New Drugs: Gotta Catch Em All! Part II

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2 New Drugs: Gotta Catch Em All! Part II Timothy Chiu, PharmD, BCPS Pharmacist Evidence Analyst & Strategist Monica Yoshinaga, PharmD, BCPS Pharmacist Evidence Analyst & Strategist Doris Kao, PharmD, BCPS, FCSHP Supervisor Kaiser Permanente Drug Information Services

3 Disclosure Tim Chiu, Monica Yoshinaga, and Doris Kao work for Kaiser Permanente and have no potential conflicts of interest to disclose.

4 Learning Objectives At the completion of this activity, the pharmacist will be able to: 1) Describe selected new drug approvals and trends at the Food and Drug Administration (FDA) from October 2015 through July ) Cite indications for at least three major oncology new drug approvals and some of the treatments to which they may offer alternatives. 3) Cite genotypes treated for by recently approved Hepatitis C medications. At the completion of this activity, the pharmacy technician will be able to: 1) List four or more new drug approvals by the FDA from October 2015 to July ) Name at least three new drugs approved for cancer indications. 3) Name two recently approved medications for Hepatitis C.

5 New Drug Approvals: CDER New Molecular Entity (NME) and New Biologic License Application (BLA) Filings and Approvals NME/BLA Approvals NME/BLA Filings *The 2015 filed numbers include those filed in CY 2015 plus those currently pending filing (i.e., within their 60 day filing period) in CY * Approved 45 novel drugs More than average number approved annually in the past decade Expedited pathways 27 (60%) of novel drugs designated in one or more expedited categories Fast Track: 14 Breakthrough Therapy: 10 Priority Review: 24 Accelerated Approval: (YTD) Approved 16 novel drugs R1. FDA New Drug Approvals. Drugs@FDA. R2. FDA-TRACK.

6 Total Drug Expenditures: 2015 New Therapies $24.2B Protected Brands $28.3B Total Drug Expenditures 12.2% $424B Generic Spending $7.9B Patent Expiries $14.2B R4. IMS Institute, Medicines Use and Spending in the US. April 2016

7 New Therapies: 2015 Major Drivers Specialty Medicines: 21.5% Hepatitis C: 250,000 patients treated Multiple Sclerosis: new oral medicines HIV Combination Therapy Oncology: 35% of all new drugs: breakthrough targeted mechanisms Inflammatory Conditions Diabetes: Insulin, DPP-IV Inhibitors, SGLT2 Inhibitors, GLP-1 Agonists R4. IMS Institute, Medicines Use and Spending in the US. April 2016

8 aripiprazole lauroxil (Aristada) injectable atypical antipsychotic FDA Approval: October 6, 2015 Indication: Treatment of schizophrenia Notes: Long-acting injectable Different active moiety than aripiprazole extended-release injectable suspension (Abilify Maintena), which is dosed monthly Dosing: Establish tolerability with oral aripiprazole prior to initiating treatment IM injection in deltoid or gluteal muscle by a healthcare professional Start at dose of 441 mg, 662 mg, or 882 mg monthly or 882 mg dose every 6 weeks Administer oral aripiprazole with the first injection for 21 consecutive days

9 aripiprazole lauroxil (Aristada) injectable atypical antipsychotic Efficacy: Efficacy data from oral aripiprazole trials 12 week, randomized, DB, PBO-controlled fixed-dose trial in patients with acute schizophrenia stabilized on oral aripiprazole (n=622) Efficacy assessed with PANSS, observed statistically significant separation on PANSS total score change from PBO Safety: Atypical Antipsychotic Boxed Warning: Increased mortality in elderly patients with dementia-related psychosis Adverse reaction incidence 5% and at least twice that for placebo): akathisia

10 patiromer (Veltassa) non-absorbed, cation exchange polymer that contains a calciumsorbitol counterion to bind potassium FDA Approval: October 21, 2015 Indication: To treat hyperkalemia, a serious condition in which the amount of potassium in the blood is too high. Notes: Limitations of Use: Veltassa should not be used as an emergency treatment for life-threatening hyperkalemia because of its delayed onset of action. Dosing: Starting dose: 8.4 grams administered orally once daily with food. Adjust dose by 8.4 grams daily as needed at one week intervals to obtain desired serum potassium target range.

11 patiromer (Veltassa) non-absorbed, cation exchange polymer that contains a calciumsorbitol counterion to bind potassium Efficacy: Three pivotal RCTs: AMETHYST-DN, PEARL-HF and OPAL-HK. All trials demonstrated that patiromer significantly reduced serum potassium levels in hyperkalemic patients with CKD and on renin-angiotensin-aldosterone system (RAAS) inhibitor therapy. Safety: Boxed Warning: Binding to other medications. Administer other oral medications at least 6 hours before or 6 hours after Veltassa. Warnings and Precautions: binding of other orally administered medications, worsening of gastrointestinal motility, hypomagnesemia. Adverse reactions: constipation (7.2%), hypomagnesemia (5.3%), diarrhea (4.8%). R2. Biomedtracker Pharma Intelligence. Biomedtracker.com

12 asfotase alfa (Strensiq) enzyme replacement therapy FDA Approval: October 23, 2015 (Orphan Drug, Fast Track, Breakthrough Therapy designations, Priority Review) Indication: Treatment of perinatal/infantile- and juvenile-onset hypophosphatasia (HPP) Notes: Human recombinant tissue-nonspecific alkaline phosphatase First FDA-approved treatment for patients with this rare (severe forms: 1:100,000 newborns) genetic metabolic disease that affects the development of bones and teeth Dosing: Weight-based: 2 mg/kg three times/wk or 1 mg/kg six times/wk Perinatal/infantile-onset HPP may increase to 3 mg/kg three times/wk if needed due to inadequate efficacy

13 asfotase alfa (Strensiq) enzyme replacement therapy Efficacy: 2 prospective, open-label, single-arm clinical trials demonstrated significant improvement in survival and invasive ventilation-free survival in patients with perinatal/infantile-onset HPP compared with untreated natural history controls Survival at point of last contact: 91% (asfotase alfa) vs 27% (historical controls) (Hazard ratio 0.14; ) 1 prospective, open-label, single-arm clinical trial (n=8) in juvenile-onset HPP demonstrated improvements in gait/mobility, growth and radiographic assessments compared with untreated natural history controls Safety: ADEs 10%: injection site reactions, lipodystrophy, ectopic calcifications, hypersensitivity reactions

14 elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (Genvoya) Integrase strand transfer inhibitor, CYP3A enzyme inhibitor plus nucleoside and nucleotide reverse transcriptase inhibitor combination FDA Approval: November 5, 2015 Indication: Complete treatment of HIV-1 infection in adults and pediatric patients 12 years Antiretroviral naïve or (1.) replace the current antiretroviral regimen, (2.) virologically-suppressed, (3.) on a stable antiretroviral regimen 6 months Notes: Prior to initiation, patients should be tested for hepatitis B infection, and baseline estimated creatinine clearance, urine glucose, and urine protein should be assessed in all patients. Dosing: Oral: One tablet once daily.

15 elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (Genvoya) Integrase strand transfer inhibitor, CYP3A enzyme inhibitor plus nucleoside and nucleotide reverse transcriptase inhibitor combination Efficacy: Non-inferior to Stribild for viral suppression (HIV-1 RNA< 50copies/mL) at 48 weeks. > 90% virological success in HIV-infected patients with renal insufficiency at 48 weeks. Safety: Boxed Warning: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases. Post treatment acute exacerbation of hepatitis B. Contraindication: contraindicated with drugs that are highly dependent on CYP3A for clearance. Warnings and Precautions: Lactic acidosis/severe hepatomegaly with steatosis, BMD, fat redistribution, immune reconstitution syndrome, pancreatitis, renal toxicity. Adverse reactions: (>5%) diarrhea, nausea, fatigue, and headache. R2. Biomedtracker Pharma Intelligence. Biomedtracker.com

16 daratumumab (Darzalex) anti-cd38, recombinant human IgG1 monoclonal antibody FDA Approval: November 16, 2015 Indication: Treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) or who are double-refractory to a PI and an IMiD Notes: First approved monoclonal antibody in multiple myeloma, may offer immunostimulary benefits May interfere with cross-matching and red blood cell antibody screening as well as determination of complete response Dosing: 16 mg/kg IV per dose; infusion rate and dose frequency titration required for infusion reaction risk Administer in a healthcare setting prepared to infusion reactions Pre- and post-infusion medications required, plus prophylaxis for herpes zoster reactivation

17 daratumumab (Darzalex) anti-cd38, recombinant human IgG1 monoclonal antibody Efficacy: Approval based on 2 pivotal trials (GEN501, SIRIUS); both Phase 2, single-arm, open-label Approximately 30% of patients treated with daratumumab responded to therapy, despite being a heavily pretreated population Responses appear durable (duration of response ranged from 1.2 to months) Recent data presentations from CASTOR and POLLUX trials, which evaluated daratumumab as part threedrug combination regimens for relapsed/refractory multiple myeloma in earlier lines of therapy

18 daratumumab (Darzalex) anti-cd38, recombinant human IgG1 monoclonal antibody Progression-Free Survival Overall Survival Safety: Common adverse reactions include infusion reactions, fatigue, back pain, nausea, pyrexia, cough, and upper respiratory tract infection Warnings include infusion reactions, interference with serological testing, and interference with determination of complete response R5. Usmani. ASH Abst 29.

19 ixazomib (Ninlaro) second generation oral proteasome inhibitor FDA Approval: November 20, 2015 Indication: In combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy Notes: First FDA approved oral proteasome inhibitor May have a lower risk of contributing to peripheral neuropathy vs. bortezomib, though a head-tohead trial is needed to draw any conclusion Dosing: 4 mg PO on days 1, 8, and 15 every 28-day cycle Take at least one hour before or at least two hours after food Lenalidomide is administered Days 1-21 and dexamethasone is administered Days 1, 8, 15, and 22 of each cycle

20 ixazomib (Ninlaro) second generation oral proteasome inhibitor Efficacy: TOURMALINE-MM1 (Phase 3, double-blind, placebo-controlled, n=722) Adding ixazomib to lenalidomide and dexamethasone resulted in a 26% reduction in risk of progression or death (median progression-free survival [PFS] of 20.6 months in study arm vs months in placebo arm) PFS benefit also observed in subgroup of patients with high-risk cytogenetics Modest improvement in response rate with addition of ixazomib (78% vs. 72% in placebo arm) Progression-Free Survival R6. Ixazomib. Dossier

21 ixazomib (Ninlaro) second generation oral proteasome inhibitor Safety: Common adverse reactions include diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, edema, and back pain Warnings include thrombocytopenia, gastrointestinal toxicity, peripheral neuropathy, edema, cutaneous reactions, and hepatotoxicity

22 Influenza vaccine, adjuvanted (Fluad) Influenza virus vaccine, inactivated FDA Approval: November 24, 2015 Indication: For active immunization of persons 65 years of age and older against influenza disease caused by influenza virus subtypes A and B contained in the vaccine. Notes: (ACIP) recommends routine annual vaccination with the seasonal influenza vaccine for all persons 6 months of age Dosing: IM: 0.5 ml/dose (1 dose per season).

23 Influenza vaccine, adjuvanted (Fluad) Influenza virus vaccine, inactivated Efficacy: 95% seroconversion Safety: Contraindication: history of severe allergic reaction (e.g. anaphylaxis) to any component of the vaccine, including egg protein. Warnings and Precautions: Guillain-Barré syndrome, allergic reactions, latex allergy, altered immunocompetence, sycope, vaccine effectiveness. Adverse reactions: moderate: pain, tenderness, myalgia, fatigue, headache, arthralgia, chills, nausea, vomiting

24 elotuzumab (Empliciti) anti-slamf7, recombinant humanized IgG1 monoclonal antibody FDA Approval: November 30, 2015 Indication: In combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma who received one to three prior therapies Notes: In early studies, no responses seen as a single-agent treatment for patients with relapsed/refractory multiple myeloma Dosing: 10 mg/kg IV per dose; infusion rate and dose frequency titration required for infusion reaction risk Premedications required Lenalidomide is administered Days 1-21 and dexamethasone on Days 1, 8, 15, and 22 of each 28-day cycle

25 elotuzumab (Empliciti) anti-slamf7, recombinant humanized IgG1 monoclonal antibody Efficacy: ELOQUENT-2 (Phase 3, randomized, open-label, placebo-controlled, n=646) Adding elotuzumab to lenalidomide and dexamethasone resulted in a 30% reduction in risk of progression or death (median PFS of 19.4 months in study arm vs months in placebo arm) PFS benefit also observed in subgroup of patients with high-risk cytogenetics Improvement in response rate also observed with addition of elotuzumab (78.5% vs. 65.5% in placebo arm) Progression-Free Survival R7. Lonial. NEJM

26 elotuzumab (Empliciti) anti-slamf7, recombinant humanized IgG1 monoclonal antibody Safety: Common adverse reactions include fatigue, diarrhea, constipation, pyrexia, cough, peripheral neuropathy, nasopharyngitis, upper respiratory tract infection, decreased appetite, and pneumonia Warnings include infusion reactions, infections, second primary malignancies, hepatoxicitiy, and interference with determination of complete response

27 sebelipase alfa (Kanuma) enzyme replacement therapy FDA Approval: December 8, 2015 Indication: Treatment of patients with a diagnosis of Lysosomal Acid Lipase (LAL) deficiency Notes: Hydrolytic lysosomal cholesteryl ester and triacylglycerol-specific enzyme LAL deficiency (LAL-D): autosomal recessive lysosomal storage disorder; complications due to lysosomal buildup of cholesteryl esters and TGs Dosing: Weight-based: intravenous infusion qwk in infants with rapidly progressive LAL-D and every other week for pediatric and adult patients with LAL-D

28 sebelipase alfa (Kanuma) enzyme replacement therapy Efficacy: Open-label, single-arm trial of infants with Wolman disease (n=9) assessing survival at age 12 months compared to untreated natural history controls (n=21) 6 infants survived beyond 12 months old compared to 0 infants 20-week, double-blind, PBO-controlled trial in children and adults with LAL-D (n=66) Statistically significant improvement in percent change from baseline in LDL-c (mean difference of -22% [95% CI 33%, -15%]), other statistically significant improvements noted for HDL-c, non-hdl-c, TGs Safety: Patients with rapidly progressive disease presenting within the first 6 months of life ( 30%): diarrhea, vomiting, fever, rhinitis, anemia, cough, nasopharyngitis, urticarial Pediatric and adult patients ( 8%): headache, fever, oropharyngeal pain, nasopharyngitis, asthenia, constipation, and nausea Warnings and Precautions: hypersensitivity reactions including anaphylaxis, hypersensitivity to eggs/egg products

29 sugammadex (Bridion) modified gamma cyclodextrin, a selective relaxant binding agent FDA Approval: December 15, 2015 Indication: Reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adults undergoing surgery. Notes: Should be administered by trained healthcare providers familiar with the use, actions, characteristics, and complications of neuromuscular blocking agents (NMBA) and neuromuscular block reversal agents. Dosing: For rocuronium and vecuronium: 2-4 mg/kg is recommended based on monitoring for twitch responses and the extent of spontaneous recovery that has occurred. For rocuronium only: 16 mg/kg, reverse neuromuscular blockade soon (approximately 3 minutes) after a single dose of 1.2 mg/kg of rocuronium.

30 sugammadex (Bridion) modified gamma cyclodextrin, a selective relaxant binding agent Efficacy: Sugammadex reverses moderate and profound neuromuscular blockade induced by rocuronium and vecuronium faster and more consistently than neostigmine. Sugammadex quickly reverses neuromuscular blockade induced high-dose rocuronium within three minutes of administration. Safety: Contraindications: patients with a history of a hypersensitivity reaction. Warnings and Precautions: anaphylaxis and hypersensitivity, marked bradycardia, respiratory function, prolonged neuromuscular blockade, other. Adverse reactions: (>5%) nausea, vomiting, abdominal pain, hypertension, hypotension, dizziness and headache. R2. Biomedtracker Pharma Intelligence. Biomedtracker.com

31 elbasvir and grazoprevir (Zepatier) inhibitor of HCV NS5A, inhibitor of HCV NS3/4A protease An estimated million people in the United States have chronic hepatitis C. FDA Approval: January 28, 2016 Indication: Indicated with or without ribavirin for the treatment of chronic hepatitis C virus (HCV) genotypes 1 or 4 infection in adults Notes: Testing patients with HCV genotype 1a infection for the presence of virus with NS5A resistanceassociated polymorphisms is recommended prior to initiation of treatment Dosing: With or without ribavirin. One tablet taken orally once daily for weeks

32 elbasvir and grazoprevir (Zepatier) inhibitor of HCV NS5A, inhibitor of HCV NS3/4A protease Efficacy: 96% achieved SVR12 (sustained virological response (HCV RNA <15 IU/mL) 12 weeks after the end of therapy). Safety: Contraindications: Patients with moderate or severe hepatic impairment (Child-Pugh B or C), Organic anion transporting polypeptides 1B1/3 (OATP1B1/3) inhibitors, strong inducers of cytochrome P450 3A (CYP3A), and efavirenz. Warnings and Precautions: increase of ALT, drug interactions, including ribavirin. Adverse reactions: fatigue (13%), headache (12%), and nausea (9%). R2. Biomedtracker Pharma Intelligence. Biomedtracker.com

33 brivaracetam (Briviact) oral and injectable anticonvulsant FDA Approval: February 18, 2016 Indication: Adjunctive therapy in the treatment of partial-onset seizures in patients 16 years of age and older with epilepsy Notes: Available as tablets, oral solution, injection for IV use C-V controlled substance Dosing: Starting dosage: 50 mg BID, adjust down to 25 mg BID or up to 100 mg BID based on tolerability and therapeutic response Adjust dose if patient has hepatic impairment

34 brivaracetam (Briviact) oral and injectable anticonvulsant Efficacy: 3 multicenter fixed-dose, randomized, DB, PBO-controlled trials in patients with partial-onset seizures not adequately controlled by AEDs (total n=1550) Primary efficacy outcomes: percent reduction in 7-day and 28-day partial-onset seizure frequency (see table) Safety: Warnings and Precautions: suicidal behavior and ideation, neurological and psychiatric adverse reactions, hypersensitivity (bronchospasm and angioedema), withdrawal (should be gradually withdrawn) Adverse reactions 5% and at least 2% more frequently than PBO: somnolence/sedation, dizziness, fatigue, N/V Study, Group 1 % Reduction Over PBO PBO (n=100) mg/day (n=99) 9.5% 100 mg/day (n=100) 17.0% 2 a PBO (n=96) mg/day (n=101) 16.9%* 3 b 100 mg/day (n=252) 25.2%* PBO (n=259) mg/day (n=249) 25.7%* *Statistically significant based on testing procedure with alpha = 0.05 a Based on 7-day seizure frequency b Based on 28-day seizure frequency

35 obiltoxaximab (Anthim) chimeric IgG1 kappa monoclonal antibody (mab) that binds the PA component of B. anthracis toxin FDA Approval: March 18, 2016 Indication: Adult and pediatric patients for the treatment of inhalational anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs. Prophylaxis of inhalational anthrax due to B. anthracis when alternative therapies are not available or not appropriate. Notes: Administer in appropriately monitored settings which are equipped to manage anaphylaxis. Dosing: Premedication with diphenhydramine is recommended. Single dose of 16 mg/kg administered intravenously over 90 minutes. Pediatric dosing based on weight.

36 obiltoxaximab (Anthim) chimeric IgG1 kappa monoclonal antibody (mab) that binds the PA component of B. anthracis toxin Efficacy: Animal studies: Single intravenous dose resulted in statistically significant improvement in survival relative to placebo, (up to 93% versus 0%) Safety: Boxed Warning: Due to the risk of hypersensitivity and anaphylaxis, it should be administered in monitored settings by personnel trained and equipped to manage anaphylaxis. Warnings and Precautions: hypersensitivity and anaphylaxis. Adverse reactions: headache (8%), pruritus (4%), URI (5%), cough (3%), vessel puncture site bruise or swelling (3%), nasal congestion (2%), infusion site pain (2%), urticaria (2%), pain in extremity (2%). R2. Biomedtracker Pharma Intelligence. Biomedtracker.com

37 venetoclax (Venclexta) B-cell lymphoma 2 (BCL-2) inhibitor FDA Approval: April 11, 2016 Indication: Treatment of patients with chronic lymphocytic leukemia with 17p deletion, as detected by an FDA approved test, who have received at least one prior therapy Notes: Recent data suggests clinical benefit may be achieved even in patients previously treated with ibrutinib or idelalisib Being studied in other B-cell malignancies, including multiple myeloma, acute myelogenous leukemia, and non-hodgkin s lymphomas Administration in the hospital for earlier doses may be needed based on tumor lysis syndrome (TLS) risk Dosing: Requires initial ramp-up dosing (by week) due to potential for TLS Administer with a meal and water, perform prophylaxis for TLS

38 venetoclax (Venclexta) B-cell lymphoma 2 (BCL-2) inhibitor Efficacy: M (Phase 2, open-label, single-arm, n=106) Responses seen in 80% of patients treated with venetoclax (7.5% were complete remissions or complete remission with incomplete marrow recovery) Responses appear durable, where the median duration of response has not been reached after approximately 12 months Cumulative Incidence of Response Duration of Response R8. Stilgenbauer. Lancet Oncol

39 venetoclax (Venclexta) B-cell lymphoma 2 (BCL-2) inhibitor Safety: Common adverse reactions include neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue Warnings include TLS, neutropenia, and do not administer live attenuated vaccines prior to, during, or after venetoclax therapy

40 pimavanserin (Nuplazid) oral atypical antipsychotic FDA Approval: April 29, 2016 (breakthrough therapy designation, priority review) Indication: Treatment of hallucinations and delusions associated with Parkinson s disease psychosis Notes: First drug to be approved to treat hallucinations and delusions associated with PD Dosing: 34 mg (two 17 mg tablets once daily) without titration and with or without food Efficacy: 6-week, randomized, PBO-controlled, parallel-group study (n=199)

41 pimavanserin (Nuplazid) oral atypical antipsychotic Efficacy: Endpoint Tx Group Mean Baseline Score (SD) LS Mean Change from Baseline (SE) PBO-subtracted Difference a (95% CI) SAPS-PD pimavanserin 15.9 (6.12) (0.66) -3.06* (-4.91, -1.20) PBO 14.7 (5.55) (0.67) -- SAPS-PD pimavanserin 11.1 (4.58) (0.46) (-3.29, -0.72) Hallucinations b PBO 10.0 (3.80) (0.46) -- SAPS-PD pimavanserin 4.8 (3.59) (0.32) Delusions b PBO 4.8 (3.82) (0.32) (-1.83, -0.04) a Difference (drug minus placebo) in least-squares mean change from baseline b Supportive analysis * Statistically significantly superior Safety: Atypical Antipsychotic Boxed Warning: Increased mortality in elderly patients with dementiarelated psychosis Warnings and Precautions: QT interval prolongation Adverse reactions ( 5% and twice the rate of placebo): peripheral edema, confusional state

42 obeticholic acid (Ocaliva) farnesoid X receptor agonist FDA Approval: May 27, 2016 Indication: Treatment of primary biliary cholangitis (PBC) in combination with or without ursodeoxycholic acid (UDCA). Notes: Antihistamine or bile acid binding resin added for patients with intolerable pruritus. Dosing: Oral: Initial: 5 mg once daily; if an adequate reduction in ALP and/or total bilirubin has not been achieved after 3 months, increase to 10 mg once daily (maximum: 10 mg/day). Adjust dose for hepatic impairment, Child-Pugh Class B and C. Adjust dose for patients with intolerable pruritus from Ocaliva.

43 obeticholic acid (Ocaliva) farnesoid X receptor agonist Efficacy: Pivotal, phase 3 RCT. Primary Composite Endpoint Ocaliva 10 mg (N=73) Ocaliva titration (N=70) Placebo (N=73) Responder rate (%) 48% 46% 10% ALP < 1.67 time ULN 55% 47% 16% ALP 15% or greater 78% 77% 29% Total bilirubin ULN 82% 89% 78% Safety: Contraindication: patients with complete biliary obstruction. Warnings and Precautions: liver-related adverse effects, severe pruritus, reduction in HDL-C. Adverse reactions: pruritus (70%), fatigue (25%), abdominal pain (10%), rash (10%), arthralgia (10%), oropharyngeal pain (8%), dizziness (7%), constipation (7%), peripheral edema (7%), palpitations (7%), pyrexia (7%), thyroid function abnormality (6%), eczema (6%). R2. Biomedtracker Pharma Intelligence. Biomedtracker.com

44 daclizumab (Zinbryta) interleukin-2 receptor blocking antibody FDA Approval: May 27, 2016 Indication: Treatment of adult patients with relapsing forms of multiple sclerosis (MS) Notes: Reserve for patients with inadequate response to 2 or more MS drugs due to safety profile Dosing: Self-administered 150 mg subcutaneously once monthly Efficacy: 2 DB, RCTs in patients with relapsing MS (RMS) 1 active-controlled trial (n=1841) comparing to interferon beta-1a (Avonex) and 1 PBO-controlled trial (n=412) Primary outcomes of annualized relapse rate; both studies found statistically significant effect on ARR

45 daclizumab (Zinbryta) interleukin-2 receptor blocking antibody Safety: Available only through a restricted distribution program (Zinbryta REMS Program) Boxed Warning: Hepatic injury including autoimmune hepatitis and other immune-mediated disorders Contraindications: Pre-existing hepatic disease or hepatic impairment, including ALT or AST at least 2 times the ULN, history of autoimmune hepatitis or other autoimmune condition involving the liver Warnings and Precautions: hypersensitivity reactions, infections, depression and suicide Adverse reactions ( 5% and 2% higher than comparator): nasopharyngitis, URI, rash, influenza, dermatitis, oropharyngeal pain, bronchitis, eczema and lymphadenopathy compared with interferon beta-1a (Avonex); and URI, depression, rash, pharyngitis, and increased ALT compared with PBO

46 sofosbuvir and velpatasvir (Epclusa) nucleotide analog HCV NS5B polymerase inhibitor and an NS5A inhibitor combination FDA Approval: June 28, 2016 Indication: Treatment of adult patients with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 infection. Notes: Cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended. Dosing: One tablet taken orally once daily with or without food for 12 weeks. Of every 100 people infected with the HCV: people chronic HCV infection people chronic liver disease 5 20 people cirrhosis in years 1 5 people die from cirrhosis or liver cancer

47 sofosbuvir and velpatasvir (Epclusa) nucleotide analog HCV NS5B polymerase inhibitor and an NS5A inhibitor combination Efficacy: ASTRAL-1 RCT: Overall SVR12 for sofosbivir/velpatasvir patients was 99.0% for genotypes 1, 2, 4, 5 and 6. (p< 0.001). ASTRAL-2 and ASTRAL-3 RCTs: SVR12 for sofosbivir/velpatasvir patients was 99.0% and 95% for genotypes 2, and 3 and was superior to sofosbuvir/ribavirin. (p< 0.001). Safety: Contraindication: patients for whom ribavirin is contraindicated. Warnings and Precautions: serious bradycardia when administered with amiodarone, decreased therapeutic effect with drugs that are inducers of P-gp and/or inducers of CYP2B6, CYP2C8, or CYP3A4. Adverse reactions: Headache (22%), fatigue (15%), Irritability ( 5%), insomnia (5%), depression (1%), skin rash (2%), nausea (9%), increased serum lipase (>3X ULN: 3% to 6%), weakness (5%), increased creatine phosphokinase ( 10X ULN: 1% to 2%). R2. Biomedtracker Pharma Intelligence. Biomedtracker.com

48 defibrotide sodium (Defitelio) oligonucleotide mixture with profibrinolytic properties FDA Approval: March 30, 2016 Indication: Treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome, with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT) Notes: Severe VOD occurs in approximately 2% of patients that receive HSCT, with mortality rate of 84% For the target patient population, survival rates 100 days post-hsct with supportive care only range from 21-31% May protect endothelial cells from damage caused by chemotherapy, tumor necrosis factor-alpha, serum starvation, and perfusion Dosing: 6.25 mg/kg IV every 6 hours (as 2-hour infusion); treat for min of 21 days (until resolution of VOD or max of 60 days)

49 defibrotide sodium (Defitelio) oligonucleotide mixture with profibrinolytic properties Efficacy: Over 3 studies (n=528), survival rates at 100 days post-hsct were 38-45% Safety: Common adverse reactions include hypotension, diarrhea, nausea, and epistaxis Warnings include hemorrhage and hypersensitivity reactions Concomitant anththrombotic/fibrinolytic therapy is contraindicated

50 Test Questions 1. Which of the following new drugs and indications is incorrectly matched up? a. daclizumab (Zinbryta) treatment of multiple sclerosis b. asfotase alfa (Strensiq) treatment of hypophosphatasia c. pimvanserin (Nuplazid) treatment of Parkinson s disease d. brivaracetam (Briviact) treatment of partial onset seizures

51 Test Questions 2. Which of the following are true? a. Both elbasvir/grazoprevir and sofosbuvir/velpatasvir are indicated for HCV infection. b. Sofosbuvir/velpatasvir was shown to be superior to sofosbuvir/ribavirin for genotype 4, 5,6. c. Elbasvir/grazoprevir is associated with drug-drug interactions while sofosbuvir/veltapasvir is not. d. Both elbasvir/grazoprevir and sofosbuvir/velpatasvir are dosed once daily. a and d.

52 Test Questions 3. Which of the following are false? a. Daratumumab and elotuzumab are both monoclonal antibodies recently approved for the treatment of multiple myeloma. b. Ixazomib is the first oral proteasome inhibitor approved for the treatment of multiple myeloma. c. Elotuzumab is approved as monotherapy for the treatment of multiple myeloma. d. Venetoclax does not require ramp-up dosing for the treatment of chronic lymphocytic leukemia c and d.

53 References R2. BiomedTracker. R3. FDA Drug Approvals. R4. IMS Institute, Medicines Use and Spending in the US. April Accessed April R5. Usmani S, Weiss B, Bahlis NJ, et al. Clinical Efficacy of Daratumumab Monotherapy in Patients with Heavily Pretreated Relapsed or Refractory Multiple Myeloma. Presented at: The 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, Abstract 29. R6. Takeda Pharmaceuticals International Co. Submission of Clinical and Economic Data Supporting Formulary Consideration of Ninlaro (ixazomib). Formulary Dossier. November 20, R7. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N Engl J Med Aug 13;373(7): R8. 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 Jun;17(6):

54 Session Code: 1. Write down the course code. Space has been provided in the daily program-at-aglance sections of your program book. 2. To claim credit: Go to before December 1, 2016.