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FDA’s Endocrinologic and Metabolic Drugs Advisory Committee Meeting

Muraglitazar BMS-298585. FDA’s Endocrinologic and Metabolic Drugs Advisory Committee Meeting. 9 September 2005. Introduction. Brian Daniels, M.D. Senior Vice President Global Clinical Development Bristol-Myers Squibb. BMS Presentation.

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FDA’s Endocrinologic and Metabolic Drugs Advisory Committee Meeting

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  1. MuraglitazarBMS-298585 FDA’s Endocrinologic and Metabolic DrugsAdvisory Committee Meeting 9 September 2005

  2. Introduction Brian Daniels, M.D. Senior Vice PresidentGlobal Clinical DevelopmentBristol-Myers Squibb

  3. BMS Presentation • Meeting the Needs for Type 2 DM David M Kendall, M.D.Associate Professor, University of Minnesota • Muraglitazar Overview Fred T Fiedorek, M.D.Vice President, Global Clinical Research • Non-Clinical Safety Mark Dominick, D.V.M., Ph.D.Distinguished Research Fellow, Drug Safety Evaluation • Clinical Efficacy Cindy Rubin, M.D.Group Director, Global Clinical Research • Clinical Safety Rene Belder, M.D.Vice President, Muraglitazar Full Development • Phamacovigilance and Fred T Fiedorek, M.D.Benefit / Risk Conclusions

  4. Medical Need in Type 2 Diabetes Mellitus David M. Kendall, M.D. Associate ProfessorUniversity of MinnesotaChief, International Diabetes Center Minneapolis, MN

  5. Current Challenges of Optimizing Treatment of Patients with Type 2 Diabetes Mellitus (T2DM) • Difficulty in achieving glycemic A1C goal • Patients with T2DM often have other CV risk factors • Dyslipidemia • High TG • Low HDL-C • Increased small dense LDL particles • Hypertension • Maintaining durable efficacy • Assuring patient compliance

  6. Microvascular Event Risk Reduction with Aggressive Glycemic Control in Patients with Diabetes Intervention Outcome % Reduction in Risk 1. DCCT Research Group: NEJM 1993;329:977-986 2. UK Prospective Diabetes Study (UKPDS) Group: Lancet 1998;352:837-853

  7. Hazards of Inadequate Treatment in Type 2 DMRelative Risk Associated with Change in Glycemic or Lipid Risk Factors Change / Parameter Outcome % Increase in Risk 1. Selvin E: Ann Intern Med2004;141:421-431 2. Turner RC: BMJ 1998;316:823-828 3. Hokanson JE: J Card Risk 1996;3:213-219

  8. ADA 2005 Standards of Medical Care in Diabetes Goals American Diabetes Association: Diabetes Care 2005 (suppl);28:S4-S36

  9. Reaching A1C, HDL-C, TG & LDL-C Targets in DiabetesNHANES (National Health and Nutrition Examination Survey) 1999-2000 Percentageat Target Saydah S et al: JAMA 2004;291:335-342 Jacobs M et al: Diab Res Clin Pract (In Press) Wong ND, Lopez V, personal communication 2005

  10. Mechanism of Action of PPAR Agonists • Peroxisome Proliferator-Activated Receptors (PPARs) • Receptors located in the cell nucleus • PPAR (fat) •  FFA,  insulin sensitivity,  glucose uptake •  plasma glucose • PPAR (liver, muscle) •  FA oxidation,  apo CIII,  apo A1 •  plasma TG,  HDL-C

  11. Muraglitazar Overview Fred T. Fiedorek, M.D. Vice President,Global Clinical ResearchBristol-Myers Squibb

  12. Muraglitazar • Designed to simultaneously activate two PPARs • PPAR – target of thiazolidinediones (TZDs): rosiglitazone and pioglitazone • PPAR – target of fibrates: gemfibroziland fenofibrate • Muraglitazar: a single molecule combining . . . • PPAR insulin-sensitizing anti-diabetic effects • PPAR HDL-C and TG lipid profile effects • Expected favorable impact on the vascular atherosclerotic/inflammatory process

  13. Muraglitazar Pharmacokinetics and Metabolism • PK characteristics support once-daily dosing • Muraglitazar has high bioavailability based on metabolic recovery studies • Population PK - no effect of age, gender, or race • Primary hepatic elimination into the bile;multiple CYP 450 metabolic pathways • No clinically meaningful drug-drug interactions

  14. Muraglitazar Development Program • Development program was designed to address benefitsand risks of muraglitazar, a dual PPAR  and  agonist • Non-Clinical Safety Evaluation • Results do not indicate that muraglitazar will pose a carcinogenic risk to humans • Clinical Efficacy Evaluation • Muraglitazar is highly efficacious in improving glycemic and lipid parameters in patients withType 2 diabetes • Clinical Safety Evaluation • Muraglitazar’s safety profile is consistent with its PPAR activity

  15. Proposed Indication for Muraglitazar • Muraglitazar is indicated as an adjunct to diet and exercise for the treatment of type 2 diabetes • For use in the following settings • Monotherapy • Combination with metformin • Combination with sulfonylureas

  16. MuraglitazarNon-Clinical Safety Mark Dominick, D.V.M., Ph.D. Distinguished Research Fellow,Drug Safety EvaluationBristol-Myers Squibb

  17. Overview of Non-clinical Safety • Comprehensive toxicology program • Single and repeat-dose toxicity • Genotoxicity • Reproductive toxicity • Safety pharmacology • Carcinogenicity • Pharmacologically mediated effects similar to marketed PPARγ agonists in repeat-dose studies • Not hepatotoxic, myotoxic, nephrotoxic, or cardiotoxic in rats or monkeys • Non-genotoxic and non-teratogenic • No off-target receptor or ion channel binding • Rodent tumor findings

  18. Muraglitazar: Non-clinical Cardiovascular Safety • hERG and Purkinje assays • In vitro assessments of potential repolarization disturbances • No effects at 2200x free Cmax at 5 mg • No QTc prolongation • Telemeterized dogs after single IV dose resulting in 120x human Cmax at 5 mg • Chronically dosed monkeys at 68x human AUCat 5 mg • QT prolongation in dogs only at overtly toxic doses • No effect on HR and minimal decrease in BP in dogs and monkeys at high multiples of clinical exposure

  19. Muraglitazar: Non-clinical Cardiovascular Safety • Increased heart weights in rats and monkeys at 53x and 44x, respectively, human AUC at 5 mg • No effects at 8x and 17x, respectively • Echocardiography in monkeys dosed for 1 year • No effects at 14x human AUC at 5 mg • No negative inotropic effects at up to 44x human AUC at 5 mg • Increased left ventricular wall thickness in females at 44x human AUC at 5 mg • No evidence of increased CHF except in aged male mice at 141x human AUC at 5 mg

  20. Muraglitazar: Mouse Carcinogenicity Study Results a Supplemental carcinogenicity study b Did not meet criteria for statistical analysis but considered drug-related due to dose response and associated focal gallbladder hyperplasia

  21. Muraglitazar: Rat Carcinogenicity Study Results * p < 0.025 (rare tumor) vs control

  22. Rat Urinary Bladder Investigative Study Results Support an Indirect Mode of Tumorigenesis • Prolithogenic changes in male rats at 50 mg/kg • Urine pH ≥6.5 throughout the day • Reduced urine citrate and increased oxalate • Dose-dependent increases in urinary calcium and magnesium solids • Necrosis and regenerative hyperplasia of urinary bladder mucosa by 3 months • Ventral bladder predilection • Transitional cell carcinomas by 9 months • Urinary bladder effects prevented by urinary acidification

  23. Incidence of Urinary Bladder Proliferative Lesions in Male Rats Treated with Muraglitazar for up to 15 Months a higher number of rats examined because of premature deaths from urinary bladder tumors

  24. Factors Impacting the Human Relevance of Crystalluria Induced Urinary Bladder Tumors in Muraglitazar-Treated Rats • Response unique to male rats • Absent in female rats and male and female mice • No urinary bladder cytotoxic, proliferative, or inflammatory changes in monkeys after 1 yearat up to 44x human AUC • No evidence of muraglitazar-related urolithiasis in Phase 3 clinical trials • Crystalluria in humans • Does not cause urinary bladder mucosal injury • Not identified as risk factor for human bladder cancer

  25. Muraglitazar: Overall Carcinogenicity Risk Assessment • Carcinogenicity hazard identified in lifetime studiesin rodents • Rodent tumor and mechanistic data do not indicate a carcinogenic risk to humans at therapeutic exposures • Crystalluria: mode for male-rat urinary bladder tumors • Not relevant to humans • High-dose rodent tumors (non-genotoxic mode) • Occurred at ≥ 48x human AUC at 5 mg • Safety margins ≥ 17x • Tumor profile similar to that observed collectively with marketed PPAR agonists

  26. Muraglitazar: Summary of Non-clinical Safety • Excellent oral tolerability in animals • Not hepatotoxic, myotoxic, nephrotoxic,or cardiotoxic in rats or monkeys • No in vitro off-target receptor or ion channel binding • Benign non-clinical cardiovascular safety profile • Non-genotoxic and not teratogenic • Carcinogenicity study results do not indicatea carcinogenic risk to humans

  27. Clinical Efficacy Cindy Rubin, M.D. Group Director,Global Clinical ResearchBristol-Myers Squibb

  28. Summary of Clinical Program • 6 Phase 2/3 Clinical Studies • 4640 subjects, 3226 muraglitazar-treated • 1 study in 320 non-diabetic dyslipidemic subjects • 5 studies in subjects with type 2 diabetes • Dose-ranging monotherapy study in 1477 subjects with more than two years of data in 745 subjects • Three placebo-controlled studies • Monotherapy • Combination with Glyburide • Combination with Metformin • Pioglitazone active comparator study

  29. Key Enrollment Criteria • Inclusion Criteria • A1C 7%–10% • Men and women, 18–70 years • BMI  41 kg/m2 • Serum TG  600 mg/dL • Exclusion Criteria • NYHA Class III and IV (Class II excluded in Phase 2) • Statin or Fibrate Use • Stable regimen to week 12, initiation / titration after week 12

  30. Demographics

  31. Study Designs • Randomized, placebo or active-control,parallel arm • Two-week placebo lead-in phase • 24-week double-blind phase (short-term) • Long-term, double-blind phase with titration steps • Based on pre-determined glycemic criteria

  32. Mura 0.5 mg Mura 1.5mg Mura 5 mg Dietaryand PboLead-in Mura 10 mg Mura 20 mg Pio 15 mg Lead-in2 wks Long Term Double-blind 2 yrs + (N = 745) Randomization Multiple titrations allowed after week 24 Study Design Dose-Ranging Study Screening Double-blind 24 wks (N = 1477) One-step rescuebegins at week 6

  33. Subject Disposition through 24 Weeks Dose-Ranging Study Muraglitazar

  34. Change from Baseline in A1C at Week 24 (LOCF) Dose-Ranging Study Muraglitazar Pio15 mg 230 8.3 Dose n = Baseline Mean (%) 0.5 mg 216 8.2 1.5 mg 235 8.2 5 mg 227 8.2 10 mg 231 8.2 20 mg 227 8.1 -0.25 -0.57 -0.57  A1C (%)with95% CI * -1.18 * -1.52 -1.76 * * p < 0.001 vs Mura 0.5 mg *

  35. Percent of Subjects to A1C Goal at Week 24 (LOCF) Dose-Ranging Study % Subjects < 7.0%% Subjects < 6.5% % 0.5 mg 1.5 mg 5 mg 10 mg 20 mg Pio 15 mg Muraglitazar Study 006 ST

  36. Selected Safety Endpoints – 24 Weeks Dose-Ranging Study Muraglitazar

  37. Dose Selection: Muraglitazar 2.5 mg and 5 mg • Based on considerations of glycemic and lipid efficacy and safety • 5 mg selected for development in Phase 3 • 2.5 mg included as lower dose for Phase 3 based on • Dose-modeling • Potential to achieve > 0.7% A1C reduction • Simple dosing multiple • 10 mg continues to be studied only as titration dose

  38. Clinical Efficacy Phase 3 Program Monotherapy Study Combination with Glyburide Combination with Metformin TZD Comparator Study

  39. Change from Baseline in A1C at Week 24 (LOCF) Monotherapy Study Muraglitazar Dose n = Baseline Mean (%) Pbo 111 8.0 2.5 mg 105 8.0 5 mg 110 7.9 5 mg OL 98 10.7  A1C (%)with95% CI * * * p < 0.001 vs. Pbo

  40. Percent of Subjects to A1C Goal at Week 24 (LOCF) Monotherapy Study % Subjects < 7.0%% Subjects < 6.5% 72 58 58 39 % 31 30 28 14 Pbo Mura 2.5 Mura 5 Mura 5 OL

  41. Monotherapy Study Lipid Parameters: % Change from Baselineat Week 12 (LOCF) Triglycerides HDL-C LDL-C apo B Baseline Mean(mg/dL) 187 193 194 45 44 42 132 130 124 104 103 102 * * %  with 95% CI * * * p < 0.001 vs Pbo

  42. Baseline MedianU/ml x mmol/L 5.2 4.7 4.3 5.6 Monotherapy Study Homeostasis Model Assessment (HOMA-IR)at Week 24 (LOCF) 9.4 -23.9 -35.6 -37.9 Pbo Mura 2.5 mg Mura 5 mg Mura 5 mg OL

  43. Clinical Efficacy Phase 3 Program Monotherapy Study Combination with Glyburide Combination with Metformin TZD Comparator Study

  44. Change from Baseline in A1C at Week 24 (LOCF) Combination Studies: Glyburide or Metformin Mura + Gly Mura + Met Pbo+ Met 197 8.0 Pbo+ Gly 195 8.2 Dose n = BL Mean (%) 2.5 mg 176 8.0 5 mg 189 8.2 2.5 mg 222 8.0 5 mg 198 8.0  A1C (%)With95% CI ** * ** * * p < 0.001 vs. Pbo + Gly ** p < 0.001 vs. Pbo + Met

  45. 59 52 34 31 13 4 Percent of Subjects to A1C Goal at Week 24 (LOCF) Combination Studies: Glyburide or Metformin % Subjects < 7.0%% Subjects < 6.5% 64 54 38 % 27 27 10 Pbo+ Gly Mura2.5 mg+ Gly Mura 5 mg+ Gly Pbo+ Met Mura2.5 mg+ Met Mura5 mg+ Met

  46. Combination with Glyburide Lipid Parameters: % Change from Baselineat Week 12 (LOCF) Triglycerides HDL-C LDL-C apo B Baseline Mean(mg/dL) 193 197 204 44 44 44 118 119 121 103 104 107 * * %  with 95% CI * * * p < 0.001 vs Pbo

  47. Clinical Efficacy Phase 3 Program Monotherapy Study Combination with Glyburide Combination with Metformin TZD Comparator Study

  48. Mean Change from Baseline in A1C at Week 24 (LOCF) TZD Comparator Study Dose n = Baseline Mean (%) Pio 30 mg + Met 550 8.1 Mura 5 mg + Met 569 8.1  A1C (%)with95% CI * * p < 0.001 vs Pio + Met

  49. Percent of Subjects to A1C Goal at Week 24 (LOCF) TZD Comparator Study % Subjects < 7.0%% Subjects < 6.5% 60 44 34 % 23 Pio 30 mg+ Met Mura 5 mg+ Met

  50. TZD Comparator Study Lipid Parameters: % Change from Baselineat Week 12 (LOCF) Triglycerides HDL-C LDL-C apo B Baseline Mean(mg/dL) 203 205 46 46 113 113 101 101 * %  with 95% CI * * * p < 0.001 vs Pio + Met

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