The KYMRIAH Experience

Transcription

1 The KYMRIAH Experience INDICATION KYMRIAH (tisagenlecleucel) is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. IMPORTANT SAFETY INFORMATION FOR KYMRIAH WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGICAL TOXICITIES Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving KYMRIAH. Do not administer KYMRIAH to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab. Neurological toxicities, which may be severe or life-threatening, can occur following treatment with KYMRIAH, including concurrently with CRS. Monitor for neurological events after treatment with KYMRIAH. Provide supportive care as needed. KYMRIAH is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS. Please see full Prescribing Information for KYMRIAH, including

2 THE LEADER IN CAR-T CELL THERAPY Novartis is proud to offer KYMRIAH (tisagenlecleucel), the first chimeric antigen receptor T-cell (CAR-T cell) therapy approved by the US Food and Drug Administration (FDA). To deliver on our commitment to patients, Novartis has designed a flexible and integrated KYMRIAH manufacturing supply chain platform that allows for a high-quality, individualized treatment approach. Our proven process includes cryopreservation of leukapheresis material and reprogramming T cells with the only FDA-approved 4-1BB CAR. Contraindications None Warnings and Precautions Cytokine Release Syndrome: CRS, including fatal or life-threatening reactions, occurred following treatment with KYMRIAH. In Study 1, CRS occurred in 79% (54/68) of patients receiving KYMRIAH, including grade 3 or 4 (Penn grading system) CRS in 49% (33/68) of patients. The median time to onset of CRS was 3 days (range: 1-22 days). Of the 54 patients with CRS, 27 (50%) received tocilizumab; 7 (13%) patients received 2 doses of tocilizumab, 3 (6%) patients received 3 doses of tocilizumab and 14 (26%) patients received addition of corticosteroids (e.g. methylprednisolone). The median time to resolution of CRS was 8 days (range: 1-36 days).

3 THE LEADER IN CAR-T CELL THERAPY Since 2011, Novartis has manufactured KYMRIAH (tisagenlecleucel) CAR-T cells for more than 300 patients, from 11 countries, across various indications in both clinical trials and the commercial setting. With this experience, we have continuously made enhancements to increase capacity in our 173,000-ft 2, FDA-inspected and audited manufacturing facility. Through our efforts, we have demonstrated a high-quality, reproducible product and strive to reduce turnaround time to meet the needs of patients. Cytokine Release Syndrome (continued): Key manifestations of CRS may include high fever, lower than normal blood pressure, difficulty breathing, and may be associated with hepatic, renal, and cardiac dysfunction, and coagulopathy. Risk factors for severe CRS are high pre-infusion tumor burden, uncontrolled or accelerating tumor burden following lymphodepleting chemotherapy, active infections, and/or inflammatory processes. Delay KYMRIAH infusion after lymphodepleting chemotherapy if patient has unresolved serious adverse reactions from preceding chemotherapies, active uncontrolled infection, active graft vs host disease, or worsening of leukemia burden.

4 OUR MANUFACTURING DIFFERENCE KYMRIAH (tisagenlecleucel) is manufactured for each individual patient, using their own cells, at the Novartis Manufacturing Facility in Morris Plains, NJ, a 30-minute drive from Newark Liberty International Airport. Novartis has enhanced our manufacturing capacity to meet the needs of patients with a target turnaround time of 22 days from receipt* to return. Because KYMRIAH is an individualized therapy, Novartis has developed a process with rigorous quality control to ensure that the Chain of Identity is maintained throughout the manufacturing process. At every step of the process, from leukapheresis to infusion, patient identity must b confirmed and product labels verified for accuracy and patient safety. * Receipt of both leukapheresis material and hospital purchase order for KYMRIAH. Target based on receipt of leukapheresis material that meet required specifications. Cytokine Release Syndrome (continued): Ensure tocilizumab is available on-site prior to KYMRIAH infusion. Monitor patients for signs or symptoms of CRS for at least 4 weeks after treatment. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur. At the first sign of CRS, immediately evaluate the patient for hospitalization and institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated.

5 OUR MANUFACTURING DIFFERENCE COLLECTION AND CRYOPRESERVATION SHIP LEUKAPHERESIS PRODUCT RECEIVED RECEIPT TO RETURN TARGET: 22 DAYS SHIP TO CENTER MANUFACTURING STARTS (REPROGRAMMING) CRYOPRESERVATION QUALITY RELEASE (INCLUDES STERILITY RESULTS) 1 day 10 to 11 days 9 days 1 day Neurological Toxicities: Neurological toxicities, which may be severe or life-threatening, can occur following treatment with KYMRIAH (tisagenlecleucel). The majority of neurological toxicities occurred within 8 weeks following KYMRIAH infusion. In Study 1, neurological toxicities within 8 weeks after KYMRIAH infusion occurred in 65% of patients, including grade 3 or 4 neurological toxicities in 18% of patients, and 75% of events resolved within 12 days. The most common neurological toxicities were headache (37%), encephalopathy (34%), delirium (21%), anxiety (13%), and tremor (9%).

6 THE KYMRIAH PROCESS Collection and Cryopreservation After an appropriate patient is identified for treatment with KYMRIAH (tisagenlecleucel), some of their white blood cells, including T cells, are collected through leukapheresis. The fresh leukapheresis material is then preserved at the treatment center s cellprocessing facility within 24 hours of collection. This is known as cryopreservation. Cryopreservation does not impair T-cell viability or function. 1-3 Researched and refined over more than 4 decades, cryopreservation has become an essential component of protocols for cell therapies, including CAR-T cell therapy. 1,3,4 Neurological Toxicities (continued): Other manifestations of neurological toxicities included disturbances in consciousness, disorientation, confusion, agitation, seizures, mutism and aphasia. Monitor patients for neurological events and exclude other causes for symptoms. Provide supportive care as needed for KYMRIAH-associated neurological events.

7 WHY CRYOPRESERVE? Cryopreservation allows for greater flexibility Adaptable Apheresis You can schedule collection as soon as a patient is identified, as you do not need to wait for a manufacturing slot. Storage You can proactively collect cells, and store leukapheresis material for up to 9 months before manufacturing begins, if you decide that is the best treatment course for your patient. 5 Cryopreserved Shipping When the cryopreserved leukapheresis material is shipped to our state-of-the-art manufacturing facility, the shipping container provides a 1-week safety net to keep cryopreserved leukapheresis material frozen in case of weather-related delays. KYMRIAH REMS to Mitigate CRS and Neurological Toxicities: Because of the risk of CRS and neurological toxicities, KYMRIAH (tisagenlecleucel) is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS. Further information is available at or KYMRIAH ( ). Hypersensitivity Reactions: Allergic reactions may occur with KYMRIAH. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide or dextran 40 in KYMRIAH.

8 THE ONLY FDA-APPROVED 4-1BB CAR-T CELL THERAPY Our proven process includes reprogramming a patient s own T cells into KYMRIAH (tisagenlecleucel), using a CAR containing a 4-1BB costimulatory domain. 6 Once the cryopreserved leukapheresis material is received at our state-of-the-art manufacturing facility, it is thawed and reprogramming can begin. Lentiviral vector Reprogrammed KYMRIAH CAR-T cell Detailed view of cell interaction Cell membrane 4-1BB: enhances expansion and persistence CD3ζ: critical signaling domain for activation and antitumor activity Lentiviral transduction delivers transgene encoding the CD19-specific CAR KYMRIAH CAR 6 KYMRIAH CAR-T cells have the ability to bind to and eliminate CD19-expressing cancerous and other B cells 6,7 Serious Infections: Serious infections, including life-threatening or fatal infections, occurred in patients after KYMRIAH infusion. In Study 1, infections (all grades) after KYMRIAH infusion occurred in 40 patients (59%), including 24 patients (35%) with grade 3 and 4 infections and 2 patients (3%) with fatal infections. Infections with an unknown pathogen occurred in 41% of patients, viral infections in 26%, bacterial infections in 19%, and fungal infections in 13%.

9 EXPANSION AND ENDURANCE Costimulatory domains vary by CARs, and play a critical role in augmenting CAR-T cell functions of expansion and endurance. 4-1BB CD28 Used in KYMRIAH Shown to enhance early expansion and long-term endurance of CAR-T cells in vivo and in vitro 7,8 Demonstrated to induce central memory T-cell differentiation for enduring protection and immunosurveillance in vitro 8 May help KYMRIAH (tisagenlecleucel) CAR-T cells evade some of the body s native immunosuppressive stimuli 9 Shown to be involved in early and rapid expansion in vitro 7 Correlated with effector memory T-cell differentiation, known to provide immediate protection with limited long-term persistence in vitro 8 Serious Infections (continued): Prior to KYMRIAH infusion, infection prophylaxis should follow local guidelines. Monitor patients for signs and symptoms of infection after treatment with KYMRIAH and treat appropriately. Febrile neutropenia (grade 3 or 4) was also observed in 37% of patients after KYMRIAH 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.

10 THE NOVARTIS COMMITMENT TO PATIENTS As a reminder of our commitment to patients and their families in need of KYMRIAH (tisagenlecleucel) CAR-T cell therapy, we have positioned the Wall of Hope in the main thoroughfare of our manufacturing facility. It lights up every time a patient s T cells are reprogrammed into KYMRIAH CAR-T cells. Serious Infections (continued): 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. HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-hbc positive. Reactivation of HBV replication is often followed by hepatitis. Perform screening for HBV, HCV and HIV in accordance with clinical guidelines before cell collection for manufacturing.

11 KYMRIAH CARES is dedicated to providing personalized support throughout the KYMRIAH (tisagenlecleucel) treatment journey. Call KYMRIAH CARES at KYMRIAH ( ) for information on KYMRIAH, treatment center locations, coverage support, and patient assistance. Prolonged Cytopenias: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and KYMRIAH infusion. Grades 3 and 4 cytopenias not resolved by Day 28 following KYMRIAH treatment included neutropenia (40%) and thrombocytopenia (27%) among 52 responding patients. At 56 days following KYMRIAH, 17% and 12% of responding patients had grades 3 and 4 neutropenia or thrombocytopenia respectively. Prolonged neutropenia has been associated with increased risk of infection. Myeloid growth factors, particularly GM-CSF, are not recommended during the first 3 weeks after KYMRIAH infusion or until CRS has resolved.

12 INDICATION KYMRIAH (tisagenlecleucel) is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. IMPORTANT SAFETY INFORMATION FOR KYMRIAH WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGICAL TOXICITIES Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving KYMRIAH. Do not administer KYMRIAH to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab. Neurological toxicities, which may be severe or life-threatening, can occur following treatment with KYMRIAH, including concurrently with CRS. Monitor for neurological events after treatment with KYMRIAH. Provide supportive care as needed. KYMRIAH is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS. Contraindications None Warnings and Precautions Cytokine Release Syndrome: CRS, including fatal or life-threatening reactions, occurred following treatment with KYMRIAH. In Study 1, CRS occurred in 79% (54/68) of patients receiving KYMRIAH, including grade 3 or 4 (Penn grading system) CRS in 49% (33/68) of patients. The median time to onset of CRS was 3 days (range: 1-22 days). Of the 54 patients with CRS, 27 (50%) received tocilizumab; 7 (13%) patients received 2 doses of tocilizumab, 3 (6%) patients received 3 doses of tocilizumab and 14 (26%) patients received addition of corticosteroids (e.g. methylprednisolone). The median time to resolution of CRS was 8 days (range: 1-36 days). Key manifestations of CRS may include high fever, lower than normal blood pressure, difficulty breathing, and may be associated with hepatic, renal, and cardiac dysfunction, and coagulopathy. Risk factors for severe CRS are high pre-infusion tumor burden, uncontrolled or accelerating tumor burden following lymphodepleting chemotherapy, active infections, and/or inflammatory processes. Delay KYMRIAH infusion after lymphodepleting chemotherapy if patient has unresolved serious adverse reactions from preceding chemotherapies, active uncontrolled infection, active graft vs host disease, or worsening of leukemia burden. Ensure tocilizumab is available on-site prior to KYMRIAH infusion. Monitor patients for signs or symptoms of CRS for at least 4 weeks after treatment. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur. At the first sign of CRS, immediately evaluate the patient for hospitalization and institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated. Please see additional Important Safety Information on next pages.

13 IMPORTANT SAFETY INFORMATION FOR KYMRIAH (continued) Neurological Toxicities: Neurological toxicities, which may be severe or life-threatening, can occur following treatment with KYMRIAH (tisagenlecleucel). The majority of neurological toxicities occurred within 8 weeks following KYMRIAH infusion. In Study 1, neurological toxicities within 8 weeks after KYMRIAH infusion occurred in 65% of patients, including grade 3 or 4 neurological toxicities in 18% of patients, and 75% of events resolved within 12 days. The most common neurological toxicities were headache (37%), encephalopathy (34%), delirium (21%), anxiety (13%), and tremor (9%). Other manifestations of neurological toxicities included disturbances in consciousness, disorientation, confusion, agitation, seizures, mutism and aphasia. Monitor patients for neurological events and exclude other causes for symptoms. Provide supportive care as needed for KYMRIAH-associated neurological events. KYMRIAH REMS to Mitigate Cytokine Release Syndrome and Neurological Toxicities: Because of the risk of CRS and neurological toxicities, KYMRIAH is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS. Further information is available at or KYMRIAH ( ). Hypersensitivity Reactions: Allergic reactions may occur with KYMRIAH. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide or dextran 40 in KYMRIAH. Serious Infections: Serious infections, including life-threatening or fatal infections, occurred in patients after KYMRIAH infusion. In Study 1, infections (all grades) after KYMRIAH infusion occurred in 40 patients (59%), including 24 patients (35%) with grade 3 and 4 infections and 2 patients (3%) with fatal infections. Infections with an unknown pathogen occurred in 41% of patients, viral infections in 26%, bacterial infections in 19%, and fungal infections in 13%. Prior to KYMRIAH infusion, infection prophylaxis should follow local guidelines. Monitor patients for signs and symptoms of infection after treatment with KYMRIAH and treat appropriately. Febrile neutropenia (grade 3 or 4) was also observed in 37% of patients after KYMRIAH 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. 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. HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-hbc positive. Reactivation of HBV replication is often followed by hepatitis. Perform screening for HBV, HCV and HIV in accordance with clinical guidelines before cell collection for manufacturing. Prolonged Cytopenias: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and KYMRIAH infusion. Grades 3 and 4 cytopenias not resolved by Day 28 following KYMRIAH treatment included neutropenia (40%) and thrombocytopenia (27%) among 52 responding patients. At 56 days following KYMRIAH, 17% and 12% of responding patients had grades 3 and 4 neutropenia or thrombocytopenia respectively. Prolonged neutropenia has been associated with increased risk of infection. Myeloid growth factors, particularly GM-CSF, are not recommended during the first 3 weeks after KYMRIAH infusion or until CRS has resolved. Please see additional Important Safety Information on next page.

14 IMPORTANT SAFETY INFORMATION FOR KYMRIAH (continued) Hypogammaglobulinemia: Hypogammaglobulinemia and agammaglobulinemia (IgG) can occur in patients with a complete remission after KYMRIAH (tisagenlecleucel) infusion. In Study 1, 43% of patients had hypogammaglobulinemia. B-cell aplasia is an on-target effect of KYMRIAH and therefore a patient may experience hypogammaglobulinemia for as long as KYMRIAH persists. Monitor immunoglobulin levels after treatment with KYMRIAH and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement standard guidelines. The safety of immunization with live viral vaccines during or following KYMRIAH treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of lymphodepleting chemotherapy, during KYMRIAH treatment, and until immune recovery following treatment with KYMRIAH. Pregnant women who have received KYMRIAH may have hypogammaglobulinemia. Assess immunoglobulin levels in newborns of mothers treated with KYMRIAH. Secondary Malignancies: Patients treated with KYMRIAH may develop secondary malignancies or recurrence of their leukemia. Monitor life-long for secondary malignancies. If a second malignancy occurs, call KYMRIAH ( ) to obtain instructions on patient samples to collect for testing. Effects on Ability to Drive and Use Machines: Due to the potential for neurological events, patients receiving KYMRIAH are at risk for altered or decreased consciousness or coordination in the 8 weeks following infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities during this initial period. Drug Interactions HIV and the lentivirus used to make KYMRIAH have limited short spans of identical genetic material (RNA). Therefore, some commercial HIV nucleic acid tests (NATs) may yield false positive results in patients who have received KYMRIAH. Pregnancy, Lactation, Females and Males of Reproductive Potential There are no available data of KYMRIAH use in pregnant or lactating women. Therefore, KYMRIAH is not recommended for women who are pregnant or breastfeeding. Pregnancy after KYMRIAH administration should be discussed with the treating physician. Pregnancy status of females of reproductive potential should be verified with a pregnancy test prior to starting treatment with KYMRIAH. Report pregnancies to Novartis Pharmaceuticals Corporation at Adverse Reactions The most common adverse reactions (incidence greater than 20%) are cytokine release syndrome, hypogammaglobulinemia, infections-pathogen unspecified, pyrexia, decreased appetite, headache, encephalopathy, bleeding, hypotension, tachycardia, nausea, diarrhea, vomiting, viral infection disorders, hypoxia, fatigue, acute kidney injury, and delirium.

15 To learn more about KYMRIAH (tisagenlecleucel), please visit KYMRIAH-hcp.com. References: 1. Shu Z, Heimfeld S, Huang Z, Liu C, Gao D. Progress in cryopreservation of stem cells and immune cells for cytotherapy. In: Demirer T, ed. Progress in Stem Cell Transplantation. Rijeka, Croatia: InTechOpen; 2015: Wang SY, Hsu ML, Tzeng CH, Hsu HC, Ho CK. The influence of cryopreservation on cytokine production by human T lymphocytes. Cryobiology. 1998;37(1): Sadeghi A, Ullenhag G, Wagenius G, Tötterman TH, Eriksson F. Rapid expansion of T cells: effects of culture and cryopreservation and importance of short-term cell recovery. Acta Oncol. 2013;52(5): Thierry C, Turc JM, Valles H, Serrou B. Routine technique of lymphocyte cryopreservation evaluated by in vitro tests of immune response. Eur J Cancer. 1977;13(4-5): Data on file. Novartis CTL019 Leukapheresis Reference Manual: Leukapheresis Collection. Novartis Pharmaceuticals Corporation; Dec Kymriah [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; Milone MC, Fish JD, Carpenito C, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther. 2009;17(8): Kawalekar OU, O Connor RS, Fraietta JA, et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity. 2016;44(2): Kalos M, Levine BL, Porter DL, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3(95):95ra73. doi: /scitranslmed Please see Important Safety Information throughout. Please see full Prescribing Information for KYMRIAH, including Novartis Pharmaceuticals Corporation East Hanover, New Jersey Novartis 3/18 KYM