Lenalidomide (REVLIMID ® ) Celgene Corporation New Drug Application (021880)

1. Lenalidomide (REVLIMID®)Celgene CorporationNew Drug Application (021880) Oncology Drug Advisory Committee Sept 14, 2005 Lenalidomide Review Team Division of Drug Oncology Products Center for Drug Evaluation and Research

2. Medical Efficacy: Maitreyee Hazarika, MD Safety: Edvardas Kaminskas, MD Ann Farrell, MD Statistics Yuan Li Shen, DrPH Rajeshwari Sridhara, PhD Pharmacology/Toxicology Pharm Tox: Anwar Goheer, PhD Reproductive Safety: Kimberly Benson, PhD John Leighton, PhD Clinical Pharmacology Gene Williams, PhD Brian Booth, PhD Chemistry Hari Sarker, PhD Nallaperumal Chidambaram, PhD Project Manager Carl Huntley, RPh, MBA NDA 21880 Review Team

3. Proposed Indication Treatment of patients with transfusion dependent anemia due to low- or intermediate-1 risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities

4. Issues for ODAC • Single-arm trial design in a heterogenous disease (MDS) (FDA recommended a randomized controlled trial) • ‘8-week transfusion-free’ endpoint to demonstrate clinical benefit • Toxicity of 10 mg dose • Benefit vs. risk of the drug for this population • Implementation of additional risk management measures

5. Outline • Drug Approvals for MDS • Reproductive Safety Assessment • Clinical Review Efficacy • Integrated Safety Summary • Risk Management • Summary

6. FDA Approval for MDS Azacitidine (Vidaza®) injection • MDS subtypes: RA, RARS, RAEB, RAEB-t, CMML • 1 randomized, controlled trial comparing azacitidine + supportive care (SC) vs. SC (N=191) • 2 single-arm studies • Response rate (16%) ≥ 4 weeks duration (p<0.0001) based on complete or partial response (CR + PR) of • bone marrow • peripheral blood (all cell counts)

7. Structural Comparison Lenalidomide Thalidomide

8. Clinical Pharmacology • Metabolism • Not a cytochromes P450 substrate • Presence and identity of circulating metabolites not studied in humans • Excretion: Approximately 2/3 eliminated as parent via urine

9. Reproductive Safety Assessment

10. Embryo-Fetal Development Study Requirements • Study in first species • Conduct confirmatory study in second species If results are negative - No evidence of drug-induced embryo-fetal development adverse events

11. Lenalidomide Embryo-Fetal Development StudiesRat Study Methods and Results • Pregnant rats dosed during gestational days 6-17 • No adverse effects seen on the embryo or fetus, including limb bud effects, at the doses studied

12. Lenalidomide Embryo-Fetal Development StudiesRat Study Conclusion • Rat not sensitive species for thalidomide limb bud developmental effects • While this study does provide some information regarding developmental effects, it is inadequate for full assessment of lenalidomide developmental effects

13. Lenalidomide Embryo-Fetal Development StudiesRabbit Study Methods and Results • Pregnant rabbits dosed during gestational days 7-19 • A Thalidomide dose group was also included • Acceptable study endpoints (maternal or developmental effects) not achieved • Thalidomide caused expected limb deformities, lenalidomide did not

14. Lenalidomide Embryo-Fetal Development StudiesRabbit Study Conclusion • This study was inadequate • Drug-related effects on maternal or developmental endpoints in the high dose group did not meet standard study criteria • There was a confounding variable - some rabbits were not eating prior to study onset

15. Conclusion • Structural similarities of lenalidomide and thalidomide suggests risk • Insufficient information to fully determine the effects on embryo-fetal development for lenalidomide • The rat is not an appropriate model for full assessment of embryo-fetal effects of this drug • The rabbit study was inadequate

16. Recommendations • If approved, Pregnancy Category D is recommended, similar to most other oncologic agents • Additional studies to fully assess potential developmental effects should be conducted

17. Clinical Review

18. Efficacy Studies

19. MDS-003 Efficacy

20. MDS-003 Study Design • Single-arm, open-label, multi-center, Phase 2 study • Local or central laboratory used to determine eligibility • Adjudication by independent hematologic and cytogenetic reviewers • Response criteria based on IWG Standardized Response Criteria for MDS (Cheson et al, Blood, 2000)

21. Study Endpoints • Primary • RBC transfusion independence • Secondary endpoints • Change of hemoglobin from baseline • Duration of response • ≥ 50% decrease in RBC transfusion requirements • Cytogenetic response • Platelet response • Neutrophil response

22. Eligibility CriteriaMDS-003 • Low- risk or intermediate- 1- risk MDS • with a del (5q) (q31-33) (del 5q isolated or associated with other cytogenetic abnormalities) • RBC transfusion- dependent anemia defined as requiring ≥ 2 units of RBCs within 8 weeks of study treatment

23. MDS-003 • Enrolled 148 patients • Doses: Oral lenalidomide • 10 mg x21 d/q28 d (syncopated) (N=45) • 10 mg daily (continuous) (N=103)

24. Disease CharacteristicsCytogeneticsMDS-003

25. Disease CharacteristicsIPSS Risk ScoreMDS-003

26. Patient CharacteristicsRBC Transfusion Dependent AnemiaMDS-003

27. Patient PopulationsMDS-003

28. FDA Evaluable for EfficacyMDS-003

29. IWG Response Criteria for MDSCheson et al,Blood, 2000 Hematologic Improvement-Erythroid Response Major response • for RBC transfusion-dependent patients, transfusion independence • For patients with pretreatment hemoglobin < 11 g/dL, greater than 2 g/dL increase in hemoglobin Minor Response • for RBC transfusion-dependent patients, 50% decrease in transfusion requirements • For patients with pretreatment hemoglobin < 11 g/dL, 1-2 g/dL increase in hemoglobin

30. IWG Response Criteria for MDSCheson et al,Blood, 2000 Hematologic Improvement • Improvements must last at least 2 months in the absence of ongoing cytotoxic therapy

31. Definition of Response * (Protocol) RBC Transfusion Independence • The absence of the intravenous infusion of any RBC transfusion during any consecutive “rolling” 56 days (8 weeks) during the treatment period • must last ≥ 2 months • ≥ 1.0 g/dL increase in Hgb *Modified IWG MDS Hematologic Improvement Criteria

32. RBC Transfusion Independence Response

33. Change in Hemoglobin from Baseline MDS-003 • Hemoglobin change • minimum hemoglobin value in the 8 week period preceding first dose of study drug for baseline and the maximum hgb value during the response period, excluding the 30 days after the last transfusion prior to the response period • ITT, Median change 3.3 g/dL • Responders, Median change 5.2 g/dL

34. ≥50% Decrease in Transfusion Requirements

35. Duration of Transfusion Independence in Responders(weeks) (N=99)MDS-003 • Response duration • Measured from end of the consecutive 56 days during which patient was free of RBC transfusions to the date of first RBC transfusion • Median 52.3 weeks(Min, Max 8.1- 74.6)

36. Relapsed Patients • Relapses from transfusion independent to transfusion dependent : 32/99 patients • Relapses occurred within treatment period: 13/32 patients

37. IWG Response Criteria for MDSCheson et al,Blood, 2000 Major Cytogenetic Response • Major: No detectable cytogenetic abnormality if preexisting abnormality was present (Requires 20 analyzable metaphases using conventional cytogenetic techniques)

38. Major Cytogenetic ResponseMDS-003

39. Major Platelet Response MDS-003 • Definition (IWG MDS Response criteria): • For patients with pre-treatment platelet count less than 100,000/mm3an absolute increase of 30,000 or more • for platelet transfusion-dependent patients, stabilization of platelet counts and platelet transfusion independence • Major platelet response rate: 0/14

40. Major Neutrophil ResponseMDS-003 • Definition (IWG MDS Response Criteria): • For ANC less than 1500/mm3 before therapy, at least a 100% increase, or • an absolute increase of more than 500/mm3, whichever is greater • Major neutrophil response: 1/6

41. MDS-001 Efficacy

42. MDS-001 Study Design • Dose-finding, phase 1/2, single-arm, single-center study • Primary endpoint: patients with major or minor erythroid response (modified from the IWG MDS Response Criteria) • Enrolled 45 patients • Doses: • 25 mg daily (N=13) • 10 mg q21 d/28 d (syncopated) (N=18) • 10 mg daily (continuous) (N=12)

43. Study Endpoints • Primary • Major or minor erythroid response • Secondary • cytogenetic response • neutrophil response • platelet count response

44. Eligibility CriteriaMDS-001 • De novo MDS: RA, RARS, RAEB, RAEB-t, CMML • RBC transfusion- dependent anemia defined as requiring ≥ 4 units of RBCs within 8 weeks of study treatment, or • Baseline mean hemoglobin < 10 g/dL (untransfused)

45. Population (N=10)MDS-001 • Transfusion dependent anemia (≥ 2 U/8 weeks) low- or intermediate-1 risk MDS with del 5 q

46. Major Erythroid Response MDS-001 • Major erythroid response • 7/10 (70%) (95% CI [35, 93]) • Minor erythroid response • none

47. Efficacy Analyses (cont’d)MDS-001 • Duration of response (7 responders) • Median: 41.4 weeks (Range: 31- 88.1 weeks) • Median change in hemoglobin values : 5.3 g/dL • Major cytogenetic response: 9/10 • Major platelet response: 1/1 • Major neutrophil response: 1/2

48. MDS-002 Efficacy

49. MDS-002 Study Design • MDS-002 identical to MDS-003 except • Study Population • Patients without del 5q cytogenetic abnormality • Enrolled 215 patients • 2 doses: • Dose 10 mg syncopated (115) • Dose 10 mg continuous (100)

50. Efficacy AnalysesMDS-002