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

2. 2 FDA Review Team for Genasense (G3139) 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.

3. 3 Presentation Outline 1.Requirements for FDA approval 2.ODAC Review of Temozolomide 3.Genasense (Oblimersen) NDA 21-649 Trial Design (GM 301) Primary Endpoint – Survival Secondary Endpoints 4.Summary

4. 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. 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. 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. 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. 8 Selected Non-approved drugs for Metastatic Melanoma Interferon –1997 Interferon alfa-2b approval for adjuvant therapy of melanoma Temozolomide –ODAC 1999

9. 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. 10 TMZ Results ITT population TMZ N=156 DTIC N=149 Hazard Ratio p value Median Survival 7.7 mo6.4 mo0.850.20 * Median PFS 53 days 42 days0.670.002 * Overall Response Rate 12.2 %9.4 %0.43 ** * log rank ** Chi square

11. 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. 12 Genasense GM301 Trial Regulatory History July 2000 - Phase 3 protocol began August 1, 2003 – Data Cutoff Date December 8, 2003 - NDA submission

13. 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. 14 Genasense GM301 Trial Design Primary Endpoint – Survival Improvement Secondary endpoints: 1.Progression-free survival (PFS) 2.Response rate (RR) 3.Duration of response 4.Durable response rate (RR at 6 months) 5.Performance status (PS) 6.Tumor-related symptoms 7.Safety

15. 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. 16 ITTG + DDTotal Number of Patients Randomized 386385771 Less number not treated152540 Still on study after day 42 (1st assessment) 186 (48%) 151 (39%) 337 (44%) Discontinued early - ( < 8 cycles) 326 (84%) 328 (85%) 654 (85%) Patient Disposition – GM301

17. 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. 18 GM 301: Primary Analysis Survival Time ITT population Number ( %) died Median Survival Time HR * Log rank p G + DTIC n = 386 266 (69%) 274 days 9.0 mo 0.890.18 DTIC n = 385 269 (70%) 238 days 7.8 mo * 95% C.I. (0.75, 1.06)

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

20. 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. 21 Outline Review of Applicant’s Analyses and Results Major FDA Concern: Lesion Assessment Times Additional FDA Concerns

22. 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. 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. 24 Review of Applicant’s PFS Analyses and Results Question: Is this a true finding?

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

26. 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. 27 Visit 1 Visit 2 Randomization = Date of Death or actual tumor progression Survival Event Date Visit 1Visit 2Randomization PFS Event Date Survival Analysis PFS Analysis Determining Event Dates

28. 28 Summary of Time to First 3 Observed Lesion Assessments (Actual Trial Data) Assessment Number Median in days Logrank p-value G3139 + DTICDTIC 14843<0.001 29487<0.001 3137129<0.001

29. 29 Time to 1 st Assessment (Trial Data)

30. 30 Time to 2 nd Assessment (Trial Data)

31. 31 Time to 3 rd Assessment (Trial Data)

32. 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. 33 Lesion Assessment Times How Bias May Be Introduced: A Hypothetical Example Patient 001 Control Patient 002 Experimental Actual day of DPDay 35 1 st time of assessmentDay 42Day 48 Recorded day of DPDay 42Day 48

34. 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. 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. 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. 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. 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. 39 Primary Endpoint – Survival No Advantage for Genasense Secondary endpoints: 1.Progression-free survival (PFS) 2.Response rate (RR) 3.Response duration 4.Durable response rate 5.Performance status (PS) 6.Tumor-related symptoms 7.Safety

40. 40 G + DTIC (N=386) DTIC (N=385) difference P value Genta / Investigator 45 (11.7%) 26 (6.8%)4.9% 0.018 Blinded Independent 26 (6.7%) 14 (3.6%) 3.1% 0.056 Comparison of RR data as of original NDA submission ( 12/8/03)

41. 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. 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. 43 Duration of Response – Genta analysis Intent-to-Treat Population G + DTICDTIC Alone Number of patientsN = 45N = 26 Mean (SD) Days175.7 (136.0)153.5 ( 99.2) Median Days 126.0127.5 Range (Days)(41, 565)(42, 390)

44. 44 Durable response rate Genta 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. 45 ECOG Performance Status There were no differences in performance status observed between study arms during treatment

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

47. 47 CategoryG + DTIC N (%) DTIC N (%) Number of patients receiving any therapy 371360 At least 1 Grade 3 or 4 adverse event (AE) 249 (67%) 154 (43%) At least 1 serious adverse event (SAE) 149 (40%) 97 (27%) At least 1 adverse event and discontinued permanently 69 (19%) 39 (11%) Adverse Events – Toxicity

48. 48 G + DTIC (N = 371) n (%) DTIC (N = 360) n (%) Grade 3 - 4 Neutropenia79 (21%)45 (12%) Grade 3 - 4 Thrombocytopenia58 (16%)23 (6%) Adverse Events Hematologic Toxicity

49. 49 Adverse Events ≥ 5% Non-hematologic Toxicity AEG + DTICDTIC Nausea231 (62%)169 (47%) Pyrexia197 (53%) 63 (18%) Fatigue170 (46%)142 (39%) Vomiting139 (38%) 75 (21%) Infections 123 (33%) 65 (18%) Anorexia 114 (31%) 56 (16%) Headache 97 (26%) 47 (13%)

50. 50 AEG + DTICDTIC Rigors 76 (21%) 16 (4%) Pruritus and Rash 57 (15% ) 18 (5%) Injection site infection 24 (7%) 4 (1%) Injection-site Reactions 21 (6%) 5 (1%) Influenza-like Illness 19 (5%) 3 (0.8%) Upper extremity thrombosis 18 (5%) 3 (0.8%) *Axillary vein, Subclavian vein, Jugular vein, injection site thrombosis and superior vena caval syndrome Adverse Events ≥ 5% Non-hematologic Toxicity

51. 51 Genasense Summary GM301Trial failed its primary protocol- specified endpoint No Survival Benefit demonstrated with the addition of Genasense to DTIC The efficacy of the control arm, DTIC alone, is consistent with other studies.

52. 52 Secondary Endpoints - PFS 1.PFS: No precedent for PFS as evidence of clinical benefit for metastatic melanoma –May not be a true finding –PFS difference may be 13 or 25 days depending on censoring technique chosen for missing data –Clinical relevance ?

53. 53 Secondary Endpoints - Response 2. Response rate: –Difference from DTIC alone: 3 - 5% –No CRs Confirmed by IRC –Clinical relevance ? 3. Durable response rate: No sig. difference (3.4% (G+DTIC) vs. 1.3% (DTIC alone)) 4. Response duration: 126 days (G+DTIC) versus 127.5 days (DTIC alone)

54. 54 Secondary endpoints- Genasense 5. Performance status: - No benefit observed from Genasense 6. Symptomatic benefit: Not observed 7. Safety: Greater toxicity for the combination of G + DTIC