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FDA’s Oncologic Drugs Advisory Committee Meeting

FDA’s Oncologic Drugs Advisory Committee Meeting

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FDA’s Oncologic Drugs Advisory Committee Meeting

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  1. FDA’s Oncologic DrugsAdvisory Committee Meeting DASATINIB(BMS-354825) 2 June 2006

  2. Donna Morgan Murray, PhD Bristol-Myers SquibbGlobal Regulatory Sciences Introduction

  3. BMS Presentation • Introduction .………………..Donna Morgan Murray, PhDBMS,Global Regulatory Sciences • Scientific Rationale ……….Neil Shah, MD, PhDUCSF School of Medicine • Clinical Program ……………Claude Nicaise, MDBMS,Global Development • Clinical Perspective ……...Hagop Kantarjian, MDMD Anderson Cancer Center • Conclusion ………………….Donna Morgan Murray, PhD

  4. Consultants Available to the Committee • Neil Shah, MD, PhDAssistant Professor Division of Hematology/OncologyDepartment of MedicineUCSF School of MedicineSan Francisco, CA • Hagop Kantarjian, MDChairman & ProfessorLeukemia DepartmentThe University of TexasMD Anderson Cancer CenterHouston, TX

  5. Medical Need for Therapeutic Options in CML Chronic Accelerated Blast • Chronic Myeloid Leukemia (CML) is usually treated with imatinib, although resistance and intolerance develops • After imatinib failure, therapeutic options are limited (e.g., escalated doses of imatinib, hydroxyurea, interferon, investigational agents, stem cell transplants) • Dasatinib offers a therapeutic option to patientsin all phases of CML after failure with imatinib

  6. Proposed Indications for Dasatinib • Treatment of adults with chronic, accelerated, or blast phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including imatinib • Treatment of adults with Philadelphia chromosome‑positive (Ph+) acute lymphoblastic leukemia (ALL) and lymphoid blast chronic myeloid leukemia with resistance or intolerance to prior therapy

  7. Neil Shah, MD, PhD UCSF School of Medicine Scientific Rationale

  8. CML The Philadelphia (Ph) Chromosome Leads to CML BCR ABL Ph chromosome BCR-ABL (activated tyrosine kinase)

  9. Chronic Phase – Frontline 16% (42 months) Chronic Phase – IFN failure 26% Accelerated Phase 73% (48 months) Blast Crisis 95% Loss of Response to Imatinib in CML Rate of Relapse/Progression For most imatinib-resistant or -intolerant patients, effective therapeutic options are severely limited Silver et al, 2004; Guilhot et al, 2004; Bhatia et al, 2002; Graham et al, 2002

  10. Clinical Resistance to Imatinib is Associatedwith Restoration of BCR-ABL Kinase Activity • Mechanisms • Outgrowth of one or more clones harboring an imatinib-resistant BCR-ABL kinase domain mutation (most common) • Overproduction of BCR-ABL via genomic amplification • BCR-ABL-independent mechanisms

  11. Map of BCR-ABL Kinase Domain Mutations Associated with Clinical Resistance to Imatinib L248V G383D L298V F311L/I L387F/M G250E/A/F A397P E453G/K E292V T315I/N M388L Q252H/R E459K/Q E450G/Q H396R/P Y253H/F F317L S417Y F486S L364I E255K/V x A C P V379I D276G M351T M244V E355G/D T277A V289A E279K F359C/V/D/I E281A Gorre et al, 2001; von Bubnoff et al, 2002; Branford et al, 2002; Hofmann et al, 2002; Roche-L’Estienne et al, 2002; Shah et al, 2002; Hochhaus et al, 2002; Al-Ali et al, 2004 Courtesy Tim Hughes

  12. Ba/F3 Bcr-Abl E255K T315I M351T M244V G250E Q252H Q252R Y253F Y253H E255V F317L E355G F359V H396R F486S Dasatinib Inhibits Growth of 14/15 Imatinib-Resistant BCR-ABL-Expressing Ba/F3 Cell Lines in vitro 1.2 Parental Ba/F3 cells 1 T315I 0.8 Normalized cell number 48 hours of drug exposure 0.6 0.4 0.2 0 0 0.5 2.5 5 25 50 Concentration of dasatinib (nM)* *Dasatinib is 300-400x more potent than imatinib in vitro Shah et al, Science, 2004

  13. Dasatinib Selectively Inhibits BCR-ABL-dependent Hematopoiesis in vitro CML imatinib-sensitive (no mutation) CML imatinib-resistant (BCR-ABL/M351T) Normal Normal vehicle vehicle BMS-354825 5 nM dasatinib nM 5 Shah et al, Science 2004

  14. Summary of Scientific Rationale: Dasatinib for Imatinib-resistant and -intolerant CML • Imatinib resistance • Potently inhibits nearly all imatinib-resistant BCR-ABL kinase domain mutations • 300-400x more potent than imatinib at inhibiting the activity of BCR-ABL • Imatinib intolerance • Structurally unrelated to imatinib, therefore, cross-intolerance not likely • Selectively inhibits the growth of BCR-ABL-positive hematopoietic progenitors

  15. Claude Nicaise, MD Bristol-Myers SquibbGlobal Development Clinical Program

  16. Clinical Program – Six Studies at 68 Centers • One Phase I Study (002) • Dose escalation study • 15 mg to 180 mg QD and 25 mg to 70 mg BID in chronic phase • 35 mg to 120 mg BID in advanced disease • Intrapatient dose escalation / decrease to safe and effective dose • Four Phase II Studies (013, 005, 006 and 015) • Open label • Patients resistant or intolerant to imatinib • One Randomized Phase II Study (017) • Open label • Control group: imatinib 800 mg/day • Cross-over for lack of response or intolerance

  17. Rationale for 70 mg BID Dose Selection • Optimal drug exposure • Pharmacokinetic parameters • Cmax: 45 ng/mL (90 nM) • Pharmacodynamics and inhibition of pCRKL • ≈ 100% at doses  100 mg/day • BID > QD • Effective dose in Phase I study (002) 70 mg BID • Acceptable safety in Phase I study (002)

  18. Imatinib Resistance • Resistance at the maximum tolerated dose of imatinib • Primary resistance • No complete hematologic response at 3 months • No cytogenetic response at 6 months • No major cytogenetic response at 1 year • Secondary resistance • Loss of complete hematologic response • Loss of major cytogenetic response • Progression to accelerated / blast

  19. Imatinib Intolerance • Imatinib toxicities leading to intolerance • Grade 3-4 non-hematologic toxicity • Grade 4 hematologic toxicity lasting more than 7 days • Patients who responded to imatinib • Developed intolerance while in response • Unable to resume therapy • Patients who never responded to imatinib • Unable to tolerate imatinib at a dose of at least 400 mg

  20. Response Criteria • Cytogenetic Response • Complete (CCyR) Partial (PCyR) Major (MCyR) • 0% Ph+ 1% – 35% Ph+ CCyR + PCyR

  21. Patients in Clinical Program Randomized Trial: Study 017 36 patients (22 dasatinib and 14 imatinib)

  22. Baseline Characteristics

  23. Studies 002, 013 and 017 Efficacy in Chronic Phase CML

  24. Chronic Phase CML Efficacy in Imatinib-resistant Patients

  25. Chronic Phase CML Major Cytogenetic Response Rate inImatinib-resistant Patients Percent Responders N = 32 29 25 28 127 98 92 60 n/N = 12/32 10/29 9/25 10/27 40/127 30/98 32/92 25/60

  26. Chronic Phase CML Efficacy in Imatinib-intolerant Patients

  27. Chronic Phase CML Major Cytogenetic Response inImatinib-intolerant Patients Percent Responders N = 8 8 59 32 n/N = 6/8 6/8 43/59 22/32

  28. Chronic Phase CML Progression-free Survival 013 Int 002 Int 013 Res 002 Res Proportion Not Progressed + + ++ Censored Months

  29. Chronic Phase CML Preliminary Data of the Randomized Study 017

  30. Studies 002 and 005 Efficacy in Accelerated Phase CML

  31. Accelerated Phase CML Efficacy Results

  32. Accelerated Phase CML Progression-free Survival 005 002 Proportion Not Progressed + + Censored Months

  33. Studies 002 and 006 Efficacy in Myeloid Blast Crisis

  34. Myeloid Blast Phase CML Efficacy Results

  35. Myeloid Blast Phase CML Progression-free Survival Proportion Not Progressed 006 002 + + Censored Months

  36. Studies 002 and 015 Efficacy in Lymphoid Blast Crisis and Ph+ ALL

  37. Lymphoid Blast Phase CML / Ph+ ALL Efficacy Results

  38. Lymphoid Blast Phase CML / Ph+ ALL Progression-free Survival Proportion Not Progressed 015 ALL 015 LB + + + Censored 002 LB/ALL Months

  39. Hematologic Responses by Mutation Status C A P • M244V • G250E • Y253H/F • E255K/V • T315I • M351T • E355G • F359C/I/V • H396R/P • MaHR • 13/17 • 19/31 • 15/20 • 8/19 • 0/19 • 12/15 • 6/10 • 8/16 • 14/21 • MCyR • 9/17 • 9/31 • 10/20 • 2/19 • 0/19 • 7/15 • 2/10 • 6/16 • 7/21 34 unique mutations 9 amino acid substitutions account for 68% of all BCR-ABL mutations

  40. Summary of Efficacy • Chronic Phase CML • High rate of major cytogenetic response in imatinib-resistant and imatinib-intolerant patients • Durable responses extending beyond 1 year • Progression-free survival at 6 months predictive oflong-term benefit • Advanced Disease (Accelerated, Blast, Ph+ ALL) • High rate of major hematologic responses • Durable, complete responses in Ph+ ALL • Long-term survivors identified at all stages including patients in blast transformation

  41. Safety

  42. Safety Overview • Safety Database • 511 leukemic patients treated with dasatinib BID • Minimum 8 months of follow-up • Major Findings • Myelosuppression, mostly thrombocytopenia • Fluid retention, including pleural effusion

  43. Myelosuppression

  44. Time to Severe Thrombocytopenia Percent (%)

  45. Adverse Reactions Relatedto Myelosuppression

  46. Management of Myelosuppression

  47. Most Common Non-hematologicAdverse Reactions

  48. Fluid Retention

  49. Pleural Effusion

  50. Management of Pleural Effusion