1. NDA 21-874 Genasense (G3139, oblimersen) for the treatment of relapsed/refractory Chronic Lymphocytic Leukemia in combination with fludarabine and cyclophosphamide ODAC September 6, 2006 Robert Kane, MD

2. 2 FDA Review Team for Genasense NDA Project management Nicholette Hemingway, MPH Medical Review –Robert Kane, MD, Medical Officer –Ramzi Dagher, MD Team Leader –Ann Farrell, MD, Acting Deputy Director Statistical Review –Shenghui Tang, PhD Stat Reviewer –Rajeshwari Sridhara, PhD, Stat Team Leader CMC Review –Xiao-Hong Chen, PhD –Ravi Harapanhalli PhD Team Leader

3. 3 Presentation Outline 1.Statutory Requirements for marketing approval 2.NCI-working group response criteria for CLL 3.Approved drugs for CLL 4.Activity of the control arm of study GL303 5.FDA analysis of Genta NDA 21-874 (GL 303) Trial Design Primary Endpoint Secondary Endpoints Efficacy Results – What does Genasense add to the chemotherapy all patients are receiving? Toxicities related to Genasense 6. Conclusions

4. 4 Requirements for Marketing Approval Substantial evidence, from “Adequate & well-controlled investigations” Demonstrating efficacy with acceptable safety Ability to generate product labeling –to define an appropriate patient population and treatment dose These requirements apply equally for accelerated approval or regular (full) approval

5. 5 Requirements for Marketing Approval FDAMA amendments 1997 - one adequate and well-controlled clinical investigation and confirmatory evidence may suffice FDA Guidance on Effectiveness 1998 – If a single trial, must be well-conducted, internally consistent, and demonstrates a compelling result – statistically strong evidence of an important clinical benefit

6. 6 FDA Guidance: Single-study characteristics to support effectiveness a. Large, multicenter study b. Consistent efficacy across key study subsets - i.e. severity of disease, stage, patient ages c. Multiple studies, pairwise comparisons within the study are consistent d. Multiple endpoints involving different events e. Statistically very persuasive – “low” p-value f. Results so compelling that an additional confirming study would be practically or ethically impossible

7. 7 CLL: NCI-WG Response categories CR – complete remission of disease, normal blood counts and marrow, all lasting at least 2 months PR – 50% reduction in blood lymphocyte count AND lymphadenopathy and some improvement in blood counts lasting ≥ 2 months nPR – nodular PR - all elements of CR present except persisting lymphoid aggregates in marrow NCI-WG response categories were developed by a consensus panel in 1988 and revised in 1996 NCI-WG CLL, BLOOD 1996

8. 8 CLL: NCI-WG Response categories nPR: Clinical significance of nPR status uncertain –Persisting marrow lymphocyte aggregates may represent residual disease or reactive normal cells or both –Likely an intermediate outcome between CR and PR Achieving a PR is also a meaningful result What are the clinical outcomes of achieving one of these response categories ?

9. 9 CLL: Time to progression by response category with Fludarabine therapy CR nPR PR nPR and PR appear similar Keating, BLOOD, 1998

10. 10 CLL: Time-to-treatment-failure by response category after FCR therapy CR nPR PR Keating, MJ American Society of Hematology; Annual Education Book 2003 NR

11. 11 FDA Approvals for CLL Therapy Recent CLL drug approvals are based on: - NCI-Working Group criteria using - Overall Response Rate: ORR - ORR consists of CR + nPR + PR - CR plus nPR plus PR should be combined in assessing treatment effect in CLL

12. 12 FDA approved drugs for CLL Alkylating agents –Chlorambucil - 1956 –Cyclophosphamide - 1959 Fludarabine (Fludara) - 1991 Alemtuzumab (Campath) - 2001

13. 13 FDA approved drugs for CLL Fludarabine – 1991 –Two studies; single-agent, single-arm design –Given after alkylating agent therapy –Response criteria were all responders: CR plus PR NCRPRORRResponse duration (median) Survival for all pts (median) MD Anderson 4813%35%48% 1.75 years 43 weeks SWOG3113%19%32% 1.25 years 52 weeks Mean Hemoglobin and Platelet counts increased also.

14. 14 FDA approved drugs for CLL Alemtuzumab (Campath) – 2001 –Three studies; single-agent, single-arm design –after alkylating agents and Fludarabine (a 3 rd line Rx) –Response criteria were all responders: CR plus PR NPrior therapy AA Flu CRPRORRResponse Duration median Study 193100% ** 2%31%33%7 mo Study 232100%34%0%21% 7 mo Study 32492%100%0%29% 11 mo AA, Alkylating agent; Flu, fludarabine; **All were Flu refractory in study 1

15. 15 Combination drug therapy for CLL: Flu/Cy Fludarabine (Flu) + Cyclophosphamide (Cy) Prior Therapy:NCR (%) Nodular nPR (%) PR (%) Overall Response (%) CR+nPR+PR None34352924 88 Alkylating agents20152545 85 Alkylating agent plus fludarabine (Sens) 46121751 80 Alkylating agent plus fludarabine (Res) 2831326 39 Sens: sensitive to last therapy = responded then later relapsed Res: refractory to last therapy = failed to respond or progressed on last therapy and majority also were judged refractory to alkylating agents (O’Brien et al)

16. 16 NDA 21-874 One phase 3 clinical study: Genta study GL303 Two arm, randomized, unblinded, multicenter add-on design study of Genasense with Flu/Cy Population: Patients with relapsed or refractory CLL who require therapy and who have previously received fludarabine Sample size calculation (N = 200) – chosen to demonstrate a 44% response rate – and an absolute increment of 20% in response – over the control arm response rate of 24%

17. 17 Genta Protocol GL303 Central Randomization using random permutated block; stratification by 3 factors: Responsive versus refractory to prior fludarabine (responsive was defined as prior fludarabine response and ≥ 6 months before the patient required additional CLL therapy) 1 to 2 prior treatment regimens versus 3 or more prior regimens Response to last prior therapy > 6 months in duration versus ≤ 6 months in duration

18. 18 GL303 Primary endpoint chosen by Genta: response rate, defined as the CR + nPR responders Primary statistical analysis: continuity-corrected Pearson Chi-Square test of response rate using the intention-to-treat population Response assessment performed by a blinded clinical expert, the study principal investigator

19. 19 GL303 Secondary Efficacy Endpoints as stated in GL303 protocol and Clinical Study Report Overall response rate: ORR All responders (CR + nPR + PR) Time To Disease Progression (TTP) Overall Survival Duration of Response ‘Clinical Benefit’ elements -

20. 20 Pre-specified ‘Clinical Benefit’ elements: GL303 protocol version 7 1. Resolution of: B-symptoms (night sweats, fever) impaired mobility due to lymphadenopathy impaired cosmesis abdominal discomfort due to hepatosplenomegaly early satiety 2. Resolution or reduction in massive splenomegaly 3. Relative improvement in ECOG performance status 4. Improvement in disease-related anemia 5. Improvement in fatigue score

21. 21 GL303 study No composite symptom endpoint or ‘symptom- free interval’ endpoint was pre-specified 6 protocol revisions one additional final statistical analysis plan submitted in August 2004

22. 22 GL303 – therapy plan Genasense (G) plus Flu/Cy arm –G: 3 mg/kg/day days 1-7; continuous IV infusion requiring indwelling IV access catheter and infusion pump ALL patients, on both arms, received same chemotherapy (Flu/Cy) –Fludarabine 25 mg/m2/day plus –Cyclophosphamide 250 mg/m2/day –Each given daily times 3 days Every 28 day cycles, total of 6 planned, for both groups

23. 23 GL303 – therapy plan All patients also required: G-CSF for at least 7 days per cycle sulfamethoxazole-trimethoprim 1 tab bid 3 days every week during and for 6 months after therapy acyclovir 400 mg tid PO daily (or equivalent) during and for 6 months after therapy erythropoietin 40,000 IU/week subcutaneously was advised for all symptomatic patients with hemoglobin values of < 10 g/dL Antiemetics prior to treatment with Flu/Cy Central venous access catheter for Genasense

24. 24 GL303 Timeline First patient enrolled: August 2001 Last patient enrolled: June 2003 Last patient completed therapy: December 2003 Data cutoff for analysis: September 2004 Survival data cutoff: June 2006 (all patients followed for ≥ 3 years) 100 study sites / 241 patients randomized NDA submitted: December 2005

25. 25 GL303: Results Two study arms appear well-balanced for baseline disease and patient characteristics - At baseline, ~ 60% were judged to be Fludarabine refractory in each study arm Average time from diagnosis of CLL to study enrollment was approximately 6 yrs Chemotherapy drug exposure was similar on both study arms –Median number of cycles was 4 for each group Patients completing all 6 cycles: –37% on Flu/Cy –30% on Genasense plus Flu/Cy

26. 26 Response rate for the Genta primary endpoint: CR + nPR patients GL303 N= 241 G plus Flu/Cy (120) n Flu/Cy (121) n P value CR113 nPR95 CR + nPR [95% CI] 20 16.7% [10.5%, 24.6%] 8 6.6% [2.9%, 12.6%] 0.025 a a: Pearson chi square test, continuity corrected

27. 27 Response Rate: ORR: All responding patients (CR + nPR + PR) protocol secondary endpoint GL303 N= 241 G plus Flu/Cy (120) Flu/Cy (121) CR + nPR n % 20 (16.7%) 8 (6.6%) PR n 29 46 ORR: CR + nPR + PR n % 49 41% 54 45%

28. 28 Response duration for all responders (CR + nPR + PR) secondary endpoint FDA analysis: there is no difference in duration of response between the two study arms in GL303

29. 29 Time to progression- TTP (All patients) No difference was demonstrated between the two treatment arms (logrank p = 0.83; hazard ratio = 1.03). In each arm, 27% were censored (mature analysis) Median TTP: Flu/Cy 9 mo G + Flu/Cy 6 mo

30. 30 GL303: Overall survival (OS) The Final OS analysis was performed in June 2006 as pre- specified, after all patients were followed at least 3 years from enrollment. No difference was demonstrated (HR = 0.99) GL303: Overall survival

31. 31 Pre-specified ‘Clinical Benefit’ elements: GL303 protocol version 7 1. Resolution of: B-symptoms (night sweats, fever) impaired mobility due to lymphadenopathy impaired cosmesis abdominal discomfort due to hepatosplenomegaly early satiety 2. Resolution or reduction in massive splenomegaly 3. Relative improvement in ECOG performance status 4. Improvement in disease-related anemia 5. Improvement in fatigue score

32. 32 GL303 Results The FDA analyzed each of Genta's secondary ‘clinical benefit’ elements separately, as pre-specified in the protocol FDA agrees with Genta's stated conclusions in the ODAC briefing document: “Analyses of clinical benefit endpoints show no statistically significant difference in findings between treatment groups." More patients receiving Genasense required red cell transfusions (36% versus 29%) More patients receiving Genasense required platelet transfusions (18% versus 5%) These individual “clinical benefit” elements were the components for the calculation of the composite endpoint “symptom-free time.” This endpoint was not pre-specified and was calculated by adding discontinuous times

33. 33 GL303 Results Additional exploratory analyses by FDA noted no improvement in response with addition of Genasense: For patients ≥ age 65 For women For patients judged by Genta as Fludarabine refractory, for either the (CR + nPR) subgroup or for all responders (CR+nPR+PR) For any of the other stratification factors

34. 34 GL303: Adverse Events (AEs) (NCI CTC version 2) Patients with at least one G plus Flu/Cy N = 115 n (%) Flu/Cy N = 115 n (%) Adverse Event (AE) 115 (100)112 (97) AE leading to drug discontinuation overall 40 (34.8) AE ≥ Grade 3 (severe) 91 (79) 75 (65) Serious AEs * 66 (57) 37 (32) serious AE considered related to study treatment 46 (40) 24 (21) AE leading to death 9 (7.8) 5 (4.3) *Serious AEs: Death, Immediately life-threatening AE, hospitalization, disability

35. 35 GL303 Results: Safety Population (AEs) All gradesGrade 3-4 Preferred termG-FC (N=115) % FC (N=115) % G-FC (N=115) % FC (N=115) % At least 1 TEAE100975044 Nausea724882 Fever48293.52.6 Fatigue443164 Vomiting3023.551 Headache23.51413 Dyspnea2116.542 Dehydration17211

36. 36 GL303 Results: Hematologic toxicity Anemia39421110 Neutropenia24331213 Thrombocytopenia49403320 Bleeding1983.51.7 All gradesGrades 3-4 G-FC (N=115) % FC (N=115) % G-FC (N=115) % FC (N=115) % Grade 3 thrombocytopenia < 50,000 Grade 3 bleeding usually indicates need for RBC transfusion

37. 37 Genasense administration issues The 7 day IV Infusion every 28 days requires Indwelling Intravenous access catheter Infusion pump Maintenance of the infusion: home health or clinic Catheter-related complications

38. 38 Genasense Catheter-related complications *Also includes pain, redness, swelling, bruising, oozing, infiltration at the catheter site GL303Genasense + Flu/Cy (115) n % Flu/Cy (115) n % Total Catheter-related infusion complications* 18 16% 3 2.6% - Catheter Infections 11 1 - Venous thrombosis 2 0

39. 39 Conclusions Genasense in combination with fludarabine and cyclophosphamide for the treatment of relapsed/refractory Chronic Lymphocytic Leukemia

40. 40 Guidance: Single-study characteristics to support effectiveness a. Large, multicenter study b. Consistent efficacy across key study subsets - i.e. severity of disease, stage, age c. Multiple studies, pairwise comparisons within the study d. Multiple endpoints involving different events e. Statistically very persuasive – low p-value f. Results so compelling that a second confirming study would be practically or ethically impossible

41. 41 GL303 In single-arm, single-agent studies in advanced and previously treated diseases, response rates provide preliminary evidence of drug activity and may be of regulatory interest if persuasive in magnitude and duration In parallel group phase 3 trials, meaningful treatment effects are better assessed by comparisons of TTP, PFS, and OS, reflecting treatment effects on the entire study population

42. 42 GL303 Genasense is described as a targeted therapy designed to inhibit the Bcl-2 pathway. However, in this study of CLL patients, no evidence is provided that Genasense inhibits Bcl-2 in these CLL patients or that altering Bcl-2 is beneficial for any group of CLL patients

43. 43 GL303 – Conclusions (1) Study GL303 is a two-arm, phase 3 unblinded add-on design trial to demonstrate the effect of adding Genasense to chemotherapy (Flu/Cy) Study GL303 is complete and provides mature data on response, time to progression, and overall survival.

44. 44 GL303 – Conclusions (2) Response: –The CR+nPR response rate was increased by 10%, to 17%, with the addition of Genasense – The overall response rate was lower with the addition of Genasense, 41%, compared with 45% for the control arm Flu/Cy Duration of response: –For all responders, there is no improvement in duration with the addition of Genasense

45. 45 GL303 – Conclusions (3) The addition of Genasense to the Flu/Cy regimen provided: - no improvement in time to progression - no improvement in overall survival

46. 46 GL303 – conclusions (4) All other pre-specified analyses, as performed by Genta and confirmed by FDA, show no improvements with the addition of Genasense for any of the secondary clinical benefit endpoints: –Resolution of B symptoms –Resolution or reduction of massive splenomegaly –Improvement in ECOG performance status –Disease-related anemia or red cell transfusions –Changes in fatigue

47. 47 GL303 – conclusions (5) The symptom-free time analysis, a composite of the individual ‘clinical benefit’ elements, was not pre-specified, is composed of discontinuous time intervals, and should be considered exploratory Although not pre-specified, an analysis of ‘symptom-free time’ for all responders (CR plus nPR plus PR) shows no difference between the two study arms

48. 48 GL303 – Conclusions (6) Toxicity is increased by the addition of Genasense to the control drug regimen, and Genasense administration requires a continuous intravenous infusion with central venous catheter and maintenance of an external infusion pump for 7 days monthly

49. 49

50. 50 Question for the committee Given these safety and efficacy results, does this single, open-label study fulfill the requirements that a single study should meet to demonstrate substantial evidence of effectiveness?

51. 51 Backup slides

52. 52 Genta table of Symptom-free duration for patients with symptoms at baseline If baseline SX present, NO DIFF in SX free duration days

53. 53 Subset Analyses Exploratory; limited by small numbers Gender Age Baseline Fludarabine resistance (Genta specified) Baseline LDH “ Baseline platelet count “ Baseline hemoglobin “

54. 54 Analysis of primary endpoint response group (CR plus nPR) by Gender Gender G3139 plus Flu/Cy N = 120 Flu/Cy N = 121 odds ratio Nn (%) N n (%) Male8918 (20.2) 89 6 (6.7) 3.5 Female31 2 (6.5) 32 2 (6.3) 1.03 Table 14.2.4.2.1; ISE

55. 55 Analysis of primary endpoint response group (CR plus nPR) by Age Age group G3139 plus Flu/Cy N = 120 Flu/Cy N = 121 N n (%) N n (%) < 65 years6712 (18%) 692 (3%) ≥ 65 years53 8 (15%) 526 (12%) Table 14.2.4.1.1; CSR

56. 56 Analysis of primary endpoint response (CR+nPR) by baseline fludarabine sensitivity or resistance Table 14.2.4.11.1, ISE Baseline Flu sensitive G3139 plus Flu/Cy N = 120 Flu/Cy N = 121 Nn (%) Nn (%) YES51 13 (25.5) 503 (6.0) NO697 (10.1) 715 (7.0)

57. 57 Analysis of response for all responders (CR+nPR+PR) by baseline fludarabine sensitivity or resistance If baseline Flu refractory: numerically better response without addition of Genasense Table 14.2.4.11.2, ISE Baseline Flu sensitive G3139 plus Flu/Cy N = 120 Flu/Cy N = 121 Nn (%) Nn (%) YES5129 (56.9) 5027 (54.0) NO6920 (29.0) 7127 (38.0)

58. 58 Analysis of response (CR plus nPR) by baseline LDH level Table 14.2.4.12.1, ISE Baseline LDH level G3139 plus Flu/Cy N = 120 Flu/Cy N = 121 Nn (%) Nn (%) Non-elevated6316 (25.4) 635 (7.9) Elevated534 (7.5) 523 (5.8)

59. 59 Analysis of response (CR plus nPR) by baseline platelet count Table 14.2.4.9.1, ISE Baseline platelet count G3139 plus Flu/Cy N = 120 Flu/Cy N = 121 Nn (%) Nn (%) ≥ 100,000/uL7718 (23.4) 78 8 (10.3) < 100,000/uL432 (4.7) 430

60. Analysis of response (CR plus nPR) by baseline hemoglobin Table 14.2.4.8.2; ISE Baseline hemoglobin G3139 plus Flu/Cy N = 120 Flu/Cy N = 121 Nn (%) Nn (%) ≥ 11 g/dL8718 (20.7) 827 (8.5) < 11 g/dL322 (6.3) 391 (2.6)

61. 61 Genta table 25; CSR page 116 b: P value from Fisher exact test CR/nPR by prior systemic therapy and treatment group

62. 62 Protocol No. GL303 Confidential – Genta Inc. (Page 47 of 68) Version 7; April 16, 2004 13.1.2 Secondary efficacy variables include: Overall response rate (CR + n-PR + PR) Survival Duration of Response Time to Disease Progression (TTP) Clinical Benefit defined as: ° Resolution of B-symptoms (impaired mobility due to lymphadenopathy, impaired cosmesis, abdominal discomfort due to hepatosplenomegaly, early satiety, night sweats, fever) ° Resolution or reduction in massive splenomegaly ° Relative improvement in performance status ° Improvement in disease-related anemia ° Improvement in fatigue as measured by the Brief Fatigue Inventory (BFI)

63. 63

64. 64 Genasense – Additional Efficacy studies 1.In a randomized study in multiple myeloma, Genasense failed to improve the overall response rate or time to progression using an add-on design of Genasense plus Dex versus Dex alone. 2.In relapsed AML, a phase 2 study of Genasense plus Gemtuzumab (GO) showed a 25% CR rate. GO alone was approved on a 30% CR rate. 3.In a large, randomized study in melanoma, Genasense failed to show a survival or PFS benefit using an add-on design of Genasense plus DTIC versus DTIC alone. 1: ASH 2004; abstract #1477 GMY302 2: Leukemia Research 2006; 30:777-783. 3: ODAC proceedings, 2004

65. 65 GM301: Melanoma study A randomized, open-label, phase 3 trial of Genasense plus DTIC versus DTIC alone as initial systemic chemotherapy for advanced melanoma. Presented to ODAC in May 2004

66. 66 G (Genasense, G3139)G + DTIC (N = 371) n (%) DTIC (N = 360) n (%) Grade 3 - 4 Neutropenia 79 (21%) 45 (12%) Grade 3 - 4 Thrombocytopenia 58 (16%) 23 (6%) GM301: Melanoma study Hematologic Toxicity

67. 67 GM301: Melanoma study Non-hematologic Toxicity AEG + DTICDTIC n (%) 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%)

68. 68 AEG + DTICDTIC n (%) Rigors 76 (21%) 16 (4%) Influenza-like Illness 19 (5%) 3 (0.8%) Injection site infection 24 (7%) 4 (1%) Injection-site Reactions 21 (6%) 5 (1%) Upper extremity thrombosis* 18 (5%) 3 (0.8%) *Axillary vein, Subclavian vein, Jugular vein, injection site thrombosis and superior vena caval syndrome GM301: Melanoma study Non-hematologic Toxicity

69. 69 FDA Approved drugs for CLL Chlorambucil 1956 –Leukemia and lymphoma –In CLL, a decrease in lymphocyte counts –In some patients, return to normal blood counts, reduction of lymph nodes and spleen noted

70. 70 FDA Approved drugs for CLL Cyclophosphamide – 1959 –Note, this was before the efficacy requirements of 1962 amndts to the Act –In CLL, a marked decrease in lymphocyte counts occurred –‘Fair to good results’ in RCS and LSA –‘Excellent results’ were observed in giant follicular lymphoma –1966 label – reduction in tumor size should be assessed

71. 71 FDA Approved drugs for CLL Alkylating agents: chlorambucil, cyclophosphamide Fludarabine: –“the treatment of patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to or whose disease has progressed during treatment with at least one standard alkylating-agent containing regimen.” Alemtuzumab (Campath) –"for the treatment of B-cell chronic lymphocytic leukemia (B-CLL) in patients who have been treated with alkylating agents and who have failed fludarabine therapy. (Determination of the effectiveness of Campath is based on overall response rates.)

72. 72 Some other drugs used for CLL but lacking FDA approval for this use Rituximab Pentostatin Cladribine Doxorubicin Mitoxantrone Vincristine

73. 73 Genta analysis of TTP

74. 74 CLL: Criteria indicating need for therapy A minimum of one of the following disease-related symptoms present: (a) Weight loss >10% within the previous 6 months. (b) Extreme fatigue (ie, ECOG PS 2 or worse; cannot work or unable to perform usual activities). (c) Fevers of greater than 100.5”F for > 2 weeks without infection. (d) Night sweats without evidence of infection. (2) Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and / or thrombocytopenia (3) Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroid (4) Massive (ie, >6 cm below the left costal margin) or progressive splenomegaly (5) Massive nodes or clusters (ie, > 10 cm in longest diameter) or progressive lymphadenopathy (6) Progressive lymphocytosis with an increase of >50% over a 2-month period, or an anticipated doubling time of less than 6 months NCI-WG, BLOOD 1996