J Urol. 2009;182(3): Aboseif SR, Kim DH, Rieder JM, et al. Sacral neuromodulation: cost considerations and clinical benefits. Urology. 2007;70(6): Hassouna MM, Sadri H. Economic evaluation of sacral neuromodulation in overactive bladder: A Canadian perspective. Can Urol Assoc J. 2015;9(7-8): Leong RK, de Wachter SG, Joore MA, van Kerrebroeck PE. Cost-effectiveness analysis of sacral neuromodulation and botulinum toxin A treatment for patients with idiopathic overactive bladder. BJU Int. 2011;108(4): Journal of Managed Care Medicine Vol. 21, No. 4

69 New Developments in the Diagnosis and Treatment of Psoriatic Arthritis Atul A. Deodhar, MD, MRCP, FACP, FACR For a CME/CEU version of this article please go to and then click the activity title. Summary Psoriatic arthritis is a complex autoimmune disease which can be disabling due to joint damage and pain, but it can effectively be treated with biologics. The biologic agents reduce symptoms, inhibit joint damage, and improve quality of life. Key Points Psoriatic arthritis occurs in approximately 30 percent of patients with psoriasis. It is underdiagnosed. Early diagnosis and effective treatment is critical to minimize poor outcomes. Biologic therapies benefit all clinical domains and inhibit progressive structural damage. TNF inhibitors, IL-17/23 inhibitors, and tofacitinib produce a 20 percent response in about 60 percent of patients. PSORIATIC DISEASE IS A COMPLEX, POLYgenic immune-mediated disease with diverse clinical features. It is not just skin manifestations of psoriasis or joint damage and pain of psoriatic arthritis. Psoriatic disease includes a myriad of other conditions, including uveitis, cardiovascular and other vascular diseases, inflammatory bowel disease, obesity, depression, and fibromyalgia (Exhibit 1). Various cardiovascular risk factors (hypertension, hyperlipidemia, heart failure, type 2 diabetes mellitus, peripheral vascular disease, and cerebrovascular disease) are found more often in those with psoriatic disease, compared to a general population. Cardiovascular risk reduction is important in those with psoriatic disease, but it is not always considered by those providing care for these patients. The focus of this article is psoriatic arthritis (PsA). There are hundreds of types of arthritis which manifest as joint aches and pains, but only some types are inflammatory arthritis, like PsA. The diagnosis of PsA is based on history, physical exam, and x- ray features. There are no laboratory tests that can diagnose PsA. Rheumatoid factor (RF) is usually negative and, if positive, the titer is usually low, unlike rheumatoid arthritis where it is typically high. RF negativity can be used to rule out rheumatoid arthritis. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) may be variably elevated. Not every arthritis in patients with psoriasis is PsA; osteoarthritis, gout, rheumatoid arthritis, and septic arthritis have to be ruled out. Although there is no widely accepted classification or diagnostic criteria, the CASPER classification criteria are the most commonly used (Exhibit 2). 1 PsA-associated nail changes considered in the criteria include crumbling nails, onycholysis (separation of nail from nail bed), onchorrhexis (ridges and splitting), splinter hemorrhages under nails, and subungual hyperkeratosis (keratin build up between the nail and nail bed).these criteria have a specificity of 98.7 percent and sensitivity of 91.4 percent. PsA is a peripheral spondyloarthritis; spondyloarthritis is an umbrella term for inflammatory diseases that involve both the joints and the entheses (the sites where the ligaments and tendons attach to the bones). 2 PsA typically affects the ankles, knees, fingers, toes, and lower back. A patient with PsA can have many different manifestations of the disease at Vol. 21, No. 4 Journal of Managed Care Medicine 69

70 Exhibit 1: Concept of Psoriatic Disease Psoriasis Depression Fibromyalgia Cardiovascular and metabolic disease Psoriatic Disease Uveitis Inflammatory bowel disease Obesity Psoriatic Arthritis Exhibit 2: Classification Criteria for PsA (CASPAR) 1 1. Psoriasis 2. Nail changes 3. A negative test for RF Established inflammatory musculoskeletal disease (joint, spine, or entheseal) with 3 or more of the following (a) Current* (b) History (c) Family history Psoriatic skin or scalp disease present today as judged by a qualified health professional A history of psoriasis that may be obtained from patient, or qualified health professional A history of psoriasis in a first or second degree relative according to patient report Typical psoriatic nail dystrophy including onycholysis, pitting and hyperkeratosis observed on current physical examination By any method except latex but preferably by ELISA or nephlemetry, according to the local laboratory reference range 4. Dactylitis (a) Current* (b) History 5. Radiological evidence of juxta-articular new bone formation Swelling of an entire digit A history of dactylitis recorded by a qualified health professional Ill-defined ossification near joint margins (but excluding osteophyte formation) on plain xrays of hand or foot *Current psoriasis awarded 2 points the same time in their hands synovitis, dactylitis, ankylosis, and mutilans. PsA not only causes bone damage, but it also causes new bone formation. The radiographic features of PsA are juxta-articular periostitis and ankylosis and joint osteolysis. The prevalence of PsA in the United States (U.S) is 3 percent, with approximately 2.3 million people affected. 3,4 It occurs in about 30 percent of people who have psoriasis. The onset of PsA is typically between 30 and 50 years of age. Psoriasis precedes PsA by 10 years in 85 percent of patients, but PsA can also precede psoriasis in 10 percent by 10 to 15 years, or both PsA and psoriasis can start together in 5 percent of patients. Unfortunately, many cases of PsA are missed by primary care providers and dermatologists. There 70 Journal of Managed Care Medicine Vol. 21, No. 4

71 Exhibit 3: Psoriatic Arthritis Treatment Recommendations 12 Which domains are involved? Peripheral Arthritis Axial Disease Enthesitis Dactylitis Skin Nails Assess activity, impact and prognostic factors NSAIDs and IAI corticosteroids as indicated DMARDs (SSZ, LFN), TNFi or PDE4i Biologics (TNFi, IL12/23i IL17i) or PDE4i Switch biologic (TNFi, IL12/23i or IL17i) Physiotherapy and NSAIDs NSAIDs only TNFi, IL17i or IL12/23i Switch biologic (TNFi, IL17i or IL12/23i) Physiotherapy NASIDs Biologics (TNFi IL12/23i, IL17i) or PDE4i Switch biologic (TNFi, IL12/23i, IL17i) or PDE4i Dactylitis Corticosteroid injections as indicated NASIDs DMARDs (LEF, SSZ) or PDE4i Biologics (TNFi, IL12/23i) Switch biologic (TNFi, IL12/23i, IL17i) or PDE4i Topicals as indicated Topicals (keratolytics, steroids, vit. D analogues, emollients, calcineurin i) Phototx or DMARDs (MTX, CSA, acitretin, fumaric acid esters) or PDE4i Biologics (TNFi, IL12/23i, IL17i) or PDE4i Topical or procedural or DMARDs (CSA, LEF, MTX, acitretin) Biologics (TNFi, IL12/23i, IL17i) or PDE4i Switch biologic (TNFi, IL12/23i, IL17i) or PDE4i Switch biologics (TNFi, IL12/23i, IL17i) or PDE4i Standard therapeutic route Expedited therapeutic route NSAID = nonsteroidal antiinflammatory IAI = intra-articular injection DMARD = disease modifying anti-rheumatic drug SSZ = sulphasalazine LFN = leflunomide TNFi = Tumor necrosis factor inhibitor IL = interleukin PDE4i = phosphodiesterase type 4 inhibitor CSA = cyclosporin A are various tools for screening for psoriatic arthritis among patients with psoriasis which should be incorporated into routine care of these patients. These include the Psoriasis and Arthritis Questionnaire (PAQ), the Swedish modification of PAQ, the Psoriasis Epidemiology Screening Tool (PEST), Psoriatic Arthritis Screening Questionnaire (PASQ) and the Psoriatic Arthritis Screening and Evaluation (PASE) questionnaire. 5-9 There is only one tool designed to screen for psoriatic arthritis among individuals with and without psoriasis - the Toronto Psoriatic Arthritis Screen (ToPAS). 10 The inciting event that starts the psoriatic disease process in those who are genetically predisposed is unknown, but it may be trauma or infection. Overall, there is dysregulation of the innate immune system in psoriatic disease. 11 Activated T cells infiltrate the dermal papillae of the skin and the sublining layer of the joint synovium, as well as the entheseal insertion. Dendritic cells, macrophages, and B cells are also involved and generate a number of proinflammatory cytokines. Key cytokines in psoriatic disease pathophysiology include Janus kinases and signal transducers and activators of transcription (JAK-STATs), tumor necrosis factor (TNF), interferon-γ, and interleukin (IL)-1, IL-6, IL-12, IL-17, IL-22, and IL-23. Biologic agents targeting some of these key cytokines have been developed to treat psoriatic disease. The pharmacologic treatment of PsA includes Vol. 21, No. 4 Journal of Managed Care Medicine 71

72 Exhibit 4: IL-23/IL-17 Inhibitors in Psoriatic Disease Ustekinumab Guselkumab, Tildrakizumab IL-23 IL-6 IL-1 TNF TGFβ Psoriatic Disease TH17 IL-17R IL-17A Brodalumab Secukinumab Ixekizumab IL-22 IFN-γ NSAIDs, corticosteroids (occasionally), diseasemodifying antirheumatic drugs (DMARDs), and biologics. Exhibit 3 presents the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations based on the disease presentation. 12 For patients with moderate to severe disease, an expedited therapeutic route is advocated by this group where the initial step of NSAIDS is skipped and therapy is started with a DMARD or a biologic. It is important to note that methotrexate does not work as a DMARD in PsA, unlike in rheumatoid arthritis. 13 Although it can benefit synovitis in PsA, methotrexate is not effective for enthesitis or dactylitis. Patients should not be required to step through treatment with methotrexate before moving on to a biologic. Biologics approved for treating PsA include the TNF inhibitors (adalimumab, certolizumab, etanercept, infliximab, and golimumab), IL-17 inhibitors (secukinumab, ixekizumab), IL-17 receptor blockers (brodalumab), and IL-23 inhibitors (ustekinumab, guselkumab). With TNF inhibitor therapy, 60 percent of patients have a 20 percent improvement in symptoms (ACR20). This class of agents improves enthesitis by 60 to 75 percent and dactylitis by 60 percent, which is very important for maintaining hand function. They also improve functional ability, quality of life, and fatigue. 14,15 In rheumatoid arthritis, TNF inhibitors reduce the rate of ischemic heart disease; this benefit has not yet been shown in PsA treatment. Exhibit 4 shows where the IL-23/IL-17 pathway inhibitors work. Tildrakizumab (Ilumya) is the most recently approved biologic for psoriasis, but it is not yet approved for PsA. In addition to IL-23, ustekinumab also inhibits IL-12. About 50 percent of patients treated with this agent will have ACR20 response. 16 Secukinumab treatment achieves an ACR20 response in 55 percent of patients who are TNF inhibitor naive. 17 Both secukinumab and ustekinumab have lower response rates in those who have previously failed on a TNF inhibitor. Eighty to 90 percent of enthesitis and dactylitis is resolved at one year of secukinumab therapy. 17 It also prevents bone damage. Ixekizumab produces an ACR20 response rate in 60 percent of patients. 18 Overall, the IL-17A inhibitors appear to be as effective as the TNF inhibitors. Guselkumab, a fully human monoclonal antibody targeting the p19 subunit of ll-23, specifically inhibits IL-23, and also produces an ACR20 response in about 60 percent of patients. 19 This agent is very effective in clearing psoriasis, with 40 percent of patients having a 100 percent clearance. 72 Journal of Managed Care Medicine Vol. 21, No. 4

73 Two small molecule agents are also available for treating PsA apremilast and tofacitinib. Apremilast is an oral PDE4 inhibitor that modulates the production of pro-inflammatory and anti-inflammatory mediators. About 45 percent of patients with PsA will achieve ACR20 within 24 weeks. 20 In those patients who do well on apremilast, the benefits seem to continue to get better over a year of treatment. In initial responders, 60 percent will have a 20 percent response at one year. Apremilast is a fairly well-tolerated agent. Tofacitinib is an oral JAK inhibitor which is FDA approved for PsA treatment. It is indicated for adults with active psoriatic arthritis in whom methotrexate or other similar DMARDs did not work well. An ACR20 response occurs in about 60 percent of patients. 21 Comparing the biologics and small molecules directly is difficult because there are few head-to head-studies. It does appear that all agents, except apremilast, are similar in efficacy in achieving ACR20 responses. There are several unanswered questions in treating PsA. Research is needed to develop a way to identify which psoriasis patients are at risk for PsA. In addition, research is also needed to determine the efficacy and safety of combination therapies in PsA, and to determine if the treatment of PsA lessens the prevalence of cardiovascular disease, diabetes and hypertension. There are also numerous therapies targeting additional cytokines on the horizon. Many of these will likely make it to market in the next five to 10 years. Conclusion Psoriatic arthritis is a unique inflammatory arthritis that occurs in approximately 30 percent of patients with psoriasis, and it remains underdiagnosed. The clinical features are diverse; however, early diagnosis and effective treatment are critical to minimize poor outcomes. Biologic therapies can benefit all clinical domains and inhibit progressive structural damage. Several new therapies are on the horizon. Atul A. Deodhar, MD, MRCP, FACP, FACR, is a Professor of Medicine in the Division of Arthritis and Rheumatic Diseases at the Oregon Health and Science University in Portland, OR. References 1. Taylor W, Gladman D, Helliwell P, et al. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum. 2006;54(8): Raychaudhuri S, Deodhar A. The classification and diagnostic criteria of ankylosing spondylitis. J Autoimmun. 2014;48-49: Kurd SK, Gelfand JM. The prevalence of previously diagnosed and undiagnosed psoriasis in U.S. adults: results from NHANES J Am Acad Dermatol. 2009;60(2): Gladman DD. Psoriatic arthritis from Wright s era until today. J Rheumatol Suppl. 2009;83: Peloso PM, Hull P, Behl M, Reeder B. The psoriasis and arthritis questionnaire (PAQ) in detection of arthritis among patients with psoriasis Arthritis Rheum 1997;40(Suppl 9):S Alenius GM, Stenberg B, Stenlund H, et al. Inflammatory joint manifestations are prevalent in psoriasis: prevalence study of joint and axial involvement in psoriatic patients, and evaluation of a psoriatic and arthritic questionnaire. J Rheumatol. 2002;29(12): Ibrahim GH, Buch MH, Lawson C, et al. Evaluation of an existing screening tool for psoriatic arthritis in people with psoriasis and the development of a new instrument: the Psoriasis Epidemiology Screening Tool (PEST) questionnaire. Clin Exp Rheumatol. 2009;27(3): Khraishi M, Mong J, Mugford G, Landells I. The electronic Psoriasis and Arthritis Screening Questionnaire (epasq): a sensitive and specific tool to diagnose psoriatic arthritis patients. J Cutan Med Surg May-Jun;15(3): Husni ME, Meyer KH, Cohen DS, Mody E, Qureshi AA. The PASE questionnaire: pilot testing a psoriatic arthritis screening and evaluation tool. J Am Acad Dermatol 2007;57: Gladman DD, Schentag CT, Tom BD, et al. Development and initial validation of a screening questionnaire for psoriatic arthritis: the Toronto Psoriatic Arthritis Screen (ToPAS). Ann Rheum Dis. 2009;68(4): Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009;361(5): Coates LC, Kavanaugh A, Mease PJ, et al. Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2015 Treatment Recommendations for Psoriatic Arthritis. Arthritis Rheumatol. 2016;68(5): Kingsley GH, Kowalczyk A, Taylor H, et al. A randomized placebo-controlled trial of methotrexate in psoriatic arthritis. Rheumatology (Oxford). 2012;51(8): Mease PJ. Psoriatic arthritis: update on pathophysiology, assessment and management. Ann Rheum Dis. 2011;70 Suppl 1:i Lemos LL, de Oliveira Costa J, Almeida AM, et al. Treatment of psoriatic arthritis with anti-tnf agents: a systematic review and meta-analysis of efficacy, effectiveness and safety. Rheumatol Int. 2014;34(10): McInnes IB, Mease PJ, Kirkham B, et al. Secukinumab, a human anti-interleukin-17a monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;386(9999): Mease PJ, McInnes IB, Kirkham B, et al. Secukinumab Inhibition of interleukin-17a in patients with psoriatic arthritis. N Engl J Med. 2015;373(14): Gottlieb AB, Strand V, Kishimoto M3, et al. Ixekizumab improves patient-reported outcomes up to 52 weeks in bdmard-naïve patients with active psoriatic arthritis (SPIRIT-P1). Rheumatology (Oxford) Jun Deodhar A, Gottlieb AB, Boehncke WH, et al. Efficacy and safety of guselkumab in patients with active psoriatic arthritis: a randomised, double-blind, placebo-controlled, phase 2 study. Lancet ;391(10136): Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis. 2014;73(6): Gladman D, Rigby W, Azevedo VF, et al. Tofacitinib for psoriatic arthritis in patients with an inadequate response to TNF inhibitors. N Engl J Med. 2017;377(16): Vol. 21, No. 4 Journal of Managed Care Medicine 73

74 Optimizing Treatment Strategies in the Management of Rheumatoid Arthritis: Novel Therapies for Improved Patient Outcomes Maureen A. McMahon, MD For a CME/CEU version of this article please go to and then click the activity title. Summary Biologics and small molecule therapies are significantly improving the outcomes of rheumatoid arthritis. These agents are typically started as second-line therapy after methotrexate has produced an insufficient response. Treating to target is the best way to maximize outcomes in RA. Key Points RA commonly leads to deformity/disability, thus it needs to be treated early and effectively. Validated disease activity measurements can guide therapy to achieve low disease activity or remission more often. Patient preferences and values need to be considered in making treatment decisions and setting targets. Traditional DMARDs, biologics, and small molecules all reduce the joint complications of RA. Compliance, individualized regimens, and effective patient-doctor relationships are key to the best outcomes. RHEUMATOID ARTHRITIS (RA) IS A SYStemic inflammatory autoimmune disease. Over time, the inflammation associated with rheumatoid arthritis can cause bone erosion, joint deformity, and cardiovascular disease. The key features for diagnosis are symptoms of greater than a six-week duration, morning stiffness for over one hour, and fatigue. Signs include inflammatory synovitis and symmetrical and polyarticular (>3 joints) impact. RA typically involves wrists and metacarpophalangeal and proximal interphalangeal joints, but it spares thoracolumbar spine and distal interphalangeal joints of the fingers and interphalangeal joints of the toes. RA can have a self-limited, minimally progressive, or progressive course. 1 For the majority of patients, the disease is aggressively progressive. The typical course in the pre-biologic era was early joint damage in most patients and early death. In one study in patients with recent-onset RA (symptoms for <1 year), 19 percent had radiographic erosions, 97 percent had MRI-proven synovitis, and 68 percent had MRI-proven bone edema, a sign of early damage. 2 Fifty percent of patients had joint space narrowing or erosions within the first two years of the disease. By 10 years, 50 percent of young working patients were disabled. Compared to a general population, women lost 10 years of life and men four years from RA and related systemic inflammatory disease. The important point is that joint damage starts at the very beginning of the disease; therefore, early diagnosis and treatment is important to 74 Journal of Managed Care Medicine Vol. 21, No. 4

75 Exhibit 1: 2010 ACR/EULAR RA Classification Criteria RA Classification Criteria > 1 joint with synovitis (excluding the DIP, first MTP, and first CMC joints) Absense of alternative diagnosis that better explains synovitis Achievement of total score of > 6 (of 10) from individual scores in 4 domains Joint involvement patterns Serologic abnormality Elevated acute-phase response Symptom duration Swollen/Tender Joints (0-5) 1 large joint large joints small joints small joints 3 > 10 joints (> 1 small joint) 5 Serology (0.3) Negative RF AND ACPA 0 Low-positive RF OR ACPA 2 High-positive RF OR ACPA 3 Symptom Duration (0.1) < 6 weeks 0 > 6 weeks 1 Acute-phase Reactants (0-1) Normal CRP AND normal ESR 0 Abnormal CRP AND abnormal ESR 1 Patients with a score of 6 have definite RA DIP = distal interphalangeal joint MTP = metatarsophalangeal; CMC = carpometacarpal interrupt this process and prevent permanent damage. Exhibit 1 shows the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) RA classification criteria. 3 It is possible to predict which patients are going to have an aggressive disease course and thus target them for more aggressive therapy. A patient is identified as having a poor prognosis when at least one of the following features is present: functional limitation, bony erosions by radiograph, extra-articular disease (e.g., presence of rheumatoid nodules, vasculitis, Felty s syndrome), or positive rheumatoid factor (RF) or anti-cyclic citrullinated peptide (anti- CCP) antibodies. 4,5 An additional prognostic factor for early, erosive RA includes very high levels of inflammatory markers, such as ESR and C-reactive protein. Smoking also increases the risk of erosive disease and anti-ccp antibodies in RA. Genetics play a role in developing RA and in RA prognosis. When patients have a Shared Epitope- Human Leukocyte Antigen Class II, they have a high predominance for more aggressive RA. A large percentage of patients (80% 90%) with IgG anticitrullinated protein antibodies (ACPAs) express the shared epitope. 6 The anti-ccp test has high sensitivity, comparable with that of RF (80%), with superior specificity (98%) for RA. ACPAs are rare in healthy individuals and in other conditions. 7 ACPAs are being used for the diagnosis of RA, to predict prognosis, and may be used in the future to help determine the best therapy. Exhibit 2 shows some of the pros and cons of using ACPAs. 8 There are other biomarkers that are starting to be used for prognosis and treatment prediction. A multi-biomarker disease activity (MBDA) panel has been used to predict radiographic progression in early disease. 9 This panel measures many markers known to be involved in RA pathophysiology. This panel is also being investigated for therapy selection; patients who score low on the MBDA panel typically do well on methotrexate, and those who score high will likely need a biologic agent. As an autoimmune disease, both B cells and T cells and the autoantibodies and inflammatory cytokines respectively derived from their activity are involved in RA pathophysiology. 10 Therapy for RA has evolved from simply symptomatic treatment with anti-inflammatories to targeting the underlying pathophysiology with disease-modifying antirheumatic drugs (DMARDs), which include standard DMARDS (methotrexate, sulfasalazine, hydroxychloroquine, leflunomide), biologics, and small molecules. Therapy goals now are to have a low or no evidence of disease activity level. Treat to Vol. 21, No. 4 Journal of Managed Care Medicine 75

76 Exhibit 2: Can ACPA be used to Help Us Manage Our Patients? 8 PRE-CLINICAL AND DIAGNOSIS PROGNOSIS PROS ACPA undergo to Fc fragment glycosylation changes enhancing the inflammatory activity of IgG at the earliest RA phases CONS ACPA are present in two-thirds of RA patients ACPA are not detected in all cases of RA and are not necessary nor sufficient for RA ACPA can be detected years before disease onset development RA cannot be reproduced experimentally by immunization with citrulinated antigens RA is not transferable by ACPA ACPA/RF seronegative patients have higher tender and swollen joint counts as well as DAS28 score than concordant seropositive RA patients ACPA is positively associated with a severe, erosive phenotype in RA ACPA is positively an independent factor of disease flare after treatment tapering/discontinuation in RA patients in remission RF is positivity associated with higher mortality rates for all causes, mainly neoplastic ACPA is positively associated with higher mortality rate for all causes, mainly cardiovascular TREATMENT CHOICE ACPA is positively associated with a more favorable response to Rituximab in randomized studies and registries data ACPA high positivity identifies RA patients with higher chance of Abatacept treatment response ACPA status does not influence treatment response to TNF-inhibitors in RA patients Despite limited data availability, Tocilizumab response rate seems not to be influenced by the ACPA status in RA patients target in RA therapy means having individualized treatment goals. For example, a young healthy patient may want to have disease remission, whereas an older patient s goal may be a reduction in pain. Providing treat to target therapy requires setting a goal, starting a treatment, assessing the response after three to six months of therapy, and making treatment changes if the goal is not met. Objective disease measures to determine medication efficacy that can be used in clinical practice include the number of swollen joints, number of tender joints, ESR rate, physician global assessment, and patient global assessment. Notably, approximately 60 percent of RA patients may have normal ESR and CRP, so significant RA disease activity can be present despite negative inflammatory marker tests. In addition to individualized treatment goals and regimens, medication compliance and effective patient-doctor relationships go a long way toward achieving minimal disease activity and reduced long-term complications of RA. Initial therapy for RA is usually standard DMARDs. If the patient does not adequately respond to standard DMARDs, agents approved for methotrexate-inadequate responders (or who are intolerant) include an interleukin one (IL-1) blocker (anakinra), tumor necrosis factor (TNF) inhibitors (infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab), an IL-6 receptor blocker (tocilizumab), a Janus kinase (JAK) tyrosine-kinase inhibitor (tofacitinib), and a blocker of co-stimulation (abatacept). The anti-cd20, B cell targeting agent rituximab is FDA approved for TNF inhibitor inadequate responders. Triple standard DMARDs (methotrexate, hydroxychloroquine, and sulfasalazine) is an option for treating patients who do not respond adequately to a single standard DMARD or are resistant to taking biologics. The combination was found to be superior to any one or two DMARDs for ACR50 (50% improvement in symptoms). 11 One cost analysis found biologic therapy to be superior to triple therapy, but with a higher incremental cost-effectiveness ratio. There are no long-term radiographic or safety data with triple therapy; this combination is used based on data obtained with each agent given as monotherapy. Patients receiving standard DMARDs need frequent monitoring. The blood, liver, lungs, and kidneys are frequent sites of adverse effects. The recommended interval of laboratory testing varies with the medication; however, four to eight week intervals are commonly needed. Most patients need to be seen three to six times a year when on standard DMARDs. In general, after DMARDs fail, TNF inhibitors 76 Journal of Managed Care Medicine Vol. 21, No. 4

77 are the next step. Clinicians have the most experience with TNF inhibitors, compared to other biologics. The combination of methotrexate and a TNF inhibitor is more effective than either agent alone and results in 50 to 60 percent of patients having an ACR50 response at one year. When patients do not respond adequately to a TNF inhibitor, a treatment decision must be made. Inadequate response can be due to antibodies against the TNF inhibitor. About 10 percent of infliximab- treated RA cases are associated with development of human anti-chimeric antibodies (HACAs). Induction of these antibodies can be reduced by giving low-dose MTX in combination with infliximab. 15,16 HACAs are associated with reduced infliximab serum levels and infusion reactions. HACAs do not affect subsequent response to adalimumab. Human anti-human antibodies (HAHAs) can develop after treatment with the humanized TNF inhibitors. If antibodies are suspected, it is reasonable to switch to a different TNF inhibitor to see if the patient will respond. Overall, patients who have an inadequate response or intolerance to monotherapy with one or more TNF inhibitors may have an improved response or tolerance when switched to another TNF inhibitor. They will have some response to a second agent, but it will be lower than the typical response in treatment naïve patients. 17 Trials of two different TNF inhibitors are sufficient before moving on to another biologic class. Lack of response to an initial TNF inhibitor should prompt switching to a different class. There are various other biologic options beyond TNF inhibitors. Abatacept selectively modulates T cell activity. Patients with incomplete responses to etanercept, infliximab, or both switched to abatacept in combination with a standard DMARD have a 50 percent ACR20 response. 18 It appears that patients can be directly switched from a TNF inhibitor to abatacept at the time the next dose is due without a break in therapy. 19 Rituximab, which decreases the number of B cells, is given twice a year by intravenous infusion. Long-term safety data with rituximab have shown that efficacy continues to improve with each additional course of the drug, and patients are more likely to enter remission with continued therapy. 20 The rate of serious infections also declines with long-term use. Tocilizumab blocks IL-6 signaling by binding to the IL-6 receptor. It is one of the few biologic DMARDs that shows efficacy as monotherapy for RA; it can be very helpful for those patients who cannot tolerate any of the standard DMARDs. Small molecule DMARDs are another option; Janus kinase inhibitors (JAK inhibitors) are currently the only available class. JAK inhibitors are involved in cytokine signaling pathways. There is JAK1, JAK2, and JAK3, which all pair up differently in the pathways and have differing effects. Tofacitinib (Xeljanz ) inhibits JAK1 and JAK3, which are primarily involved in generating IL-7, IL-15, and IL- 21 in RA. Compared to adalimumab and placebo, tofacitinib improves quality of life and appears to have similar efficacy to adalimumab. 21 Baricitinib (Olumiant ) is the second JAK inhibitor approved for treating RA (June 2018). It is a JAK1 and JAK2 blocker, so it will likely have a different safety and possibly a different efficacy profile from tofacitinib. It was approved based on a placebo-controlled trial showing superiority in RA. 22 Herpes zoster occurs at a higher rate with JAK inhibitors, compared to placebo. Vaccination prior to therapy should be considered, especially in Asian Americans. In some patients, it may be possible to stop DMARD therapy for a period of time. In one trial, standard DMARDs were withdrawn after two years of therapy if there was very low disease activity. Medication-free remission was 13 percent after four years and 14 percent after five years. 23,24 In another trial, patients withdrawn from standard DMARDs had a 9 to 15 percent medication-free remission. 25 Predictors of sustained remission off therapy include short symptom duration before treatment, shared epitope-negativity, RF-negativity, non-smoking, and minimal X-ray changes (i.e., low risk of progressive disease prior to therapy). A study in ACPApositive patients with early RA (active synovitis for 8 weeks) found a higher rate of drug-free remission in those treated with abatacept and methotrexate, compared with methotrexate alone. Drug-free remission was associated with lower symptom duration and lower disease activity scores. 26 ACPAs and RF arise many years prior to RA onset; approximately 50 percent of patients with high levels of ACPAs or RF will go on to develop RA. There is an ongoing National Institute of Health sponsored clinical trial to determine whether hydroxychloroquine treatment for six months can prevent progression to RA in high-risk patients (anti- CCP positive subjects who do not meet RA criteria or first degree relatives of RA patients). This is an exciting concept that will hopefully be successful. Conclusion RA commonly leads to deformity/disability; therefore, it needs to be treated early and effectively. Validated disease activity measurements can guide therapy to achieve low disease activity or remission Vol. 21, No. 4 Journal of Managed Care Medicine 77

78 more often. Patient preferences and values need to be considered in making treatment decisions and setting targets. The broad range of agents, administration routes (including new oral agents), and mechanisms of action enhance clinical opportunities. Compliance, individualized regimens, and effective patient-doctor relationships are always key to the best outcomes. Maureen A. McMahon, MD, is an Associate Clinical Professor at the UCLA David Geffen School of Medicine, Los Angeles, CA. References 1. Pincus T. Assessment of long-term outcomes of rheumatoid arthritis. How choices of measures and study designs may lead to apparently different conclusions. Rheum Dis Clin North Am. 1995;21(3): McGonagle D, Conaghan PG, O Connor P, et al. The relationship between synovitis and bone changes in early untreated rheumatoid arthritis: a controlled magnetic resonance imaging study. Arthritis Rheum. 1999;42(8): Aletaha D, Neogi T, Silman AJ, et al Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9): Krol A, Garred P, Heegaard NH, et al. Interactions between smoking, increased serum levels of anti-ccp antibodies, rheumatoid factors, and erosive joint disease in patients with early, untreated rheumatoid arthritis. Scand J Rheumatol. 2015;44(1): Singh JA, Furst DE, Bharat A, et al update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64(5): Kallberg H, Padyukov L, Plenge RM, et al. Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. Am J Hum Genet. 2007;80(5): Schellekens GA, Visser H, de Jong BA, et al. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum. 2000;43(1): Alivernini S, Galeazzi M, Peleg H, et al. Is ACPA positivity the main driver for rheumatoid arthritis treatment? Pros and cons. Autoimmun Rev. 2017;16(11): Li W, Sasso EH, van der Helm-van Mil AH, Huizinga TW. Relationship of multi-biomarker disease activity score and other risk factors with radiographic progression in an observational study of patients with rheumatoid arthritis. Rheumatology (Oxford). 2016;55(2): Dalakas MC. Invited article: inhibition of B cell functions: implications for neurology. Neurology. 2008;70(23): Bansback N, Phibbs CS, Sun H, et al. Triple Therapy Versus Biologic Therapy for Active Rheumatoid Arthritis: A Cost-Effectiveness Analysis. Ann Intern Med. 2017;167(1): Klareskog L, van der Heijde D, de Jager JP, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet. 2004;363(9410): St Clair EW, van der Heijde DM, Smolen JS, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum. 2004;50(11): Breedveld FC, Weisman MH, Kavanaugh AF, et al. The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006;54(1): Wagner CL, Schantz A, Barnathan E, et al. Consequences of immunogenicity to the therapeutic monoclonal antibodies ReoPro and Remicade. Dev Biol (Basel). 2003;112: van der Bijl AE, Breedveld FC, Antoni CE, et al. An open-label pilot study of the effectiveness of adalimumab in patients with rheumatoid arthritis and previous infliximab treatment: relationship to reasons for failure and anti-infliximab antibody status. Clin Rheumatol. 2008;27(8): Kim HL, Lee MY, Park SY, et al. Comparative effectiveness of cycling of tumor necrosis factor-α (TNF-α) inhibitors versus switching to non-tnf biologics in rheumatoid arthritis patients with inadequate response to TNF- inhibitor using a Bayesian approach. Arch Pharm Res. 2014;37(5): Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med. 2005;353(11): Schiff M, Pritchard C, Huffstutter JE, et al. The 6-month safety and efficacy of abatacept in patients with rheumatoid arthritis who underwent a washout after anti-tumour necrosis factor therapy or were directly switched to abatacept: the ARRIVE trial. Ann Rheum Dis. 2009;68(11): Edwards JC, Szczepanski L, Szechinski J, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004;350(25): van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367(6): Genovese MC, Kremer J, Zamani O, et al. Baricitinib in Patients with Refractory Rheumatoid Arthritis. N Engl J Med. 2016;374(13): van der Kooij SM, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, et al. Drug-free remission, functioning and radiographic damage after 4 years of response-driven treatment in patients with recent-onset rheumatoid arthritis. Ann Rheum Dis. 2009;68(6): Klarenbeek NB, Güler-Yüksel M, van der Kooij SM, et al. The impact of four dynamic, goal-steered treatment strategies on the 5-year outcomes of rheumatoid arthritis patients in the BeSt study. Ann Rheum Dis. 2011;70(6): van der Woude D, Young A, Jayakumar K, et al. Prevalence of and predictive factors for sustained disease-modifying antirheumatic drug-free remission in rheumatoid arthritis: results from two large early arthritis cohorts. Arthritis Rheum. 2009;60(8): Emery P, Burmester GR, Bykerk VP, et al. Evaluating drug-free remission with abatacept in early rheumatoid arthritis: results from the phase 3b, multicentre, randomised, active-controlled AVERT study of 24 months, with a 12-month, double-blind treatment period. Ann Rheum Dis. 2015;74(1): Journal of Managed Care Medicine Vol. 21, No. 4

79 Novel Treatment Advances and Approaches in the Management of Advanced Renal Cell Carcinoma (RCC) Robert A. Figlin, MD, FACP For a CME/CEU version of this article please go to and then click the activity title. Summary The past decade of research in renal cell carcinoma (RCC) has resulted in numerous new treatments and some challenges for patients and health care delivery. The paradigm for treating metastatic disease has changed significantly recently based on new studies and FDA approvals. Key Points Median survival for metastatic RCC has increased from eight to12 months, and to 45 months with targeted therapy. Newer targeted therapies and checkpoint inhibitor therapy are becoming the standard of care in metastatic disease. THE AMERICAN CANCER SOCIETY ESTImates there will be 63,340 new cases of renal cell carcinoma (RCC) and approximately 14,970 people will die from this disease in the United States (U.S.) in Most people with this cancer are older, with an average age of 64 at diagnosis. It is very uncommon in people younger than age 45. RCC affects more men than women. Numerous genetic abnormalities have been identified in RCC. These genetic mutations in the endothelial cell drive tumor angiogenesis, which drives tumor growth and metastases. Most of the advances in metastatic RCC treatment have targeted the endothelial cells (Exhibit 1). Newer therapies are also targeting the tumor cells. Not all patients with metastatic disease require immediate treatment because some RCC tumors grow very slowly. A subset can be observed before starting initial therapy. 2 The average time for observation is 13 months. Once a decision is made to treat, treatment options for metastatic RCC in 2018 are numerous. Immunotherapy with interleukin two (IL-2), interferon alpha, and nivolumab; vascular endothelial growth factor (VEGF) inhibition with sunitinib, sorafenib, pazopanib, bevacizumab in combination with IFN-α, and axitinib; mtor inhibition with temsirolimus and everolimus; targeting both the endothelial and tumor cells with cabozantinib; and combination therapy with lenvatinib and everolimus are all available. With all these therapies, the challenge is figuring how best to use the individual agents. While there are many agents, few comparative effectiveness trials are available. Most of these agents have been studied in the first- or second- line metastatic setting; yet, many patients are surviving to need third-line and beyond therapies. The treatment paradigm for RCC two years ago had been to use VEGF inhibitors in those who were treatment-naïve as first-line therapy and then use second-line VEGF inhibitors (axitinib) or an m- TOR inhibitor (everolimus) as second-line therapy. High-dose interleukin-2 is still used in about 5 percent of patients at selected centers. It can induce a durable response in approximately 11 percent of those that receive it (progression-free survival (PFS) Vol. 21, No. 4 Journal of Managed Care Medicine 79

80 Exhibit 1: Signaling Pathways and Selective Inhibitors in RCC VEGF Growth factor (e.g., PDGF, TGF-α, MET, FGF, AXL) Bevacizumab VEGF Endothelial Cell VEGFR Tumor cell Growth factor receptor Sorafenib Sunitinib Pazopanib Axitinib Cabozantinib Lenvatinib Vascular permeability Akt P13K P P Raf MEK EC survival MAPK Erk EC proliferation EC migration P P Sorafenib Temsirolimus Everolimus Akt P13k mtor P P P P Raf MEK Erk Tumor cell proliferation HIF1-α expression Cediranib* Dovitinib* Erlotinib Cabozantinib Lenvatinib * Investigational EC = endothelial cell EGF = epidermal growth factor FGF = fibroblast growth factor PDGF = platelet derived growth factor VEGFR = vascular endothelial growth factor receptor HIF1-α = Hypoxia-inducible factor 1-alpha TGF = transforming growth factor MET, hepatocyte growth factor AXL = AXL receptor tyrosine kinas 3 years). 3 This therapy is difficult to endure, causes significant toxicity, and no selection criteria (aside from clear cell biology and good physiology) exists for deciding which patients should receive it. For a highly motivated patient who wants to try for a cure, interleukin- 2 is the only agent that can achieve it. Three new therapies for RCC are changing the treatment paradigm. Cabozantinib (Cabometyx ), which targets both the endothelial and tumor cells, was FDA approved in late Compared to sunitinib in those with metastatic RCC at intermediate or poor risk with no prior therapy, cabozantinib improved PFS (8.2 months vs 5.6 months), overall response rate (ORR 46% vs 18%) and overall survival (OS 30.3 months vs 21.8 months). 4 Cabozantinib is a recommended agent for first-line treatment of patients with metastatic RCC who have intermediate or poor risk. 5 While not curing patients, lives are being significantly extended by this agent. It is also effective in patients with bone metastases, which are very painful and difficult to effectively treat. There is an unmet need for improved treatment outcome of metastatic RCC patients resistant to standard VEGF-targeted therapies and mtor inhibitors. Fibroblast growth factor (FGF) pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies. Lenvatinib (Lenvima ), which was initially FDA approved in 2015, is a highly potent tyrosine kinase inhibitor of VEGF receptors one to three and FGF receptor one. The combination of lenvatinib and everolimus in the second-line setting produces better results than either alone in those who have had disease progression on or after prior VEGF-targeted therapy. Exhibit 2 shows the results of this trial. 6 The highest rate and longest duration of response was observed with the combination, and the study results suggest an overall survival benefit for lenvatinib/everolimus over everolimus. Using carbozantinib first line and lenvatinib/everolimus second line results in a median survival of 45 months, compared with eight to 12 months ten years ago. In subjects who had disease progression on a prior VEGF inhibitor, cabozantinib treatment produces a better PFS, OS, and ORR than everolimus. 7 The observed clinical benefits are consistent across all subgroups evaluated. Cabozantinib is now a preferred agent for patients with advanced RCC, after prior antiangiogenic therapy. 5 A challenge for clinicians is choosing between carbozantinib or lenvatinib/everolimus or axitinib or nivolumab, which are all Category 1 recommended agents in the second-line setting. 5 The third agent changing the treatment paradigm 80 Journal of Managed Care Medicine Vol. 21, No. 4

81 Exhibit 2: Summary of Efficacy 5 Lenvatinib/Everolimus (n = 51) Lenvatinib (n = 52) Everolimus (n = 50) Progression-free survival Median (mo) % Cl Benefits vs everolimus P =.0005 P =.048 N/A Objective response rate, % Median (mo) % Cl Benefits vs everolimus P <.0001 P =.007 N/A Overall survival Median (mo) % Cl 16.4 NE Benefits vs everolimus P =.024 P =.12 N/A Exhibit 3: Toxicity With Immunotherapy Agents Immune adverse effects (iraes) May be due to cytokine release by activated T cells May be unfamiliar to clinicians Requires a multidisciplinary approach Can be serious Requires prompt recognition and treatment Requires patient and HCP education iraes occur in certain organ systems: Skin Endocrine system Liver Gastrointestinal tract Nervous system Eyes Respiratory system Hematopoietic cells is immunotherapy with immune checkpoint therapy. Nivolumab (Opdivo ), an anti-programmed death one (anti-pd-1) agent, is now FDA approved for metastatic RCC; it improved survival compared with everolimus in the second-line setitng. 8 The value proposition for immunotherapy suggests that health care dollars will actually be saved when compared to standard of care in RCC. 9 The adverse effects tend to be less with immunotherapy, compared with targeted therapy; patients typically feel much better when on immunotherapy. Activation of the immune system against tumors can result in a novel spectrum of immune-related adverse effects (iraes) in 5 to 10 percent of patients, which can be life threatening (Exhibit 3). Each irae has different kinetics of onset; rash occurs first, followed by colitis, hypophysitis, and finally hepatitis. 10 Early recognition and intervention are critical for the successful management of iraes with immune checkpoint inhibitors. Overall, PD-1 blockade with Vol. 21, No. 4 Journal of Managed Care Medicine 81

82 Exhibit 4: Renal Cell Carcinoma Therapeutic Journey Surgical Resection Metastatic Disease Metastatic Disease Progression Third Line High Risk Sunitinib Low Risk Observation Clinical Trial Good Risk Sunitinib Intermediate/Poor Risk Cabozantinib Observation Axitinib Cabozantinib Lenvatinib/Everolimus Nivolumab Everolimus Clinical Trial? Clinical Trial nivolumab has the potential to improve and prolong the lives of patients by producing stable disease. About 25 percent of patients will have a durable response. While some patients who are treated beyond first progression may benefit, most do not. Based on recent clinical trials and new FDA approvals, the new paradigm for treating metastatic RCC is using carbozantinib, lenvatinib/everolimus, and nivolumab. The likely progression of therapy from initial diagnosis through third-line therapy for metastatic disease is shown in Exhibit 4. Overall, effective therapy management requires the appropriate selection of an agent, treatment duration, dosing, and adverse effect management. In metastatic RCC, decreasing dose, or dose interruptions, leads to reduced benefit. With targeted therapies, fatigue, hand-foot syndrome, stomatitis, and diarrhea are the major adverse effects which are not necessarily well managed. Proactive management of adverse effects can help with maintaining effective dosing and thus optimal outcomes. Treatment must also be continued in order to have benefit; anti-angiogenesis therapy only works while being given. Conclusion It is an exciting time for clinicians treating patients with metastatic RCC. There are numerous treatment options which are prolonging survival significantly, and many more are on the horizon. Clinicians have some challenges in deciding which agents to use and in what order. Robert A. Figlin, MD, FACP, is the Steven Spielberg Family Chair in Hematology Oncology; Professor of Medicine and Biomedical Sciences; Director of the Division of Hematology Oncology; and Deputy Director of the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center in Los Angeles CA. References 1. American Cancer Society. Key statistics about kidney cancer. Available at Accessed 8/10/ Rini BI, Dorff TB, Elson P, et al. Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial. Lancet Oncol. 2016;17(9): McDermott DF, Cheng SC, Signoretti S, et al. The high-dose aldesleukin select trial: a trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma. Clin Cancer Res. 2015;21(3): Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance A CABOSUN trial. J Clin Oncol. 2017;35(6): National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines In Oncology. Kidney Cancer. Version Available at Accessed 8/10/ Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16(15): Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19): Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19): McCrea C, Johal S, Yang S, Doan J. Cost-effectiveness of nivolumab in patients with advanced renal cell carcinoma treated in the United States. Exp Hematol Oncol. 2018;7: Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21): Journal of Managed Care Medicine Vol. 21, No. 4

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