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1 Genasense in Relapsed/Refractory Chronic Lymphocytic Leukemia Oncologic Drug Advisory Committee September 6, 2006 update Footer w/ current “v#” on handouts.

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Presentation on theme: "1 Genasense in Relapsed/Refractory Chronic Lymphocytic Leukemia Oncologic Drug Advisory Committee September 6, 2006 update Footer w/ current “v#” on handouts."— Presentation transcript:

1 1 Genasense in Relapsed/Refractory Chronic Lymphocytic Leukemia Oncologic Drug Advisory Committee September 6, 2006 update Footer w/ current “v#” on handouts

2 2 Genasense is a novel therapeutic agent that augments the activity of chemotherapy by stimulating apoptosis through downregulation of Bcl-2

3 3 Genasense Drug Substance (Oblimersen Sodium, G3139) 18-base DNA oligonucleotide 18-base DNA oligonucleotide TCTCCCAGCGTGCGCCAT TCTCCCAGCGTGCGCCAT Selectively targets Bcl-2 RNA Selectively targets Bcl-2 RNA Decreases Bcl-2 protein Decreases Bcl-2 protein Phosphorothioate backbone Phosphorothioate backbone

4 4 Genasense Indication Genasense in combination with Fludarabine and Cyclophosphamide is indicated for the treatment of patients with relapsed/refractory CLL

5 5 Agenda Introduction Loretta Itri, MD Relapsed/Refractory CLL Michael Keating, MB, BS Clinical Efficacy/Safety Loretta Itri, MD Risk/Benefit Susan O’Brien, MD Conclusion Loretta Itri, MD

6 6 Expert Advisors Clinical Michael Keating, MB BSProfessor of Medicine – Leukemia, MDACC Susan O’Brien, MDProfessor of Medicine – Leukemia, MDACC Kanti Rai, MB BSChief, Division of Hematology/Oncology, LIJMC Clinical Pharmacology Anthony Tolcher, MDDirector, Clinical Research Cancer Therapy Research Center Histopathology John Bennett, MDProf. of Pathology and Laboratory Medicine, URCC Cell/Molecular Biology John Reed, MD, PhDPresident & Chief Executive Officer The Burnham Institute Biostatistics Richard Kay, PhDHonorary Lecturer Biostatistics University of Cardiff Gary Koch, PhDProfessor of Biostatistics, UNC, Chapel Hill Drug Administration Margaret Green, RN, OCNResearch Nurse Associate – Leukemia Program University of Chicago MC

7 7 ODAC Meeting on Accelerated Approvals, March 2003 Criteria for Accelerated Approval Substantial evidence from well-controlled clinical trials regarding a surrogate end-point Substantial evidence from well-controlled clinical trials regarding a surrogate end-point Surrogate end-point reasonably likely to predict clinical benefit Surrogate end-point reasonably likely to predict clinical benefit Serious or life-threatening disease Serious or life-threatening disease Drug must provide benefit over available therapy Drug must provide benefit over available therapy Post-marketing studies must verify clinical benefit Post-marketing studies must verify clinical benefit

8 8 Relapsed/Refractory Chronic Lymphocytic Leukemia Michael Keating, MB, BS

9 9 CLL Patients Express Bcl-2 A Schena et al. Blood 1992;79:2981, B Hanada et al. Blood 1993;15:1820, C Robertson et al. Leukemia 1996;10:456, D Zaja F, Leuk Lymphoma 1998;28:567, E Aviram et al. Eur J Haematol 2000;64:80, F Klobusicka et al. Neoplasma 2002;49:387, G Menendez et al. Leukemia 2004;18:491, H Tracey et al. J Pathology 2005;206:123 Published Study % Bcl-2 Positive ADEFGBCH

10 10 Relapsed/Refractory Chronic Lymphocytic Leukemia Highly symptomatic Highly symptomatic –Fever, night sweats, weight loss, fatigue, lymphadenopathy, splenomegaly Poor Prognosis Poor Prognosis Fatalities from infection or bleeding Fatalities from infection or bleeding Limited treatment options: Limited treatment options: –Repeat Fludarabine –Alemtuzumab –Rituximab (unapproved for CLL) –Investigational agents

11 11 Relapsed/Refractory CLL Treatment Objective PALLIATION IS NO LONGER THE DESIRED CLINICAL ENDPOINT Prior to 2000: Palliation Partial reduction Partial reduction –Tumor volume –Symptoms –Peripheral blood abnormalities Currently: Prolonged Remission Complete resolution Complete resolution –Tumor volume –Symptoms –Peripheral blood abnormalities –Durable CR/nPR

12 12 Prior FDA Approval Studies in Relapsed/Refractory CLL Fludarabine(1991)Alemtuzumab(2001) Study Type Non-randomized Phase 1-2 Non-randomized Phase 2 Number of pts Efficacy: CR 13% † 2%** PR19-35%31% Response Duration mos 7 mos Safety*: Died on study 22%10% Grade 4 neutropenia 59%37% Pneumonia16-22%15% †Chlorambucil failure, Non NCI-WG criteria, No CT *Campath ODAC presentation **No CT Silver Bullet

13 13 CR and nPR Require Normalization of All Disease Parameters Parameter CR/nPRPR (2 Months Minimum Duration) Lymph Nodes None 50% decrease Liver/Spleen Not palpable 50% decrease Constitutional Symptoms None allowed No improvement required ALC < 5,000 50% decrease GranulocytesPlateletsHemoglobin > 1,500 > 100,000 > % improvement* (*Only one parameter required) Bone Marrow < 30% lymphocytes +/- presence of nodules on bone marrow biopsy No improvement required NCI WG; Cheson, Blood, 1996 Silver Bullet

14 14 Bone Marrow nPR vs. CR nPR with Nodule CR Clear of Nodules Baseline

15 15 CR and nPR Correlate with Increased Survival in CLL Keating et al., Blood 92:1165, CR (n=51) nPR (n=56) PR (n=30) Fail (n=32) Proportion Surviving Months Fludarabine + Prednisone Previously Untreated Wierda: JCO Fludarabine/Cyclophosphamide/Rituximab Months nPR CR PR NR ED Relapsed / Refractory

16 16 Summary Relapsed/Refractory CLL: Relapsed/Refractory CLL: –Rapidly progressive –Highly symptomatic –Resistant to chemotherapy –Fatalities due to infection and/or bleeding –Limited medical options CR/nPR is the most relevant current endpoint in CLL CR/nPR is the most relevant current endpoint in CLL Unmet medical need Unmet medical need

17 17 Clinical Efficacy & Safety Loretta Itri, MD

18 18 Genasense CLL Program Phase 1-2 Single agent (N=40) Phase 1-2 Single agent (N=40) –Part A - dose finding –Part B - efficacy and safety Phase 3 (N=241) Phase 3 (N=241) –Randomized pivotal combination study with chemotherapy Safety Database (N>1000) Safety Database (N>1000)

19 19 Genasense Phase 1-2 (Part A) Relapsed/Refractory CLL (N=14) Established MTD 3mg/kg/day (5-7 day CIV infusion) Established MTD 3mg/kg/day (5-7 day CIV infusion) Dose limiting toxicities Dose limiting toxicities –Cycle 1 infusion reactions High spiking fever, rigors and hypotensionHigh spiking fever, rigors and hypotension –Tumor lysis syndrome –Other side effects Nausea, fatigue, thrombocytopeniaNausea, fatigue, thrombocytopenia

20 20 Genasense Phase 1-2 (Part B) Single Agent Efficacy Relapsed/Refractory CLL (N=26) Anti Leukemic Response n (%) (%) ≥ 50%  CLL cells 11/2250 ≥ 50%  Lymph nodes 7/2232 ≥ 50%  spleen 7/1741 PR2/268 Stable12/2646 Median number of prior regimens = 3 Genasense 3 to 7 mg/kg/d x 5-7d O’Brien et al., J Clin Oncol, 2005

21 21 GL303 Pivotal Randomized Phase 3 Study of Fludarabine and Cyclophosphamide with or without Genasense in Relapsed/Refractory CLL

22 22 GL303 Phase 3 Study Design Fludarabine/CyclophosphamideFludarabine/Cyclophosphamide Fludarabine/CyclophosphamideGenasenseFludarabine/CyclophosphamideGenasense Stratification/RandomizationStratification/Randomization 241 patients 241 patients Relapsed/refractory: ≥ 1 fludarabine regimen Relapsed/refractory: ≥ 1 fludarabine regimen Stratification: Stratification: –Fludarabine “refractory” vs. non-refractory –No. of prior regimens: 1-2 vs. ≥ 3 –Response to last therapy: > 6 vs. ≤ 6 months

23 23 Fludarabine Sensitivity Criteria* Refractory Refractory –Failure to achieve at least a PR or –Recurrence within 6 months of treatment Relapsed Relapsed –Recurrence after ≥ PR lasting ≥ 6 months * Identical to criteria employed in Alemtuzumab BLA

24 24 Protocol Therapy Dosing Regimens Days Genasense 3mg/kg/day CIV days 1-7 Fludarabine CTX 123 Fludarabine CTX Randomization Fludarabine 25 mg/m 2 CTX 250 mg/m 2

25 25 Protocol Endpoints Primary endpoint Primary endpoint –CR + nPR NCI-WG criteriaNCI-WG criteria CT/US confirmationCT/US confirmation Central blinded expert reviewCentral blinded expert review Secondary endpoints Secondary endpoints –Response duration (CR + nPR, CR + nPR + PR) –Overall response (CR + nPR + PR) –Time to progression –Overall survival –Clinical benefit –Safety

26 26 Central Blinded Assessment of Response and Disease Progression Histopathologic review of bone marrow Histopathologic review of bone marrow –Dr. Gregory Threatte Clinical response assessment Clinical response assessment –Dr. Kanti Rai Disease progression determination Disease progression determination –Dr. Kanti Rai

27 27 Demographics and Baseline Characteristics GFC(N=120)FC(N=121) Age, yrs (median) 6363 Male / Female 89 / / 32 ECOG PS ≥ 1, n (%) 78 (66) 80 (68) Time from diagnosis, months (median) 7058 Hgb, median (range) 12 (7-16) 12 (7-17) Platelets, median (range) 130 (24-291) 120 (16-344) B-microglobulin > 4, n (%) 52 (43) 47 (39) Elevated LDH, n (%) 53 (44) 52 (43) Splenomegaly, n (%) 51 (42) Splenectomy, n (%) 11 (9) 4 (3)

28 28 Baseline Active Disease Signs and Symptoms GFC(N=120) n (%) FC(N=121) Weight loss (> 10% prior to study) 17 (14) 15 (12) Extreme Fatigue (≥ Gr 2) 35 (29) 30 (25) Fever (> 100.5° F ≥ 2 weeks) 7 (6) 4 (3) Night sweats 43 (36) 38 (31) Worsening anemia or thrombocytopenia 48 (40) 40 (33) Massive splenomegaly (> 6 cm) 29 (24) 22 (18) Lymphadenopathy 111 (93) 109 (90) Progressive lymphocytosis 62 (52) 55 (46) P<0.05

29 29 Stratification Factors GFC(N=120) n (%) FC(N=121) Fludarabine sensitivity Relapsed 51 (43) 50 (41) Refractory 69 (58) 71 (59) Number of prior regimens (50) 63 (52) ≥ 3 60 (50) 58 (48) Response to last therapy > 6 months 54 (45) 52 (43) ≤ 6 months 66 (55) 69 (57)

30 30 Prior Chemotherapy Well Balanced GFC(N=120) FC(N=121) Fludarabine cycles, mean (SD) 7 (5.8) 5.5 (3.2) Cytoxan/Chlorambucil 84 (70%) 86 (71%) Rituximab 34 (28%) Alemtuzumab 7 (6%) 9 (7%) Other 68 (57%) 71 (59%)

31 31 Randomized Phase 3 Study Relapsed/Refractory Chronic Lymphocytic Leukemia Efficacy

32 32 Primary Endpoint Achieved Significant Increase in CR/nPR n=5 n=9 n=3 n=11 GFCFC CR nPR MajorResponse(%) 17% 7% CR/nPR p=0.025 (Chi-Square) Silver Bullet Fisher’s exact test: CR/nPRp=0.016 CR onlyp=0.03 CR onlyp=0.03

33 MonthsFCGFC Proportion Without PD CR/nPR Significantly More Durable with Genasense/FC From Date of Initial Response GFCFC MedianNot Reached22 mos Events/N5/20 (25%)6/8 (75%) HR0.29 P=0.031 Silver Bullet GFC FC

34 34 CR/nPR Duration of Response During Treatment and Post Treatment FCGFC = During Treatment = Post Treatment + = Ongoing Months Silver Bullet Median Duration Post Chemo GFC = Not Reached (est. >31 mos) FC = 20 mos

35 35 Four-Fold Increase in CR/nPR in Chemosensitive Patients GFC(N=120)FC(N=121) Fludarabine sensitivity Relapsed 13/51 (25) 3/50 (6) Refractory 7/69 (10) 5/71 (7) Number of prior regimens /60 (23) 4/63 (6) ≥ 3 6/60 (10) 4/58 (7) Response to last therapy > 6 months 12/54 (22) 3/52 (6) ≤ 6 months 8/66 (12) 5/69 (7)

36 Duration (Month) of Response FCGFC Proportion of Subjects Without PD Overall Response Rate (ORR*) and Response Duration * ORR = CR/nPR + PR GFCFC ORR %4145 Events n(%)31/49 (63)38/54 (70) Hazard ratio0.76 P0.26 GFC FC

37 Months from Randomization Proportion Without PD FCGFC Time to Progression Intent-to-Treat Population GFCFC Events n(%)87/120 (73)88/121 (73) Hazard ratio1.03 Logrank P0.83 GFC FC

38 38 TTP ≥ 2 Years Correlates with Response (CR/nPRs Have Greatest Benefit) *P< DF Chi-Square Test of Trend Numerator is number with observed TTP > 2 years 64% (18/28) CR/nPRPR

39 Months from Randomization Proportion of Subjects Who Survived FCGFC Overall Survival Intent-to-Treat Population GFCFC Median Events n(%)58/120 (48%)62/121 (52%) Logrank P0.96 HR % C.I GFC FC

40 40 Survival ≥ 3 Years Correlates with Response (CR/nPRs Have Greatest Benefit) *P< DF Chi-Square Test of Trend Numerator is number with observed survival > 3 years 61% (17/28) CR/nPRPR

41 41 Durable Symptom Relief Correlates With Response (CR/nPR Have Longest Symptom Free Duration) CR/nPRPR

42 42 GL303: Relapsed/Refractory Chronic Lymphocytic Leukemia Safety

43 43 Non-Hematologic Adverse Events % Grade 3 % Grade 3 % Grade 4 All-grade events occurring in ≥ 20% GFCFCGFCFC Nausea8200 Fatigue6302 Vomiting5110 Dyspnea4210 Pyrexia4300 Constipation2100 Headache1300 Silver Bullet

44 44 Hematologic Toxicity GFC(N=115) n (%) FC(N=115) Neutropenia (Gr 3-4) G-CSF Antibiotics Opportunistic infections Febrile neutropenia 22 (19) 98 (85) 114 (99) 5 (4) 13 (11) 28 (24) 111 (97) 113 (98) 8 (7) 9 (8) Anemia (Gr 3-4) Erythropoietin RBC Transfusion 17 (15) 42 (37) 41 (36) 17 (15) 36 (31) 33 (29) Thrombocytopenia (Gr 3-4) Platelet Transfusions 38 (33) 21 (18) 23 (20) 6 (5) Silver Bullet

45 45 Platelets Median and Inter-quartile Range GFCFC

46 46 Platelet Transfusions and Bleeding Events GFC(N=115)FC(N=115) Transfusions216 Transfusions with platelet count >25K >25K62 > <25K123 <10K <10K31 Bleeding events associated with transfusions 2*2*2*2* > <25K21 <10K <10K01 * 1 grade 3, 1 grade grade 1, 1 grade 3

47 47 Hematologic Parameters Median and Inter-quartile Range GFCFC

48 48 Deaths and Discontinuations (On Study) Treatment Related GFC (N=115) n (%) FC (N=115) n (%) AE leading to discontinuation 29 (25) 29 (25) 27 (24) 27 (24) AE with outcome of death 5 (4) 5 (4) 2 (2) Sepsis21 Tumor lysis syndrome/ First cycle reaction 20 Elevated creatinine (progressive disease) 10 Pseudomonal pneumonia 01 Silver Bullet

49 49 Infusion Reactions Reaction: Reaction: –Spiking fever, nausea, dehydration, rigor, back pain, hypotension, renal insufficiency –Lymphoid malignancies only Incidence: 1.7% at 3 mg/kg Incidence: 1.7% at 3 mg/kg Preventive/supportive care: Preventive/supportive care: –Hydration, antiemetics, analgesics and observation

50 50 Hospitalizations: Grade 3-4 AEs GFC(N=115) n (%) FC(N=115) Febrile neutropenia 10 (9) 3 (3) Sepsis 2 (2) Catheter related infection 3 (3) 1 (1) Anemia0 3 (3) Pneumonia 1 (1) 4 (4) Gr 3-4 AEs >3%

51 51 Catheter-Related Events Protocol catheter requirement for Genasense Protocol catheter requirement for Genasense Infection Infection –No grade 4 events –Hospitalization:GFC - 3, FC - 1 –Treatment interruption:GFC- 1, FC - 1 Thrombosis Thrombosis –No grade 4 events –Two Grade 3 events in GFC arm: subclavian vein and jugular vein thrombosis

52 52 Other Complications GFC(N=115)FC(N=115) Opportunistic infection 58 Autoimmune hemolytic anemia 30 Autoimmune thrombocytopenia 01 Second malignancies * +Waldenstrom’s Macroglobulinemia *AML, PTCL, Hodgkin’s disease, MDS

53 53 Summary and Benefit–Risk Assessment Susan M. O’Brien, MD

54 54 Thrombocytopenia Platelet Count by Cycle GFC FC

55 55 Silver Bullet Adverse Reactions Tumor lysis syndrome Tumor lysis syndrome –Seen with active anti-leukemia agents Infusion-related reactions Infusion-related reactions –Common to many CLL therapies –70-80% incidence with monoclonal antibodies

56 56 Genasense Does Not Worsen Neutropenia GFC FC

57 57 Approval Studies in CLL Fludarabine(1991)Alemtuzumab(2001)Genasense/FC(2006) Study Type Non-RandNon-RandRandomized Efficacy Number of pts CR/nPR 13% † – 17% 17% CR– 2% 2%9% No CT Confirmation CT/US Confirmed PR 19-35% † 31% 24% 24% Safety Number of pts Grade 4 neutropenia 59%37% 7%* 7%* Pneumonia16-22%15%6% Died on study 22%10%8% † Non NCI-WG criteria *GCSF use Silver Bullet

58 58 Addition of Genasense Converts PRs into Durable CR/nPRs PRCR/nPR FCGFC Sensitization

59 59 Proportion of Subjects Without PD Months from Randomization PRCRSDOthernPR CR vs PR= p < CR vs nPR= p = 0.21 nPR vs PR= p = GL303 – Relapsed/Refractory CLL CR/nPR Superior to PR for TTP

60 60 Response Considerations How does the pattern of response compare to that seen in other trials in relapsed/refractory CLL? How does the pattern of response compare to that seen in other trials in relapsed/refractory CLL? How does the magnitude of improvement compare with other trials, and is it clinically important? How does the magnitude of improvement compare with other trials, and is it clinically important?

61 61 Months Proportion in Remission Historical comparison of sequential studiesAdapted from Weirda et al., Cancer 2006 FCFCR CR/nPR28%42% ORR67%72% Time-to-Progression: Responders Only No CT Response and TTP in Relapsed CLL Flu/Cy vs. Flu/Cy/Rituximab FCR FC

62 62 Recent Randomized Studies in CLL % CR 24 7 Flu Flu/Cy 16 5 Flu/Cy Flu (Confirmed by CT) Eichhorst et al., 2006 Previously Untreated Patients 7 22 Flu/Cy Flu Flinn et al., 2004 N=278 N= % CR/nPR 17 7 Flu/Cy GenasenseFlu/Cy (Confirmed by CT) GL303 Relapsed/Refractory Patients N=241

63 63 GL303 Relapsed/Refractory CLL CR/nPR Duration of Response During Treatment and Post Treatment FCGFC = During Treatment = Post Treatment + = Ongoing Months Silver Bullet Median Duration Post Chemo GFC = Not Reached (est. >31 mos) FC = 20 mos

64 64 Confirmatory Study in Previously Untreated CLL SPA requested SPA requested Multicenter, open label study (N=722) Multicenter, open label study (N=722) Primary Endpoint: PFS Primary Endpoint: PFS Stratification: Stratification: –FISH: 17p - vs. 11q - vs. Other –Rai stage –LDH –Investigative center Fludarabine/RituximabFludarabine/Rituximab Fludarabine/Rituximab + Genasense Fludarabine/Rituximab Stratification/RandomizationStratification/Randomization

65 65 GL303 Relapsed/Refractory CLL Criteria Met for Accelerated Approval Substantial evidence from well-controlled clinical trial Study GL303 Serious or life-threatening disease Relapsed /Refractory CLL Surrogate end-point for clinical benefit Durable CR/nPR predict for TTP, OS and symptom benefit Benefit over available therapy Superior to Flu/Cy Confirmatory post-marketing study SPA near final

66 66 Reduction in Tumor Volume May Serve as a Surrogate for Clinical Benefit 1,2 FDA Guidance on Surrogacy of Reduction in Tumor Volume 3 FDA Guidance on Surrogacy of Reduction in Tumor Volume 3 The association of reduction in tumor volume is stronger in the setting of The association of reduction in tumor volume is stronger in the setting of –Undetectable tumor volume –17 vs. 7% CR/nPR (p=0.025) Reduction is durable Reduction is durable –GFC median duration of response estimated to exceed 36 months (not yet reached) vs. 22 months Reduction extends beyond the period of toxic agent administration Reduction extends beyond the period of toxic agent administration –GFC median duration of response estimated to exceed 31 months (not yet reached) vs. 20 months Silver Bullet 1 Guidance for Industry: Providing Clinical Evidence for Effectiveness for Human Drug and Biological Product (Oncology Supplement) May Reinventing the Regulation of Cancer Drugs - March BLA Reference number (Alemtuzumab)

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