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2015 Post-ASH Report

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2015 Post-ASH Report Datamonitor Healthcare Trialtrove Biomedtracker Pharma intelligence | Pharma intelligence | Pharma intelligence | 2015 Post-ASH Report RACHEL MEIGHAN-MANTHA Principal Analyst, Citeline JOSEPH HEDDEN Senior Analyst, Datamonitor Healthcare Summary Profiled themes at the 57th Annual Meeting and Exposition of the American Society of Hematology (ASH), held December 5-8, 2015, in Orlando, Florida, included Genomic Profiling and Chemical Biology, Genome Editing and Gene Therapy, Epigenetic Mechanisms, Immunologic Treatments, Stem Cell Biology and Regenerative Medicine and Preventing Venous Thromboembolic Disease. This report will mainly focus on the theme of Immunologic Treatments because of the importance and popularity of immunotherapies for many different hematological cancers. Also covered in this report are the results from pivotal trials presented at ASH, as well as highlights from other drugs/therapies of interest. In addition, we felt it was important to cover first-in-human trials since (hopefully) some of these drugs/therapies will be in pivotal trials in a few years. At the end of the report, we’ve included a section showcasing drugs that had top- line results presented at ASH, followed by a list of other data presentations supplied by BioMedTracker (BMT). Accompanying links to BioMedTracker events along with changes to the drugs’ likelihood of approval (LOA) are also provided throughout the report. Finally, additional supplemental material related to ASH is listed in the Appendix. 2 Datamonitor Healthcare Trialtrove Biomedtracker 2 Pharma intelligence | Pharma intelligence | Pharma intelligence | Contents Advancements in Immuno-Oncology 4 CAR-T Cell Therapies 4 CAR-BCMA for Multiple Myeloma 4 CTL019 for Diffuse Large B-Cell Lymphoma (DLBCL) - NHL 5 JCAR014 for Hematologic Cancer 6 CD30.CARTs for CD30+ Hodgkin and Non-Hodgkin Lymphomas 6 CTL019 for Acute Lymphocytic Leukemia (ALL) 7 JCAR015 for Acute Lymphocytic Leukemia (ALL) 8 CTL119 for CD19+ Acute Lymphocytic Leukemia (ALL) 8 KTE-C19 for Acute Lymphocytic Leukemia (ALL) 9 KTE-C19 for Indolent Non-Hodgkin's Lymphoma - NHL 9 CAR-T Cell Therapy Trials in Hematological Malignancies 10 Advancements in PD-1 Development 11 Opdivo for Hodgkin's Lymphoma 12 Keytruda for Hodgkin's Lymphoma 12 Keytruda for Chronic Lymphocytic Leukemia (CLL)/Small Cell Lymphocytic 14 Lymphoma (SLL) - NHL Keytruda for Multiple Myeloma (MM) 15 Other Key Immunotherapy Data 16 Darzalex for Multiple Myeloma (MM) 16 Empliciti for Multiple Myeloma (MM) 17 Other Drugs/Therapies of Interest 19 Zydelig for Chronic Lymphocytic Leukemia (CLL)/Small Cell Lymphocytic 19 Lymphoma (SLL) - NHL Acalabrutinib for Chronic Lymphocytic Leukemia (CLL)/Small Cell 20 Lymphocytic Lymphoma (SLL) - NHL Pivotal Trials 21 Midostaurin for Acute Myelogenous Leukemia (AML) 21 Imbruvica for Chronic Lymphocytic Leukemia (CLL)/Small Cell 22 Lymphocytic Lymphoma (SLL) - NHL Ninlaro for Multiple Myeloma (MM) 24 First-in-Human in Hematological Malignancies 26 Top-Line Results Presented at ASH 28 Additional Results Presented at ASH 31 Appendix: Additional ASH Content 38 3 Datamonitor Healthcare Trialtrove Biomedtracker 3 Pharma intelligence | Pharma intelligence | Pharma intelligence | Advancements in Immuno-Oncology CAR-T Cell Therapies CAR-T cell therapies certainly generated lots of interest this year at ASH based on audience numbers in the sessions where these therapies were presented. However, in contrast to the euphoria generated at previous ASH meetings, the focus this year was directed towards practical issues associated with using CAR-T cell therapies. Results still generated continued interest but this excitement was tempered by persistent issues of safety, durability of response, relapse and manufacturing. Highlights of several presentations are covered in the tables below. CAR-BCMA for Multiple Myeloma Remissions of Multiple Myeloma during a First-in-Humans Clinical Trial of T Cells Expressing an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor (Abstract #LBA1) Primary CAR-BCMA Disease r/r BCMA+ MM Trial ID NCT02215967 Drug Sponsor NCI Treatment Cy/Flu lymphodepletion before CAR-BCMA infusion (0.3 – 9 x 106 T cells/kg) 12 pts; 1 stringent CR in high disease burden pt Results 2-10+ wk DOR Substantial but reversible toxicity A bluebird bio Phase I trial with a similar BCMA-CAR-T candidate (bb2121) is Comment expected to begin enrollment in early 2016. Dr. Kochenderfer will serve as one of the principal investigators for this trial. 4 Datamonitor Healthcare Trialtrove Biomedtracker 4 Pharma intelligence | Pharma intelligence | Pharma intelligence | CTL019 for Diffuse Large B-Cell Lymphoma (DLBCL) - NHL Phase IIa – NHL (Penn) Change to BMT LOA: 0% Sustained Remissions Following Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) in Patients with Relapsed or Refractory CD19+ Lymphomas (Abstract #183) Primary CTL019 Disease r/r Adult CD19+ NHL Trial ID NCT02030834 Drug Sponsor University of Pennsylvania-Abramson/Novartis Treatment Lymphodepletion d-4 to d-1 before CTL019 infusion (1-5 x 108 T cells/kg) 43 pts; DLBCL = 26, FL = 14 and MCL = 3; 30/43 pts infused DLBCL (n = 15): 3 mo ORR 47%; 3 CR at 3 mo – 6 CR at 6 mo; mPFS 3 mo Results FL (n = 11): 3 mo ORR 73%; 4 CR at 3 mo – 7 CR at 6 mo; mPFS not reached No relapses observed for CR pts CRS generally Grade 2 Response, improvement of response after infusion and duration of response Comment look most promising in follicular lymphoma patients. 5 Datamonitor Healthcare Trialtrove Biomedtracker 5 Pharma intelligence | Pharma intelligence | Pharma intelligence | JCAR014 for Hematologic Cancer Phase I/II – NHL/CLL/ALL Change to BMT LOA: 0% Anti-CD19 Chimeric Antigen Receptor-Modified T Cell Therapy for B Cell Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia: Fludarabine and Cyclophosphamide Lymphodepletion Improves In Vivo Expansion and Persistence of CAR-T Cells and Clinical Outcomes (Abstract #184) Primary Adult, CD19+ B-cell JCAR014 Disease Trial ID NCT01865617 Drug NHL, CLL and ALL Sponsor University of Washington - Fred Hutchinson Lymhodepletion (Cy, Cy/E or Cy/Flu) d-4 to d-2 before 1:1 CD4+:CD8+ Treatment JCAR014 infusion (2 x 105 – 107 T cells/kg) NHL 32 pts: 63% CRS (13% severe); 25% Grade 3/4 neurotoxicity Cy/Flu lymphodepletion improved CAR-T cell expansion and persistence, Results reduced transgene immune responses and enabled responses to 2nd infusion non-Cy/Flu: 50% ORR / 8% CR vs. Cy/Flu: 72% ORR / 50% CR CLL 9 pts: 89% ORR / 44% CR Promising results for heavily pretreated patients (median of five prior Comment therapies). Beneficial effects of balanced CD4+/CD8+ CAR-T cells and Cy/Flu lymphodepletion need to be confirmed. CD30.CARTs for CD30+ HL and NHL Chimeric T Cells for Therapy of CD30+ Hodgkin and Non-Hodgkin Lymphomas (Abstract #185) Primary CD30.CARTs Disease CD30+ HL and NHL Trial ID NCT01316146 Drug Sponsor Baylor College Treatment 3 DLs: 2 x 107 – 2 x 108 T cells/m2 (no prior lymphodepletion) 9 pts; 2 CR and 1 PR to date Results Viral immunity not comprised in pts Larger patient population is needed to confirm results. Presenter concluded Comment adequate lymphodepletion is needed for CAR-T cell expansion. 6 Datamonitor Healthcare Trialtrove Biomedtracker 6 Pharma intelligence | Pharma intelligence | Pharma intelligence | CTL019 for Acute Lymphocytic Leukemia (ALL) Phase II – Pediatric (UPenn) Change to BMT LOA: 0% Durable Remissions in Children with Relapsed/Refractory ALL Treated with T Cells Engineered with a CD19-Targeted Chimeric Antigen Receptor (CTL019) (Abstract #681) Primary CTL019 Disease r/r Pediatric CD19+ ALL Trial ID NCT02228096 Drug Sponsor University of Pennsylvania - Abramson/Novartis Treatment Lymphodepletion 1 wk before CTL019 infusion (107 to 108 T cells/kg) 59 pts; 55 CR (93%); 6 mo RFS: 76%; 12 mo RFS: 55%; 12 mo OS: 79%; 18 pts in remission beyond 1 yr Response similar in MRD+ or MRD- pts IL-6 levels correlated with severe cytokine release syndrome (CRS) Results CRS in 88 % of pts - severity related to disease burden CD19+ relapse highly enriched in pts that lose CARs before 3-6 mo B-cell aplasia, observed in all responding pts, managed with IVIg replacement therapy The highest manufacture failure rate was observed in patients less than Comment three years of age. 7 Datamonitor Healthcare Trialtrove Biomedtracker 7 Pharma intelligence | Pharma intelligence | Pharma intelligence | JCAR015 for Acute Lymphocytic Leukemia (ALL) Phase I – Adults (MSKCC) Change to BMT LOA: 0% Implications of Minimal Residual Disease Negative Complete Remission (MRD-CR) and Allogeneic Stem Cell Transplant on Safety and Clinical Outcome of CD19-Targeted 19-28z CAR Modified T Cells in Adult Patients with Relapsed, Refractory B-Cell ALL (Abstract #682) Primary JCAR015 Disease r/r Adult CD19+ B-cell ALL Trial ID NCT01044069 Drug Sponsor Memorial Sloan-Kettering /Juno Lymphodepletion (Cyclophosphoshamide +/- Fludarabine) d-2 Treatment before CTL019 infusion (1 or 3 x 108 T cells/kg) 45 pts; 37/45 overall CR (82%); overall MRD- CR 30/36 (83%); median time to CR = 21 d 13/37 (35%) pts proceeded to allo HSCT after CT Results 18 pts relapsed during follow-up Overall median OS = 8.0; CR pts mOS = 10.6 mo; MRD- CR mOS not reached; MRD+ mOS = 6 mo Severe CRS = 24%; Grade 3/4 neurotoxicity = 28%; Grade 5 = 6% Did adding fludarabine to the lymphodepletion regimen improve CAR-T cell Comment expansion and persistence? CTL119 for CD19+ Acute Lymphocytic Leukemia (ALL) Efficacy and Safety of Humanized Chimeric Antigen Receptor (CAR)-Modified T Cells Targeting CD19 in Children with Relapsed/ Refractory ALL (Abstract #683) Primary CTL119 Disease r/r Pediatric CD19+ ALL Trial ID NCT02374333 Drug Sponsor University of Pennsylvania - Abramson/Novartis Retreatment with CTL119 in relapsed pts previously treated w/ CD19 CAR-T Treatment cells that had partial or no response 6 pts; CRS and neurotoxicity observed – no Grade 4 CRS nor encephalopathy Chronic B cell aplasia required IVIg replacement Results Early B cell recovery (< 6 mo) associated w/ higher risk of relapse Humanized CTL119 induced remissions (50% CR and 83% relapse) The patient population is too small to make conclusions about the benefits Comment of reinfusion/retreatment.
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