1 / 100

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.

topper
Download Presentation

FDA’s Endocrinologic and Metabolic Drugs Advisory Committee Meeting

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related