Division of Oncology Drug Products Presentation NDA 21-649 Genasense (Oblimersen) for metastatic melanoma ODAC May

1. Division of Oncology Drug Products Presentation NDA 21-649 Genasense (Oblimersen) for metastatic melanomaODAC May 3, 2004

2. Project Management Nicholette Hemingway, MPH Medical Review Robert Kane, MD Ann Farrell, MD Statistical Review Peiling Yang, Ph.D. Rajeshwari Sridhara, Ph.D. Pharmacology Lilliam Rosario, Ph.D. David E. Morse, Ph.D Chemistry Haripada Sarker, Ph.D. Hasmukh Patel, Ph.D. Clin. Pharm/Biopharm Gene Williams, Ph.D. Brian Booth, Ph.D. FDA Review Team for Genasense (G3139)

3. Presentation Outline • Requirements for FDA approval • ODAC Review of Temozolomide • Genasense (Oblimersen) NDA 21-649 • Trial Design (GM 301) • Primary Endpoint – Survival • Secondary Endpoints • Summary

4. Requirements - New Drug Approval • FD&C Act 1962 - Substantial evidence of effectiveness required by Congress • Adequate & well-controlled investigations • Generally understood to mean evidence from at least 2 adequate and well-controlled studies

5. Requirements - New Drug Approval • FDAMA - 1997 One trial may suffice with other confirmatory evidence • Effectiveness Guidance Document - 1998 A single trial should be of excellent design, internally consistent, and demonstrate a compelling result – statistically strong evidence of an important clinical benefit such as survival.

6. New Drug Approval Efficacy Requirement • Regular approval • clinical benefit or established surrogate • Accelerated Approval • uses a surrogate endpoint reasonably likely to predict clinical benefit • confirmation of clinical benefit required

7. Approved drugs - Metastatic Melanoma • Hydroxyurea (1967) - 10% response rate • Dacarbazine (1975) – DTIC single arm studies Response Rate (RR) = 23% (6%CR) Survival times range 5 – 9 months • To date, no evidence for Survival or Progression-free Survival (PFS) benefit for DTIC • RR: 5% - 24% in other studies No evidence for survival advantage for any combination over DTIC alone • Aldesleukin (1998) – IL-2 • RR: 16% (6% CR with duration 2-5 yrs)

8. Selected Non-approved drugs for Metastatic Melanoma • Interferon • 1997 Interferon alfa-2b approval for adjuvant therapy of melanoma • Temozolomide • ODAC 1999

9. Temozolomide (TMZ) • One main study: open label, 305 patients with metastatic melanoma randomized to DTIC IV each 3 weeks versus TMZ p.o. each 4 weeks • Primary Endpoint – Survival (superiority) from median 6 mo-DTIC to 9 mo-TMZ • Secondary endpoints: PFS and RR

10. TMZ Results ITT population

11. TMZ was not approved • Failed Primary Endpoint: No Survival benefit • PFS, a secondary endpoint, small magnitude • ODAC questioned the PFS difference • No symptomatic benefit demonstrated • A post-hoc survival analysis using a 6 month endpoint was not convincing

12. Genasense GM301 TrialRegulatory History • July 2000 - Phase 3 protocol began • August 1, 2003 – Data Cutoff Date • December 8, 2003 - NDA submission

13. Genasense GM301 Trial Design • Large, multicenter, unblinded study • Prolonged central venous access required for Genasense (G) • Protocol specified IRC for responders • Intellectual, emotional, and physical ability to maintain an ambulatory infusion pump (for patients assigned to G + DTIC)

14. Genasense GM301 Trial Design • Primary Endpoint – Survival Improvement Secondary endpoints: • Progression-free survival (PFS) • Response rate (RR) • Duration of response • Durable response rate (RR at 6 months) • Performance status (PS) • Tumor-related symptoms • Safety

15. Genasense Trial Design - GM301 • Trial design - to show a 2 month median improvement in survival from 6 months with DTIC alone to 8 months with Genasense plus DTIC; 90% power • Trial Primary endpoint – survival • Trial Primary analysis – unadjusted log rank analysis of the intention-to-treat population

16. Patient Disposition – GM301

17. Genasense study GM301 • Data cutoff date August 1, 2003 • Analysis occurred at 535 deaths (70%) • Primary Endpoint Analysis: Using the protocol specified analysis with the ITT population, no survival benefit was demonstrated by adding Genasense to DTIC treatment versus DTIC alone.

18. GM 301: Primary Analysis Survival Time ITT population

19. Statistical Review of Efficacy: Progression-Free Survival (PFS) (Secondary Endpoint)

20. Results • Failed to demonstrate efficacy in the primary endpoint, overall survival • at two-sided alpha level of 0.05 • Strength of efficacy findings in the secondary endpoint, progression-free survival, is uncertain

21. Outline • Review of Applicant’s Analyses and Results • Major FDA Concern: Lesion Assessment Times • Additional FDA Concerns

22. Review of Applicant’s PFS Analyses and Results • PFS • Time from date of randomization to date of disease progression/death • Recorded Date of Disease Progression • The assessment date • Assessment date in each cycle: • The latest date among different lesion assessments in that cycle

23. Review of Applicant’s PFS Analyses and Results • Protocol-Specified Analysis: • Logrank: p-value = 0.0003 • Median:74 (G3139 + DTIC) vs. 49 days (DTIC) • Cox Model (supportive): Hazard Ratio = 0.73 • Alternative Approach: • Logrank: p-value = 0.0006 • Median:61 (G3139 + DTIC) vs. 48 days (DTIC) • Cox model (supportive): Hazard Ratio = 0.75

24. Review of Applicant’s PFS Analyses and Results • Question: Is this a true finding?

25. Major FDA Concern: Lesion Assessment Times • Imbalance in Observed Lesion Assessment Times between Treatment Arms

26. Lesion Assessment Times • Planned Timing for Lesion Assessments • In Practice: • Not always as planned. • Even when assessed in planned cycles, there were differences in timing between arms.

27. Determining Event Dates Survival Analysis Survival Event Date Randomization Visit 1 Visit 2 PFS Analysis PFS Event Date Randomization Visit 1 Visit 2 = Date of Death or actual tumor progression

28. Summary of Time to First 3 Observed Lesion Assessments (Actual Trial Data)

29. Time to 1st Assessment(Trial Data)

30. Time to 2nd Assessment(Trial Data)

31. Time to 3rd Assessment(Trial Data)

32. Lesion Assessment Times • Impact of Imbalance in Assessment Times on PFS Analysis: • Bias may be introduced in estimating PFS • Even a small imbalance may lead to incorrect conclusion

33. Lesion Assessment Times

34. Lesion Assessment Times Impact of systematic bias: Simulation study • Distribution identical in both arms (Median PFS = 50 days, 300 subjects in each arm) • Systematic increase by 2 days in assessment time in one arm • In 98% of the 5000 simulations p-values were < 0.05 (average p-value = 0.004)

35. Additional FDA Concern • Missing data was observed • Missing assessments visits • Missing individual lesion measurements • In presence of missing data • Bias could be introduced, especially in an open-label study

36. Summary of PFS Finding The claimed PFS benefit may not be a true finding because of: • Difference in assessment intervals may explain observed PFS effect • Questions regarding reliability of data collected in an open-label study

37. Summary of Statistical Review • Study failed to achieve the primary objective of the study – No Overall Survival Benefit • Secondary endpoints – PFS analysis: • Existence of effect ? • Magnitude of effect ? • Multiplicity Issues

38. PFS analysis - continued • Assessments done only at 6 week intervals, however PFS difference only 2-3 weeks • PFS difference is highly statistically significant, but may be fully accounted for by asymmetry in timing of assessments between arms • Magnitude of the effect size is uncertain • PFS: Real problem: what is the clinical relevance

39. Primary Endpoint – Survival No Advantage for Genasense • Secondary endpoints: • Progression-free survival (PFS) • Response rate (RR) • Response duration • Durable response rate • Performance status (PS) • Tumor-related symptoms • Safety

40. Comparison of RRdata as of original NDA submission (12/8/03)

41. Response Concordance • 5 CRs identified by Genta/site investigators • 3 in G + DTIC arm and 2 in DTIC arm • None were adjudicated as CRs by Independent Review • 44% of responders (CR or PR) by Genta/site investigators were determined not assessable or unconfirmed by Independent Review. • 49% full concordance rate for response category between Genta and Independent Review.

42. Genta New Response Data provided April 9, 2004 • New data is being examined • Problems with data developed outside of the study protocol: • Ascertainment bias between arms can occur when analysis is not prospectively planned • Subsequent therapies, e.g. surgery, not part of the protocol treatment may not be applied symmetrically

43. Duration of Response – Genta analysis

44. Durable response rateGenta Analysis • Genta has pre-specified a response of ≥ 6 months as a durable response. • Durable response rate for G + D = 3.4% • Durable response rate for D = 1.3% • Difference - not significant

45. ECOG Performance Status • There were no differences in performance status observed between study arms during treatment

46. Tumor-related symptoms • There were no differences in symptoms observed between study arms during treatment

47. Adverse Events – Toxicity

48. Adverse Events Hematologic Toxicity

49. Adverse Events ≥5%Non-hematologic Toxicity

50. Adverse Events ≥ 5%Non-hematologic Toxicity