PARGLUVA ® ( Muraglitazar) Bristol-Myers Squibb and Merck & Co., Inc. New Drug Application 21-865

1. PARGLUVA® (Muraglitazar)Bristol-Myers Squibb and Merck & Co., Inc.New Drug Application 21-865 Clinical Safety Julie Golden, M.D. Medical Officer Division of Metabolic and Endocrine Drug Products September 9, 2005 Silver Spring, MD Center for Drug Evaluation and Research

2. Outline • Background • Subject Disposition • Safety Issues • Concerns/Points to Consider • Questions for Discussion

3. Regulatory Issues • First PPAR-γ (troglitazone) removed from the market in 2000 due to cases of idiosyncratic liver failure • PPARs and carcinogenicity: all clinical studies > 6 mo currently on clinical hold unless preclinical carcinogenicity studies submitted to the Agency

4. Background • Safety profile of muraglitazar is generally consistent with PPAR-γ and PPAR-α pharmacology • Potential concerns with PPAR compounds • PPAR-γ: edema, weight gain, congestive heart failure, anemia, neutropenia • PPAR-α: myopathy, cholelithiasis

5. Clinical Safety Database • 22 Clinical Pharmacology Studies • 6 Phase 2b and 3 Studies • 5 Type 2 Diabetes Studies • 2 Monotherapy • 3 Combination Therapy • 1 Mixed Dyslipidemia Study

6. Clinical Safety Database • 3226 subjects received at least one dose of muraglitazar in the Phase 2/3 studies • Type 2 diabetes: 2969 • Monotherapy: 1560 • Combination therapy: 1409 • ~ 2000 subjects received muraglitazar for at least 24 weeks • ~ 700 subjects received muraglitazar for at least 104 weeks

7. Type 2 Diabetes Studies, Treatment Groups

8. Pooling • Muraglitazar ≤ 5 mg: • CV168006: Mur 0.5 mg, 1.5 mg, 5 mg (titration possible) • Phase 3 Studies: Mur 2.5 and 5 mg • Pioglitazone ≤ 45 mg: • CV168006: Pio 15 mg (titration to 45 mg possible) • CV168025: Pio 30 mg

9. Pooling • Monotherapy: CV168006 and CV168018 • Combination therapy • CV168021: + glyburide • CV168022 and CV168025: + metformin

10. Subject Disposition 24 Weeks

11. AEs Leading to Discontinuation,Type 2 Diabetes Studies 24 Weeks

12. Safety Issues • Deaths • Edema Events • Heart Failure Events • Weight Gain • Cardiovascular Events

13. Deaths

14. Deaths, Type 2 Diabetes StudiesAll Data

15. Cardiovascular Deaths • 52 yo male (Mur 2.5 + Met): myocardial infarction • 54 yo male (Mur 5 + Met): myocardial infarction* • 67 yo male (Mur 5 + Met): sudden death • 53 yo male (Mur 5 + Met): stroke • 56 yo female (Mur 5 + Gly): myocardial infarction • 66 yo female (Mur 5 + Met): sudden death* • 61 yo male (Mur 5 + Met): “found dead” • 60 yo female (Mur 5 + Met): stroke • 59 yo male (Mur 20): myocardial infarction* • 62 yo male (Placebo + Gly): pulmonary embolism

16. Subject CV168022-153-2Muraglitazar 5 mg + metformin • 54 year-old white male with 6-year history of type 2 diabetes, obesity, hypertension, coronary artery disease, and coronary thrombosis • Day 115: CHF symptoms • 1 day hospitalization, single dose of furosemide 40 mg I.V. • Day 117: normal chest x-ray • Day 118: • body weight increase of 10 lbs. from Day 90 • elevated NT-proBNP (1236 pg/mL; screening 548 pg/mL) • physical exam and outpatient cardiac exam refused • Day 125: found dead in home • death certificate: myocardial infarction and occult coronary artery disease

17. Subject CV168025-193-9Muraglitazar 5 mg + metformin • 66 year-old white female with 4-year history of type 2 diabetes, CHF, hypertension, peripheral vascular disease, transient ischemic attack, bilateral lower extremity fluid retention, atrial flutter, mitral insufficiency, obesity, and tobacco use • Day 201: dyspnea; reported as CHF • Day 202: sudden death • autopsy not performed; cause of death reported as myocardial infarction

18. Subject CV168006-11-8Muraglitazar 20 mg • 59 year old white male with 2-year history of type 2 diabetes, previous tobacco use, hypertension, iron overload with fatty liver, and psoriasis • Day 43: bilateral pitting edema in ankles • Day 49: admitted with myocardial infarction and CHF • increasing exertional dyspnea for the previous month • markedly elevated cardiac enzyme levels • clinical deterioration; intubation • Day 50: • cardiac catheterization: 99% left main arterial distal stenosis • echocardiogram: moderately dilated left ventricle with severe global hypokinesis; ejection fraction 15 - 20% • Day 60: life support withdrawn; patient died

19. Cancer Deaths • 69 yo male (Mur 1.5): lung cancer • 69 yo female (Mur 1.5): acute myeloid leukemia • 49 yo male (Mur 2.5 + Met): hepatocellular carcinoma • 56 yo female (Mur 5 + Met): breast cancer • 70 yo female (Mur 5): lung cancer • 63 yo female (Mur 5 + Met): lung cancer • 50 yo female (Mur 5 + Met): pancreatic cancer • 66 yo male (Pio 15): throat cancer

20. Deaths 5 cardiovascular deaths from 3 sites (out of 234): Site 193 = Netherlands, 2 deaths, 8 randomized subjects Site 241 = Russia, 2 deaths, 38 randomized subjects Site 314 = Finland, 1 death, 2 randomized subjects

21. Edema

22. Edema-Related Predefined Preferred Terms • Fluid retention/overload • Generalized edema • Peripheral edema • Swelling • Hypervolemia

23. Edema Adverse Events, CV16800624 Weeks

24. Edema Adverse Events Phase 3 Studies24 Weeks

25. Edema Adverse Events Phase 3 Studies24 Weeks

26. Congestive Heart Failure

27. CHF Adverse Events, CV16800624 Weeks

28. CHF Adverse EventsPhase 3 Studies24 Weeks

29. Congestive Heart Failure: Monotherapy vs. Combination TherapyType 2 Diabetes Studies24 Weeks

30. CHF Adjudication Committee:Predefined Preferred Terms • Cardiac failure • Pulmonary edema • Ventricular failure • Dyspnea • Edema (moderate or greater intensity)

31. CHF Adjudication Committee Results Phase 3 Studies24 Weeks

32. Weight Gain

33. Weight Change: Type 2 Diabetes, 24 Weeks

34. Cardiovascular Events

35. Cardiovascular Adverse Events: Predefined Preferred Terms • Myocardial infarction • Coronary revascularization • Coronary artery disease • Angina/myocardial ischemia • Cardiac death • Stroke • Transient ischemic attack * NOT congestive heart failure

36. Cardiovascular Adverse Events Type 2 Diabetes Studies24 Weeks

37. Cardiovascular Events: Monotherapy vs. Combination TherapyType 2 Diabetes Studies, 24 Weeks

38. Cardiovascular Events: Phase 3 Combination Studies24 Weeks

39. Muraglitazar 2.5 mg: 64 yo M: Non-Q wave MI, day 85 52 yo F: TIA, day 31 64 yo M: Unstable angina, day 11 59 yo F: Stroke, day 9 Muraglitazar 5 mg: 68 yo M: MI, day 1 (prior to first dose) 54 yo F: Stroke, d26; Brain tumor, day 43 62 yo M: Coronary artery disease, day 111 70 yo M: Angina, days 17, 37, 56, and 66 52 yo F: TIA, day 78 46 yo M: Myocardial ischemia, day 85 60 yo M: Stroke, day 139 Cardiovascular Events: Study CV16802124 Weeks

40. Inclusion/Exclusion CriteriaBaseline Characteristics

41. Inclusion/Exclusion Criteria • No history of MI, coronary angioplasty or bypass graft(s), valvular disease or repair, unstable angina pectoris, TIA or cerebrovascular accidents within 6 months prior to entry into the study • Monotherapy: No antihyperglycemic therapy more than 3 consecutive or a total of 7 non-consecutive days 4-6 weeks prior to Screening • Combination Therapy: Receiving treatment with sulfonylurea (CV168021) or metformin (CV168022, CV168025) for at least 6 weeks prior to Screening

42. Baseline Characteristics ª Includes all doses of muraglitazar except OL

43. Baseline Coronary Artery Disease Phase 3 Studies

44. Concerns/Points to Consider

45. Deaths • Most deaths in the muraglitazar-treatment group were due to cardiovascular events and cancer • Congestive heart failure may have contributed to the cardiac event leading to death in 3 subjects on muraglitazar • No clear pattern has emerged

46. Deaths • Most cardiovascular deaths were from one study • CV168025: metformin add-on, active control • 5 cardiovascular deaths from 3 study sites

47. Cardiovascular Events • Diverse events with no clear pattern • Increased incidence in combination studies • Imbalance driven by one study • CV168021: glyburide add-on, placebo-controlled study

48. Cardiovascular Events • When combination studies pooled, events were not dose-related • Inconsistent rate of events in placebo groups from combination studies • Low number of events, particularly in comparator groups, make incidence rates unstable

49. Questions for Discussion • Is it likely that the excess of cardiovascular deaths and events in the muraglitazar group are related to the dose-related fluid retention? • If not, is there a plausible pharmacological explanation? • Are subjects on combination therapy (i.e., longer history of diabetes) or with a relevant medical history more vulnerable to the adverse effects of muraglitazar? • Cardiovascular events • Fluid-related events

50. Medical Review Team Robert Misbin, M.D. Eric Colman, M.D. David Orloff, M.D. Statistical Review Team Lee Ping Pian, Ph.D. J. Todd Sahlroot, Ph.D. Project Management Jena Weber Pharmacology/Toxicology Review Team John Colerangle, Ph.D. Jeri El Hage, Ph.D. Biopharmaceutics Review Team Jaya Vaidyanathan, Ph.D. Hae Young Ahn, Ph.D. Acknowledgements