FDAs Endocrinologic and Metabolic Drugs Advisory Committee Meeting

1
FDAs Endocrinologic and Metabolic DrugsAdvisory
Committee Meeting
MuraglitazarBMS-298585
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
Reduction in Risk
Outcome
1. DCCT Research Group NEJM 1993329977-986 2.
UK Prospective Diabetes Study (UKPDS) Group
Lancet 1998352837-853
7
Hazards of Inadequate Treatment in Type 2
DMRelative Risk Associated with Change in
Glycemic or Lipid Risk Factors
Change / Parameter
Increase in Risk
Outcome
1. Selvin E Ann Intern Med 2004141421-431 2.
Turner RC BMJ 1998316823-828 3. Hokanson JE J
Card Risk 19963213-219
8
ADA 2005 Standards of Medical Care in Diabetes
Goals
American Diabetes Association Diabetes Care 2005
(suppl)28S4-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 2004291335-342 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
  bilemultiple 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
• Muraglitazars 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 PPAR? 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 lt 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 710
• Men and women, 1870 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
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
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
Dose n Baseline Mean ()
-0.25
-0.57
-0.57
? A1C ()with95 CI

-1.18

-1.52
-1.76

p lt 0.001 vs Mura 0.5 mg

35
Percent of Subjects to A1C Goal at Week 24 (LOCF)
Dose-Ranging Study
Subjects lt 7.0 Subjects lt 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 gt 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 ()
2.5 mg 105 8.0
5 mg 110 7.9
Pbo 111 8.0
5 mg OL 98 10.7
? A1C ()with95 CI


p lt 0.001 vs. Pbo
40
Percent of Subjects to A1C Goal at Week 24 (LOCF)
Monotherapy Study
Subjects lt 7.0 Subjects lt 6.5
72
58
58
39

31
30
28
14
Pbo
Mura 2.5
Mura 5
Mura 5 OL
41
Lipid Parameters Change from Baselineat Week
12 (LOCF)
Monotherapy Study
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 lt 0.001 vs Pbo
42
Homeostasis Model Assessment (HOMA-IR)at Week 24
(LOCF)
Monotherapy Study
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
2.5 mg 176 8.0
5 mg 189 8.2
Dose n BL Mean ()
2.5 mg 222 8.0
5 mg 198 8.0
? A1C ()With95 CI




p lt 0.001 vs. Pbo Gly
p lt 0.001 vs. Pbo Met
45
Percent of Subjects to A1C Goal at Week 24 (LOCF)
Combination Studies Glyburide or Metformin
Subjects lt 7.0 Subjects lt 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
Lipid Parameters Change from Baselineat Week
12 (LOCF)
Combination with Glyburide
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 lt 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
Mura 5 mg Met 569 8.1
Pio 30 mg Met 550 8.1
Dose n Baseline Mean ()
? A1C ()with95 CI

p lt 0.001 vs Pio Met
49
Percent of Subjects to A1C Goal at Week 24 (LOCF)
TZD Comparator Study
Subjects lt 7.0 Subjects lt 6.5
60
44
34

23
Mura 5 mg Met
Pio 30 mg Met
50
Lipid Parameters Change from Baselineat Week
12 (LOCF)
TZD Comparator Study
Triglycerides
HDL-C
LDL-C
apo B
Baseline Mean(mg/dL)
203 205
46 46
113 113
101 101

? with 95 CI


p lt 0.001 vs Pio Met
51
Mean A1C Over Time (LOCF) 50 Weeks
TZD Comparator Study
(N 550)
(N 569)
7.39
? A1C()
6.99
Week
52
Other Efficacy Parameters Muraglitazar 2.5 mg
and 5 mg
Phase 3
53
Summary of EfficacyMuraglitazar 2.5 mg and 5 mg

• Dose-dependent, consistent, clinically meaningful
  reductions in A1C
• Up to 70 achieve A1C goals lt 7
• Durable glycemic effect
• Dose-dependent improvements in lipid parameters
• ?TG, ?HDL-C
• ?apoB, no deleterious effect on LDL-C
• Dose-dependent reductions in albumin/creatinine,h
  s-CRP, PAI-1 and fibrinogen

54
Clinical Safety
Rene Belder, M.D. Vice President,Muraglitazar
Full DevelopmentBristol-Myers Squibb
55
Exposure by Dose
Complete Dataset Phase 2 and 3 Short-term and
Long-term
1515
Additional Data Includedin Complete Dataset NDA
Patient Years Exposure
623
516
440
414
333
343
251
80
73
0.5
1.5
5
10
20
15
2.5
30
45
Pbo
Pioglitazone
Muraglitazar
56
Medical History and Concomitant Medications
Complete Dataset
Percent of Subjects
57
Presentation of Safety Data

• Quantification of drug effects during 24-week
  (short-term) treatment presented by dose
• Edema
• Weight gain
• Complete Dataset assessments
• Heart Failure
• CV Events
• Cancer
• Hepatic Safety
• Muscle Safety

58
Percent of Subjects Reporting Edema Events 24
Weeks
Phase 3 Short-term
59
Percent of Subjects Discontinuing Due to Edema
Events 24 Weeks
Phase 3 Short-term
60
Change from Baseline in Body Weight (kg)at Week
24 (LOCF)
Phase 3 Short-term
Combination w/Gly
Combination w/Met
TZDComparator
Monotherapy
Dose (mg)BL Mean (kg)
Pbo 2.5 5
Pio 30 5
Pbo 2.5 5
Pbo 2.5 5
88 91 89
91 90
87 83 83
89 90 89
4.1
2.8
2.6
2.1
? (kg)
1.4
1.4
1.1
0.6
0.4
-0.7
-0.8
61
Heart Failure and PPAR? Agonists

• PPAR? agonists reported hazard ratio for heart
  failure of 1.2 to 1.8 compared to other oral
  antihyperglycemic therapy1,2
• Dose-related increase in plasma volume likely
  responsible for increase in heart failure
• Heart failure more commonly reported in patients
  with pre-existing ventricular dysfunction
• PPAR? agonists do not appear to directly affect
  myocardial function

1. Karter AJ, 2005. Diabet Med22(8)986-93. 2.
Delea TE, 2003. Diabetes Care26(11)2983-9.
62
Investigator-Reported Heart Failure
Complete Dataset
63
Kaplan-Meier Estimates for Time to First Heart
Failure Event
Complete Dataset
Mura 10 mg
Proportion of Patients with Heart Failure AE
Mura 5 mg
Mura 2.5 mg
64
Investigator-Reported Heart Failure
Complete Dataset
2.5 mg 516 p-y
5 mg 1515 py
Pio 771 p-y
C not resolved at time of study discontinuation
Heart failure resolved. Patient died 9
days later.
65
Heart Failure Adjudication in Phase 3

• Objective to confirm investigator-reported cases
  and to screen for potential undiagnosed heart
  failure events
• Methods blinded assessment of patients with
  reported predefined adverse event terms
• Results
• All except one case of investigator-diagnosed
  heart failure confirmed
• More than half of the heart failure events were
  due to intercurrent events
• A small number of events of edema/dyspnea
  adjudicated as mild heart failure resolved with
  treatment while muraglitazar was continued in
  most patients

66
Heart Failure Risk Factors
Phase 3 Short-term and Long-Term
67
Heart Failure Summary

• Consistent with marketed PPAR? agonists, a low
  incidence of investigator-diagnosed events was
  observed in muraglitazar-treated patients
• Heart failure incidence
• Dose dependent
• Higher in patients with a known AHA/ADA risk
  factor for heart failure
• Resolved with treatment and discontinuation of
  muraglitazar
• Infrequently, patients with moderate edema or
  dyspnea were adjudicated to have clinically
  unrecognized heart failure. Symptoms resolved
  with treatment while continuing on muraglitazar.

68
Cardiovascular (CV) Events

• Imbalance in small numbers of non-fatal CV events
  in one study and fatal CV events in another study
• Analyzed taking into account differences in
  durationof exposure
• Discontinued subjects were not followed long-term
• CV events defined by
• 52 predefined terms from MedDRA 8.0 dictionary
• Acute and chronic cardiac and cerebrovascular
  events

69
Predefined CV Events

• Acute atherosclerotic events
• Acute atherothrombotic cardiac events(e.g.,
  myocardial infarction, acute coronary syndrome,
  coronary occlusion)
• Acute atherothrombotic cerebrovascular events
  (e.g., stroke, TIA)
• CV death, including sudden or unwitnessed death
• Chronic atherosclerotic events
• Including angina, coronary artery disease,
  myocardial ischemia

70
Number of Subjects with CV Events
Complete Dataset
Placebo N 528
Muraglitazar N 2969
Pioglitazone N 823
71
CV Events and Exposure to Study Drug
Complete Dataset
72
CV Events by Dose
Complete Dataset
Incidence per 1000 patient-years (95 CI)
73
Kaplan-Meier Estimates for Time to First CV Event
Complete Dataset
Mura 2.5 mg
Mura 5 mg
Proportion of Patients with CV Event
Mura 10 mg
74
CV Death
Complete Dataset
Incidence per1000 patient-years (95 CI)
75
Summary of CV Event Analysis

• Complete Dataset assessment of CV events
  indicates comparable incidences of CV events and
  deaths for muraglitazar and placebo when analyzed
  by patient year of exposure
• Lack of biologic plausibility for CV risk with
  muraglitazar based on
• Beneficial effects on markers of CV risk
• Broad diversity among reported CV events
• No increase in CV events with increasing dose
• Absence of off-target CV toxicity in non-clinical
  or clinical studies

76
Cancer
Complete Dataset
Incidence per1000 patient-years (95 CI)
77
All Cause Death
Complete Dataset
Deaths per1000 patient-years
78
Liver Parameters
Phase 2 and 3 Short-term Complete Dataset
79
CK Evaluations
Complete Dataset
No associated muscle symptoms on muraglitazar
One elevation occurred in a subject on Mura 5 /
10 mg
Investigator report of rhabdomyolysis
associated with yard work CK returned to
below threshold while on treatment
80
Summary of Muraglitazar Safety

• Development program confirmed anticipated,
  dose-related, PPAR? agonist-associated risks for
  edema, weight gain, and low incidence of heart
  failure
• Complete Dataset does not indicate increased
  risks for hepatotoxicity, myotoxicity, CV events
  or cancer
• Proposed post-approval pharmacovigilance program
  will enrich knowledge regarding safety of
  muraglitazar

81
Pharmacovigilance,Ensuring Appropriate Use and
Benefit / Risk Summary for Muraglitazar

• Fred T. Fiedorek, M.D.

82
Proposed Pharmacovigilance

• Enhanced Pharmacovigilance Plan
• Events of special interest
• Unanticipated low frequency events
• Targeted questionnaires to physicians
• Periodic, cumulative assessments
• Pharmacoepidemiology Study
• Risk assessment
• Monitor product education and communication
  effectiveness

83
Pharmacoepidemiology Study

• Objectives
• To estimate relative incidences of safety events
  with muraglitazar relative to other T2DM
  treatments
• To characterize T2DM treatment patterns
• Patient recruitment and follow up will be from a
  large US managed care database (includes
  physician, pharmacy, and hospital claims data)
• This cohort study will enroll a total of 15,000
  patients
• 5000 Muraglitazar users
• 5000 TZD users
• 5000 Metformin, SU, Insulin
• Accrual into the study will depend on
  prescription rates
• Patient experience data will be reviewed
  quarterly for 1st year
• Active follow up of patients through annual
  questionnaires will begin 1 year after database
  recruitment for next 5 years

84
Plans for Ensuring Appropriate Use of Muraglitazar
85
Muraglitazar Steps to Assure Appropriate Use

• Key Communication Points
• Do not use in patients with NYHA Class III /
  IVheart failure
• Evaluate and treat, if appropriate, patients
  developing edema or dyspnea
• Any patient developing severe edema, rapid weight
  gain or dyspnea should be evaluated and
  treated,if appropriate, for heart failure
• Heart failure education for muraglitazar tailored
  fromthe AHA/ADA Consensus Guidance publication
• Communication Tools to Aid Appropriate Use
• Patient package insert
• Healthcare professional communication materials

86
Guiding Principles for Expanding Knowledge
Pharmacovigilance and Assuring Appropriate Use

• Plans to enrich post-marketing product
  knowledgefor muraglitazar
• Collection of post-launch safety data
• Collection of post-launch treatment experience
• Glucophage (metformin) experience will help to
  guide communication activities for assuring
  appropriate use and tracking patient safety
• As with all new BMS products, no branded direct
  to consumer advertising for the first year

87
Benefit / Risk of Muraglitazar
88
Treatment of Type 2 Diabetes

• Need for treatment remains high
• Patients not at glycemic and/or lipid goals
• Low durability of efficacy for existing drugs
• No available single agent meets both glycemic and
  lipid (HDL-C, TG) treatment needs
• Outcomes trials show that meeting glycemic and
  lipid goals reduces micro and macro vascular
  events

89
Muraglitazar Proven Glycemic Benefits
90
Muraglitazar Proven Lipid Benefits
91
Hazards of Inadequate Treatment in Type 2
DMRelative Risk Associated with Change in
Glycemic or Lipid Risk Factors
Change / Parameter
Increase in Risk
Outcome
1. Selvin E Ann Intern Med 2004141421-431 2.
Turner RC BMJ 1998316823-828 3. Hokanson JE J
Card Risk 19963213-219
92
DCCT / EDIC CV Outcomes Benefits withPast
Intensive Glycemic Control

• At completion of DCCT 1993
• Intensive control A1C 7.2 vs.Conventional
  control A1C 9.1
• Now, in 2005

Relative Risk Reduction(95 CI)
Outcome
Nathan D. American Diabetes Association 2005
Scientific Sessions June 10-14, 2005San Diego,
CA
93
Benefits of Treatment with a PPARa Agonist
VA-HIT Diabetes Efficacy of Gemfibrozil in
Preventing CV Events
Outcome
Hazard ratio (p-value)
(n 769 subjects with diabetes)
Rubins HB Arch Int Med 20021622597-2604
94
Planned Clinical Outcomes Trial

• Rationale To demonstrate benefits of dual PPAR
  activation in T2DM
• Large randomized controlled clinical trial
• Adjudicated CV outcomes as primary endpoint
• Duration of approximately 5 years, driven by
  number of required events
• Design to be finalized following results of
  ongoing trials
• Muraglitazar
• PROactive (pioglitazone)
• FIELD (fenofibrate)

95
Muraglitazar PPARg Agonist-associated Risk

• Heart Failure
• Incidence is low and dose-dependent
• Symptomatic and recognizable to both patient and
  practitioner
• Manageable with treatment and discontinuation of
  muraglitazar

96
Dosing RecommendationsMuraglitazar 2.5 mg and 5
mg

• Muraglitazar 2.5 mg
• Appropriate starting dose in patients with mild
  degrees of hyperglycemia
• Appropriate starting dose in patients expectedto
  be less tolerant of fluid retention, such as
  NYHAClass II heart failure
• Titration to 5 mg as necessary to achieveADA
  goals
• Muraglitazar 5 mg
• Appropriate starting dose for patients with more
  severe hyperglycemia

97
Proposed Warnings

• Muraglitazar should not be used in patients with
• NYHA Class III and IV heart failure
• Moderate to severe hepatic insufficiency
• Muraglitazar has not been studied and is thusnot
  indicated
• For use in combination with insulin
• For use in pediatric patients
• Muraglitazar will also not be recommended
• For use with TZDs and fibrates

98
Conclusion

• Muraglitazar, the first dual PPARa/? agonist
• Achieves and maintains glycemic goals
• Improves diabetic dyslipidemia
• Muraglitazar has an acceptable safety and
  tolerability profile
• Events related to fluid retentionwell-characteriz
  ed and manageable
• Muraglitazar offers a new treatment option for
  patients with type 2 diabetes with a favorable
  benefit / risk assessment

99
Consultants Available to the Committee

• Rachel Bijou, M.D.
• Assistant Professor of Medicine Division of
  CardiologyColumbia University, New York, NY
• Samuel Cohen, M.D., Ph.D.
• Professor and Chair, Departmentof Pathology
  MicrobiologyUniversity of NebraskaMedical
  Center, Omaha, NE
• Ralph DeFronzo, M.D.
• Professor of MedicineChief, Diabetes
  DivisionUniversity of Texas Health Sciences
  Center, San Antonio, TX

• Henry N. Ginsberg, M.D.
• Irving Professor of Medicine Director, Irving
  Center forClinical ResearchColumbia University,
  New York, NY
• Robert Henry, M.D.
• Professor of MedicineChief, Section of
  Endocrinology, Metabolism and Diabetes
  University of California San DiegoSan Diego, CA
• Anthony Keech, M.D.
• Professor, Department of Medicine Deputy
  Director, National Health Medical Research
  Council Clinical Trials Centre,The University of
  SydneyCamperdown, Australia

100
Consultants Available to the Committee

• David M. Kendall, M.D.
• Associate Professor of Medicine University of
  MinnesotaChief, International Diabetes
  CenterMinneapolis, MN
• James D. Neaton, Ph.D.
• Professor, Biostatistics Division School of
  Public HealthUniversity of Minnesota
  Minneapolis, MN

• Brian Strom, M.D., M.P.H.
• Professor of Medicine Chair,
  Department of Biostatistics and Epidemiology
  University of Pennsylvania
  Philadelphia, PA
• Alexander Walker, M.D., Dr.Ph.
• Senior Vice President for Epidemiology at i3 Drug
  Safety, Ingenix, Newton, MAFormer Professor and
  Chair, Department of Epidemiology Harvard School
  of Public Health Boston, MA