1
MuraglitazarMuraglitazarBMS-298585BMS-298585
FDA’s Endocrinologic and Metabolic DrugsFDA’s Endocrinologic and Metabolic DrugsAdvisory Committee MeetingAdvisory Committee Meeting
9 September 20059 September 2005
2
IntroductionIntroductionBrian Daniels, M.D.Brian Daniels, M.D.Senior Vice PresidentSenior Vice PresidentGlobal Clinical DevelopmentGlobal Clinical DevelopmentBristol-Myers SquibbBristol-Myers Squibb
3
Meeting the Needs for Type 2 DM Meeting the Needs for Type 2 DM David M Kendall, M.D.David M Kendall, M.D.Associate Professor,Associate Professor,University of MinnesotaUniversity of Minnesota
Muraglitazar OverviewMuraglitazar Overview Fred T Fiedorek, M.D.Fred T Fiedorek, M.D.Vice President,Vice President,Global Clinical ResearchGlobal Clinical Research
Non-Clinical SafetyNon-Clinical Safety Mark Dominick, D.V.M., Ph.D.Mark Dominick, D.V.M., Ph.D.Distinguished Research Fellow,Distinguished Research Fellow,Drug Safety EvaluationDrug Safety Evaluation
Clinical EfficacyClinical Efficacy Cindy Rubin, M.D.Cindy Rubin, M.D.Group Director,Group Director,Global Clinical ResearchGlobal Clinical Research
Clinical SafetyClinical Safety Rene Belder, M.D.Rene Belder, M.D. Vice President,Vice President,
Muraglitazar Full DevelopmentMuraglitazar Full Development
Phamacovigilance andPhamacovigilance and Fred T Fiedorek, M.D.Fred T Fiedorek, M.D.Benefit / Risk ConclusionsBenefit / Risk Conclusions
BMS PresentationBMS Presentation
4
Medical Need in Type 2 Medical Need in Type 2 Diabetes MellitusDiabetes Mellitus
David M. Kendall, M.D.David M. Kendall, M.D.Associate ProfessorAssociate ProfessorUniversity of MinnesotaUniversity of MinnesotaChief, International Diabetes Center Chief, International Diabetes Center Minneapolis, MNMinneapolis, MN
5
Current Challenges of Optimizing Treatment of Current Challenges of Optimizing Treatment of Patients with Type 2 Diabetes Mellitus (T2DM)Patients with Type 2 Diabetes Mellitus (T2DM)
Difficulty in achieving glycemic A1C goalDifficulty in achieving glycemic A1C goal
Patients with T2DM often have other CV risk Patients with T2DM often have other CV risk factorsfactors
– Dyslipidemia Dyslipidemia
• High TG High TG
• Low HDL-C Low HDL-C
• Increased small dense LDL particlesIncreased small dense LDL particles
– HypertensionHypertension
Maintaining durable efficacyMaintaining durable efficacy
Assuring patient complianceAssuring patient compliance
6
Microvascular Event Risk Reduction with Aggressive Microvascular Event Risk Reduction with Aggressive Glycemic Control in Patients with DiabetesGlycemic Control in Patients with Diabetes
1. DCCT Research Group: NEJM 1993;329:977-9862. UK Prospective Diabetes Study (UKPDS) Group: Lancet 1998;352:837-853
Intensive versus conventional Intensive versus conventional diabetes therapy - DCCTdiabetes therapy - DCCT11
Retinopathy (Primary)Retinopathy (Primary) 76% (62%-85%)76% (62%-85%)
Retinopathy Progression Retinopathy Progression (Secondary)(Secondary)
54% (39%-66%)54% (39%-66%)
NeuropathyNeuropathy 60% (38%-74%)60% (38%-74%)
AlbuminuriaAlbuminuria 54% (19%-74%)54% (19%-74%)
MicroalbuminuriaMicroalbuminuria 39% (21%-52%)39% (21%-52%)
Intensive versus conventional Intensive versus conventional diabetes therapy – UKPDS 33diabetes therapy – UKPDS 3322
Microvascular Events Microvascular Events (retinopathy, vitreous hemorrhage, (retinopathy, vitreous hemorrhage, fatal / non-fatal renal failure)fatal / non-fatal renal failure)
25% (7%-40%)25% (7%-40%)
InterventionIntervention % Reduction in Risk% Reduction in RiskOutcomeOutcome
7
Hazards of Inadequate Treatment in Type 2 DMHazards of Inadequate Treatment in Type 2 DMRelative Risk Associated with Change in Glycemic or Lipid Risk FactorsRelative Risk Associated with Change in Glycemic or Lipid Risk Factors
1. Selvin E: Ann Intern Med 2004;141:421-4312. Turner RC: BMJ 1998;316:823-8283. Hokanson JE: J Card Risk 1996;3:213-219
A1C: + 1% increaseA1C: + 1% increase11 CV Disease CV Disease + 18%+ 18%
Fatal / Non-fatal CHDFatal / Non-fatal CHD + 13%+ 13%
StrokeStroke + 17%+ 17%
PADPAD + 28%+ 28%
HDL-C: - 3.9 mg/dL decreaseHDL-C: - 3.9 mg/dL decrease22 CHDCHD + 15%+ 15%
TG: + 88 mg/dL increaseTG: + 88 mg/dL increase33 CHDCHD + 14% (men) + 14% (men)
+ 37% (women)+ 37% (women)
Change / ParameterChange / Parameter % Increase in Risk% Increase in RiskOutcomeOutcome
8
ADA 2005 Standards of Medical Care in DiabetesADA 2005 Standards of Medical Care in Diabetes
Glycemic ControlGlycemic Control
A1CA1C < 7.0%< 7.0%
LipidsLipids
LDL-CLDL-C
TriglyceridesTriglycerides
HDL-CHDL-C
Blood PressureBlood Pressure
< 100 mg/dL< 100 mg/dL
< 150 mg/dL< 150 mg/dL
> 40 mg/dL (men)> 40 mg/dL (men)> 50 mg/dL (women)> 50 mg/dL (women)
< 130/80 mmHg< 130/80 mmHg
American Diabetes Association: Diabetes Care 2005 (suppl);28:S4-S36
GoalsGoals
9
Reaching A1C, HDL-C, TG & LDL-C Targets in DiabetesReaching A1C, HDL-C, TG & LDL-C Targets in DiabetesNHANES (National Health and Nutrition Examination Survey) 1999-2000NHANES (National Health and Nutrition Examination Survey) 1999-2000
37 36 38
25
20
10
20
30
40
50
60
70
A1C HDL-C TG LDL-C All 4 RiskFactors
Saydah S et al: JAMA 2004;291:335-342Jacobs M et al: Diab Res Clin Pract (In Press)Wong ND, Lopez V, personal communication 2005
PercentagePercentageat Targetat Target
ADA TargetsADA Targets
A1CA1C < 7%< 7%
HDL-CHDL-C > 40 mg/dL> 40 mg/dL> 50 mg/dL> 50 mg/dL
(men)(men)(women)(women)
TGTG < 150 mg/dL< 150 mg/dL
LDL-CLDL-C < 100 mg/dL< 100 mg/dL
10
Mechanism of Action of PPAR AgonistsMechanism of Action of PPAR Agonists
Peroxisome Proliferator-Activated Receptors Peroxisome Proliferator-Activated Receptors (PPARs)(PPARs)
Receptors located in the cell nucleusReceptors located in the cell nucleus
PPARPPAR (fat) (fat)
FFA, FFA, insulin sensitivity, insulin sensitivity, glucose uptake glucose uptake
plasma glucoseplasma glucose
PPARPPAR (liver, muscle) (liver, muscle)
FA oxidation, FA oxidation, apo CIII, apo CIII, apo A1 apo A1
– plasma TG, plasma TG, HDL-C HDL-C
11
Muraglitazar OverviewMuraglitazar Overview
Fred T. Fiedorek, M.D.Fred T. Fiedorek, M.D.Vice President,Vice President,Global Clinical ResearchGlobal Clinical ResearchBristol-Myers SquibbBristol-Myers Squibb
12
MuraglitazarMuraglitazar
Designed to simultaneously activate two PPARsDesigned to simultaneously activate two PPARs
– PPARPPAR – target of thiazolidinediones (TZDs): – target of thiazolidinediones (TZDs): rosiglitazone and pioglitazonerosiglitazone and pioglitazone
– PPARPPAR – target of fibrates: gemfibrozil – target of fibrates: gemfibroziland fenofibrateand fenofibrate
Muraglitazar: a single molecule combining . . .Muraglitazar: a single molecule combining . . .
– PPARPPAR insulin-sensitizing anti-diabetic effects insulin-sensitizing anti-diabetic effects
– PPARPPAR HDL-C and TG lipid profile effects HDL-C and TG lipid profile effects
– Expected favorable impact on the vascular Expected favorable impact on the vascular atherosclerotic/inflammatory processatherosclerotic/inflammatory process
13
Muraglitazar Pharmacokinetics and MetabolismMuraglitazar Pharmacokinetics and Metabolism
PK characteristics support once-daily dosing PK characteristics support once-daily dosing
Muraglitazar has high bioavailability based on Muraglitazar has high bioavailability based on metabolic recovery studiesmetabolic recovery studies
Population PK - no effect of age, gender, or racePopulation PK - no effect of age, gender, or race
Primary hepatic elimination into the bile;Primary hepatic elimination into the bile;multiple CYP 450 metabolic pathwaysmultiple CYP 450 metabolic pathways
No clinically meaningful drug-drug interactionsNo clinically meaningful drug-drug interactions
14
Muraglitazar Development ProgramMuraglitazar Development Program
Development program was designed to address benefitsDevelopment program was designed to address benefitsand risks of muraglitazar, a dual PPAR and risks of muraglitazar, a dual PPAR and and agonist agonist
Non-Clinical Safety EvaluationNon-Clinical Safety Evaluation
– Results do not indicate that muraglitazar will pose Results do not indicate that muraglitazar will pose a carcinogenic risk to humansa carcinogenic risk to humans
Clinical Efficacy EvaluationClinical Efficacy Evaluation
– Muraglitazar is highly efficacious in improving Muraglitazar is highly efficacious in improving glycemic and lipid parameters in patients withglycemic and lipid parameters in patients withType 2 diabetes Type 2 diabetes
Clinical Safety EvaluationClinical Safety Evaluation
– Muraglitazar’s safety profile is consistent with its Muraglitazar’s safety profile is consistent with its PPARPPAR activity activity
15
Proposed Indication for MuraglitazarProposed Indication for Muraglitazar
Muraglitazar is indicated as an adjunct to diet and Muraglitazar is indicated as an adjunct to diet and exercise for the treatment of type 2 diabetesexercise for the treatment of type 2 diabetes
For use in the following settingsFor use in the following settings
MonotherapyMonotherapy
Combination with metforminCombination with metformin
Combination with sulfonylureasCombination with sulfonylureas
16
MuraglitazarMuraglitazarNon-Clinical SafetyNon-Clinical SafetyMark Dominick, D.V.M., Ph.D.Mark Dominick, D.V.M., Ph.D.Distinguished Research Fellow,Distinguished Research Fellow,Drug Safety EvaluationDrug Safety EvaluationBristol-Myers SquibbBristol-Myers Squibb
17
Overview of Non-clinical SafetyOverview of Non-clinical Safety Comprehensive toxicology programComprehensive toxicology program
– Single and repeat-dose toxicitySingle and repeat-dose toxicity– GenotoxicityGenotoxicity– Reproductive toxicityReproductive toxicity– Safety pharmacologySafety pharmacology– CarcinogenicityCarcinogenicity
Pharmacologically mediated effects similar to Pharmacologically mediated effects similar to marketed PPARmarketed PPARγγ agonists in repeat-dose studies agonists in repeat-dose studies
Not hepatotoxic, myotoxic, nephrotoxic, or Not hepatotoxic, myotoxic, nephrotoxic, or cardiotoxic in rats or monkeyscardiotoxic in rats or monkeys
Non-genotoxic and non-teratogenicNon-genotoxic and non-teratogenic
No off-target receptor or ion channel bindingNo off-target receptor or ion channel binding
Rodent tumor findingsRodent tumor findings
18
Muraglitazar: Non-clinical Cardiovascular SafetyMuraglitazar: Non-clinical Cardiovascular Safety hERG and Purkinje assays hERG and Purkinje assays
– In vitro assessments of potential In vitro assessments of potential repolarization repolarization disturbances disturbances
– No effects at 2200No effects at 2200x free Cmax at 5 mgx free Cmax at 5 mg
No QTc prolongation No QTc prolongation
– Telemeterized dogs after single IV dose resulting Telemeterized dogs after single IV dose resulting in 120x human Cmax at 5 mgin 120x human Cmax at 5 mg
– Chronically dosed monkeys at 68x human AUCChronically dosed monkeys at 68x human AUCat 5 mgat 5 mg
QT prolongation in dogs only at overtly toxic dosesQT prolongation in dogs only at overtly toxic doses
No effect on HR and minimal decrease in BP in dogs No effect on HR and minimal decrease in BP in dogs and monkeys at high multiples of clinical exposureand monkeys at high multiples of clinical exposure
19
Muraglitazar: Non-clinical Cardiovascular SafetyMuraglitazar: Non-clinical Cardiovascular Safety
Increased heart weights in rats and monkeys at 53x Increased heart weights in rats and monkeys at 53x and 44x, respectively, human AUC at 5 mgand 44x, respectively, human AUC at 5 mg
– No effects at 8x and 17x, respectivelyNo effects at 8x and 17x, respectively
Echocardiography in monkeys dosed for 1 yearEchocardiography in monkeys dosed for 1 year
– No effects at 14x human AUC at 5 mgNo effects at 14x human AUC at 5 mg
– No negative inotropic effects at up to 44x human No negative inotropic effects at up to 44x human AUC at 5 mgAUC at 5 mg
– Increased left ventricular wall thickness in Increased left ventricular wall thickness in females at 44x human AUC at 5 mg females at 44x human AUC at 5 mg
No evidence of increased CHF except in aged male No evidence of increased CHF except in aged male mice at 141x human AUC at 5 mgmice at 141x human AUC at 5 mg
20
Muraglitazar: Mouse Carcinogenicity Study ResultsMuraglitazar: Mouse Carcinogenicity Study Results
MouseMouseStudy IStudy I
Mouse Mouse Study IIStudy IIaa
Dose (mg/kg)Dose (mg/kg) 00 11 55 2020 00 4040
Multiple of Human Multiple of Human 5 mg AUC5 mg AUC 00 3x3x 17x17x 62x62x 00 141x141x
Gallbladder Gallbladder Adenoma (Males)Adenoma (Males)bb 0/830/83 0/420/42 0/420/42 1/381/38 0/440/44 2/322/32
a a Supplemental carcinogenicity studySupplemental carcinogenicity studybb Did not meet criteria for statistical analysis but considered Did not meet criteria for statistical analysis but considered drug-related due to drug-related due to
dose response and associated focal gallbladder hyperplasiadose response and associated focal gallbladder hyperplasia
21
Muraglitazar: Rat Carcinogenicity Study ResultsMuraglitazar: Rat Carcinogenicity Study Results
Dose (mg/kg)Dose (mg/kg) 00 11 55 3030 5050
Multiples of Human Multiples of Human 5 mg AUC5 mg AUC 1.3-1.8x1.3-1.8x 7-8x7-8x 37-45x37-45x 48-48-
59x59x
Subcutaneous Subcutaneous Liposarcoma (Males)Liposarcoma (Males) 1/1301/130 1/651/65 1/651/65 1/651/65 7/65*7/65*
Subcutaneous Subcutaneous Lipoma (Females)Lipoma (Females) 0/1300/130 0/650/65 0/650/65 1/651/65 2/65*2/65*
Urinary Bladder Urinary Bladder Papilloma/CarcinomPapilloma/Carcinoma (Males)a (Males)
5/1305/130 3/653/65 9/659/65** 26/6526/65** 38/6538/65**
** p < 0.025 (rare tumor) vs controlp < 0.025 (rare tumor) vs control
22
Rat Urinary Bladder Investigative Study Results Rat Urinary Bladder Investigative Study Results Support an Indirect Mode of TumorigenesisSupport an Indirect Mode of Tumorigenesis
Prolithogenic changes in male rats at 50 mg/kg Prolithogenic changes in male rats at 50 mg/kg
– Urine pH ≥6.5 throughout the dayUrine pH ≥6.5 throughout the day
– Reduced urine citrate and increased oxalate Reduced urine citrate and increased oxalate
Dose-dependent increases in urinary calcium and Dose-dependent increases in urinary calcium and magnesium solidsmagnesium solids
Necrosis and regenerative hyperplasia of urinary Necrosis and regenerative hyperplasia of urinary bladder mucosa by 3 monthsbladder mucosa by 3 months
– Ventral bladder predilection Ventral bladder predilection
Transitional cell carcinomas by 9 monthsTransitional cell carcinomas by 9 months
Urinary bladder effects prevented by urinary Urinary bladder effects prevented by urinary acidificationacidification
23
Incidence of Urinary Bladder Proliferative Lesions in Incidence of Urinary Bladder Proliferative Lesions in Male Rats Treated with Muraglitazar for up to 15 MonthsMale Rats Treated with Muraglitazar for up to 15 Months
DietDiet NormalNormal AcidifiedAcidified
Dose (mg/kg)Dose (mg/kg) 00 11 5050 00 11 5050
No. Examined (Months 6-15)No. Examined (Months 6-15) 5959 6060 7575aa 5454 5656 6363
Transitional Cell HyperplasiaTransitional Cell Hyperplasia 22 55 3434 11 00 00
Transitional Cell PapillomaTransitional Cell Papilloma 00 00 33 00 00 00
Transitional Cell CarcinomaTransitional Cell Carcinoma 00 11 1919 00 00 00
a higher number of rats examined because of premature deaths from urinary bladder tumors
24
Factors Impacting the Human Relevance of Crystalluria Factors Impacting the Human Relevance of Crystalluria Induced Urinary Bladder Tumors in Muraglitazar-Treated RatsInduced Urinary Bladder Tumors in Muraglitazar-Treated Rats
Response unique to male ratsResponse unique to male rats
– Absent in female rats and male and female miceAbsent in female rats and male and female mice
– No urinary bladder cytotoxic, proliferative, or No urinary bladder cytotoxic, proliferative, or inflammatory changes in monkeys after 1 yearinflammatory changes in monkeys after 1 yearat up to 44x human AUCat up to 44x human AUC
No evidence of muraglitazar-related urolithiasis in No evidence of muraglitazar-related urolithiasis in Phase 3 clinical trialsPhase 3 clinical trials
Crystalluria in humansCrystalluria in humans
– Does not cause urinary bladder mucosal injuryDoes not cause urinary bladder mucosal injury
– Not identified as risk factor for human bladder Not identified as risk factor for human bladder cancercancer
25
Muraglitazar: Overall Carcinogenicity Risk Muraglitazar: Overall Carcinogenicity Risk AssessmentAssessment
Carcinogenicity hazard identified in lifetime studiesCarcinogenicity hazard identified in lifetime studiesin rodentsin rodents
Rodent tumor and mechanistic data do not indicate a Rodent tumor and mechanistic data do not indicate a carcinogenic risk to humans at therapeutic exposurescarcinogenic risk to humans at therapeutic exposures
– Crystalluria: mode for male-rat urinary bladder Crystalluria: mode for male-rat urinary bladder tumorstumors
• Not relevant to humansNot relevant to humans
– High-dose rodent tumors (non-genotoxic mode)High-dose rodent tumors (non-genotoxic mode)
• Occurred at ≥Occurred at ≥ 48x human AUC at 5 mg 48x human AUC at 5 mg
• Safety margins Safety margins ≥≥ 17x 17x
Tumor profile similar to that observed collectively Tumor profile similar to that observed collectively with marketed PPARwith marketed PPAR agonists agonists
26
Muraglitazar: Summary of Non-clinical SafetyMuraglitazar: Summary of Non-clinical Safety
Excellent oral tolerability in animalsExcellent oral tolerability in animals
Not hepatotoxic, myotoxic, nephrotoxic,Not hepatotoxic, myotoxic, nephrotoxic,or cardiotoxic in rats or monkeysor cardiotoxic in rats or monkeys
No in vitro off-target receptor or ion channel No in vitro off-target receptor or ion channel bindingbinding
Benign non-clinical cardiovascular safety profileBenign non-clinical cardiovascular safety profile
Non-genotoxic and not teratogenicNon-genotoxic and not teratogenic
Carcinogenicity study results do not indicateCarcinogenicity study results do not indicatea carcinogenic risk to humansa carcinogenic risk to humans
27
Clinical EfficacyClinical EfficacyCindy Rubin, M.D.Cindy Rubin, M.D.Group Director,Group Director,Global Clinical ResearchGlobal Clinical ResearchBristol-Myers SquibbBristol-Myers Squibb
28
Summary of Clinical ProgramSummary of Clinical Program
6 Phase 2/3 Clinical Studies6 Phase 2/3 Clinical Studies
4640 subjects, 3226 muraglitazar-treated4640 subjects, 3226 muraglitazar-treated
1 study in 320 non-diabetic dyslipidemic subjects1 study in 320 non-diabetic dyslipidemic subjects
5 studies in subjects with type 2 diabetes5 studies in subjects with type 2 diabetes
– Dose-ranging monotherapy study in 1477 subjects Dose-ranging monotherapy study in 1477 subjects with more than two years of data in 745 subjectswith more than two years of data in 745 subjects
– Three placebo-controlled studiesThree placebo-controlled studies
• MonotherapyMonotherapy
• Combination with Glyburide Combination with Glyburide
• Combination with MetforminCombination with Metformin
– Pioglitazone active comparator studyPioglitazone active comparator study
29
Key Enrollment CriteriaKey Enrollment Criteria
Inclusion CriteriaInclusion Criteria A1C 7%–10% A1C 7%–10% Men and women, 18–70 years Men and women, 18–70 years BMI BMI 41 kg/m 41 kg/m22
Serum TG Serum TG 600 mg/dL 600 mg/dL
Exclusion CriteriaExclusion Criteria NYHA Class III and IV (Class II excluded in Phase 2)NYHA Class III and IV (Class II excluded in Phase 2)
Statin or Fibrate UseStatin or Fibrate Use Stable regimen to week 12, initiation / titration after Stable regimen to week 12, initiation / titration after
week 12week 12
30
DemographicsDemographics
MonotherapyMonotherapy
N = 1095N = 1095
Combination TherapyCombination Therapy
N = 2394N = 2394
Median Duration of Diabetes (yrs)Median Duration of Diabetes (yrs) 1.51.5 55
Mean age (yrs)Mean age (yrs) 5353 5555
Age Age ≥ 65 yrs (%)≥ 65 yrs (%) 1212 1515
Gender (%)Gender (%)
MaleMale
FemaleFemale
5656
44 44
5151
4949
Race (%)Race (%)
White White
Black Black
OtherOther
8181
6 (11 in US)6 (11 in US)
1313
8888
7 (13 in US)7 (13 in US)
5 5
Ethnicity (%)Ethnicity (%)
Hispanic / LatinoHispanic / Latino
1919
2929
31
Study DesignsStudy Designs
Randomized, placebo or active-control,Randomized, placebo or active-control,parallel armparallel arm
Two-week placebo lead-in phaseTwo-week placebo lead-in phase
24-week double-blind phase (short-term)24-week double-blind phase (short-term)
Long-term, double-blind phase with titration stepsLong-term, double-blind phase with titration steps
– Based on pre-determined glycemic criteria Based on pre-determined glycemic criteria
32
Study DesignStudy Design
One-step rescueOne-step rescuebegins at week 6begins at week 6
Multiple titrations Multiple titrations allowed after week 24allowed after week 24
Long TermLong TermDouble-blindDouble-blind
2 yrs +2 yrs +
(N = 745)
Double-blindDouble-blind24 wks24 wks
ScreeningScreening
DietaryDietaryand Pboand PboLead-inLead-in
Randomization
Lead-inLead-in2 wks2 wks
Dose-Ranging StudyDose-Ranging Study
(N = 1477)
Mura 20 mgMura 20 mg
Mura 0.5 mgMura 0.5 mg
Mura 1.5mgMura 1.5mg
Mura 5 mgMura 5 mg
Mura 10 mgMura 10 mg
Pio 15 mgPio 15 mg
33
0.5 mg0.5 mg 1.5 mg1.5 mg 5 mg5 mg 10 mg10 mg 20 mg20 mgPioPio
15 mg15 mg
RandomizedRandomized 236236 259259 245245 249249 239239 251251
Data set for Data set for A1C analysesA1C analyses
216216 235235 227227 231231 227227 230230
RescuedRescued 9393 8282 4848 2424 N/AN/A 7979
D/C due to AEsD/C due to AEs 44 1111 88 2222 3131 1111
Subject Disposition through 24 WeeksSubject Disposition through 24 WeeksDose-Ranging StudyDose-Ranging Study
Muraglitazar
34-2.0
-1.5
-1.0
-0.5
0.0
Change from Baseline in A1C at Week 24 (LOCF)Change from Baseline in A1C at Week 24 (LOCF)
0.5 mg0.5 mg
216216
8.28.2
1.5 mg1.5 mg
235235
8.28.2
5 mg5 mg
227227
8.28.2
10 mg10 mg
231231
8.28.2
20 mg20 mg
227227
8.18.1
PioPio15 mg15 mg
230230
8.38.3
Dose-Ranging StudyDose-Ranging Study
* p < 0.001 vs Mura 0.5 mg* p < 0.001 vs Mura 0.5 mg
MuraglitazarMuraglitazar
DoseDose
n =n =
Baseline Mean (%)Baseline Mean (%)
**
**
**
** A1C (%)A1C (%)withwith
95% CI95% CI
-0.25
-0.57
-1.18
-1.52
-1.76
-0.57
35
31
40
59
74
82
43
14
24
38
52
67
21
0
10
20
30
40
50
60
70
80
90
Percent of Subjects to A1C Goal at Week 24 (LOCF)Percent of Subjects to A1C Goal at Week 24 (LOCF)Dose-Ranging StudyDose-Ranging Study
0.5 mg 1.5 mg 5 mg 10 mg 20 mg Pio 15 mg
% Subjects < 7.0%% Subjects < 7.0%
% Subjects < 6.5%% Subjects < 6.5%
Muraglitazar
%%
Study 006 STStudy 006 ST
36
Selected Safety Endpoints – 24 WeeksSelected Safety Endpoints – 24 Weeks
0.5 mg0.5 mgN = 236N = 236
1.5 mg1.5 mgN = 259N = 259
5 mg5 mgN = 245N = 245
10 mg10 mgN = 249N = 249
20 mg20 mgN = 239N = 239
Pio Pio 15 mg15 mg
N = 251N = 251
Mean Weight Mean Weight Change from Change from Baseline at Baseline at Week 24 (kg) Week 24 (kg)
-1.1-1.1 -0.2-0.2 1.61.6 3.23.2 4.94.9 0.20.2
Incidence of Incidence of Edema Events Edema Events (%)(%)
10.610.6 9.79.7 8.68.6 24.924.9 40.140.1 14.314.3
Heart Failure Heart Failure Events (n)Events (n) 00 00 00 55 22 00
Dose-Ranging StudyDose-Ranging Study
MuraglitazarMuraglitazar
37
Dose Selection: Muraglitazar 2.5 mg and 5 mgDose Selection: Muraglitazar 2.5 mg and 5 mg
Based on considerations of glycemic and lipid efficacy Based on considerations of glycemic and lipid efficacy and safetyand safety
5 mg selected for development in Phase 3 5 mg selected for development in Phase 3
2.5 mg included as lower dose for Phase 3 based on2.5 mg included as lower dose for Phase 3 based on
– Dose-modelingDose-modeling
– Potential to achieve > 0.7% A1C reductionPotential to achieve > 0.7% A1C reduction
– Simple dosing multipleSimple dosing multiple
10 mg continues to be studied only as titration dose10 mg continues to be studied only as titration dose
38
Clinical EfficacyClinical EfficacyPhase 3 ProgramPhase 3 Program
Monotherapy StudyMonotherapy Study
Combination with GlyburideCombination with Glyburide
Combination with MetforminCombination with Metformin
TZD Comparator StudyTZD Comparator Study
39
-0.32
-1.05-1.23
-2.62
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
2.5 mg2.5 mg
105105
8.08.0
5 mg5 mg
110110
7.97.9
PboPbo
111111
8.08.0
5 mg OL5 mg OL
9898
10.710.7
Change from Baseline in A1C at Week 24 (LOCF)Change from Baseline in A1C at Week 24 (LOCF)
* p 0.001 vs. Pbo
DoseDose
n =n =
Baseline Mean (%)Baseline Mean (%)
Monotherapy StudyMonotherapy Study
A1C (%)A1C (%)withwith
95% CI95% CI**
**
MuraglitazarMuraglitazar
40
0
10
20
30
40
50
60
70
80
Percent of Subjects to A1C Goal at Week 24 (LOCF)Percent of Subjects to A1C Goal at Week 24 (LOCF)
Pbo Mura 2.5 Mura 5
% Subjects < 7.0%% Subjects < 7.0%
% Subjects < 6.5%% Subjects < 6.5%
3030
1414
5858
3131
7272
5858
Mura 5 OL
3939
2828
Monotherapy StudyMonotherapy Study
%%
41
Lipid Parameters: % Change from BaselineLipid Parameters: % Change from Baselineat Week 12 (LOCF)at Week 12 (LOCF)
012
-2 -7
10
-18-1 -12
16
-27
-1
-40
-30
-20
-10
0
10
20
Pbo
Mura 2.5 mg
Mura 5 mg
TriglyceridesTriglycerides HDL-CHDL-C LDL-CLDL-C apo Bapo B
* p < 0.001 vs Pbo* p < 0.001 vs Pbo
*
*
% % with with
95% CI95% CI
Baseline MeanBaseline Mean(mg/dL)(mg/dL) 187 193 194187 193 194 45 44 4245 44 42 132 130 124132 130 124 104 103 102104 103 102
Monotherapy StudyMonotherapy Study
*
*
42
Homeostasis Model Assessment (HOMA-IR)Homeostasis Model Assessment (HOMA-IR)at Week 24 (LOCF)at Week 24 (LOCF)
-60
-40
-20
0
20
40
60
Median from
Baseline (%)
Q1, Q3
Baseline MedianBaseline MedianU/ml x mmol/LU/ml x mmol/L 5.2 4.7 4.3 5.6
Monotherapy StudyMonotherapy Study
PboPbo Mura 2.5 mgMura 2.5 mg Mura 5 mgMura 5 mg Mura 5 mg OLMura 5 mg OL
9.4
-23.9
-35.6 -37.9
43
Clinical EfficacyClinical EfficacyPhase 3 ProgramPhase 3 Program
Monotherapy StudyMonotherapy Study
Combination with GlyburideCombination with Glyburide
Combination with MetforminCombination with Metformin
TZD Comparator StudyTZD Comparator Study
44
-0.05
0.16
-0.91-1.00
-1.16-1.21
-1.4
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
0.2
0.4
**
**
Change from Baseline in A1C at Week 24 (LOCF)Change from Baseline in A1C at Week 24 (LOCF)
2.5 mg2.5 mg
176176
8.08.0
5 5 mgmg
189189
8.28.2
PboPbo+ Gly+ Gly
195195
8.28.2
* p < 0.001 vs. Pbo + Gly* p < 0.001 vs. Pbo + Gly
DoseDose
n =n =
BL Mean (%)BL Mean (%)
Mura + GlyMura + Gly
A1C (%)A1C (%)WithWith
95% CI95% CI
****
****
** p < 0.001 vs. Pbo + Met** p < 0.001 vs. Pbo + Met
2.5 mg2.5 mg
222222
8.08.0
5 mg5 mg
198198
8.08.0
PboPbo+ Met+ Met
197197
8.08.0
Mura + MetMura + Met
Combination Studies: Glyburide or Metformin Combination Studies: Glyburide or Metformin
45
0
10
20
30
40
50
60
70
Percent of Subjects to A1C Goal at Week 24 (LOCF)Percent of Subjects to A1C Goal at Week 24 (LOCF)
PboPbo+ Gly+ Gly
MuraMura2.5 mg2.5 mg+ Gly+ Gly
MuraMura5 mg5 mg+ Gly+ Gly
% Subjects < 7.0%% Subjects < 7.0%
% Subjects < 6.5%% Subjects < 6.5%
1313
44
5252
3131
5959
3434%%
2727
1010
5454
2727
6464
3838
Pbo+ Met
Mura2.5 mg+ Met
Mura5 mg+ Met
Combination Studies: Glyburide or Metformin Combination Studies: Glyburide or Metformin
46
03
03
-5
7
-14
4
-11
14
-26
2
-30
-25
-20
-15
-10
-5
0
5
10
15
20
Pbo + Gly
Mura 2.5 mg + Gly
Mura 5 mg + Gly
Lipid Parameters: % Change from BaselineLipid Parameters: % Change from Baselineat Week 12 (LOCF)at Week 12 (LOCF)
Triglycerides HDL-C LDL-C apo B
*
*
Combination with GlyburideCombination with Glyburide
% % with with
95% CI95% CI
Baseline MeanBaseline Mean(mg/dL)(mg/dL) 193 197 204193 197 204 44 44 4444 44 44 118 119 121118 119 121 103 104 107103 104 107
* p < 0.001 vs Pbo* p < 0.001 vs Pbo
*
*
47
Clinical EfficacyClinical EfficacyPhase 3 ProgramPhase 3 Program
Monotherapy StudyMonotherapy Study
Combination with GlyburideCombination with Glyburide
Combination with MetforminCombination with Metformin
TZD Comparator StudyTZD Comparator Study
48
**
Mean Change from Baseline in A1C at Week 24 (LOCF)Mean Change from Baseline in A1C at Week 24 (LOCF)
-0.85
-1.14
-1.3
-1.2
-1.1
-1.0
-0.9
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0.0
Mura 5 mg Mura 5 mg + Met+ Met
569569
8.18.1
Pio 30 mg Pio 30 mg + Met+ Met
550550
8.18.1
* p < 0.001 vs Pio + Met* p < 0.001 vs Pio + Met
TZD Comparator StudyTZD Comparator Study
DoseDose
n =n =
Baseline Mean (%)Baseline Mean (%)
A1C (%)A1C (%)withwith
95% CI95% CI
49
0
10
20
30
40
50
60
70
Percent of Subjects to A1C Goal at Week 24 (LOCF)Percent of Subjects to A1C Goal at Week 24 (LOCF)
Mura 5 mg+ Met
Pio 30 mg+ Met
% Subjects < 7.0%% Subjects < 7.0%
% Subjects < 6.5%% Subjects < 6.5%6060
3434
4444
2323
TZD Comparator StudyTZD Comparator Study
%%
50
% % with with
95% CI95% CI
Lipid Parameters: % Change from BaselineLipid Parameters: % Change from Baselineat Week 12 (LOCF)at Week 12 (LOCF)
-6
14
-14
4
-12
19
-28
3
-35
-30
-25
-20
-15
-10
-5
0
5
10
15
20
25
Pio 30 mg + Met
Mura 5 mg + Met
TriglyceridesTriglycerides HDL-CHDL-C LDL-CLDL-C apo Bapo B
*
*
*
* p < 0.001 vs Pio + Met* p < 0.001 vs Pio + Met
TZD Comparator StudyTZD Comparator Study
Baseline MeanBaseline Mean(mg/dL)(mg/dL) 203 205203 205 46 4646 46 113 113113 113 101 101101 101
51
6.00
6.50
7.00
7.50
8.00
8.50
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Pio 30 mg + Met
Mura 5 mg + Met
Mean A1C Over Time (LOCF) – 50 WeeksMean A1C Over Time (LOCF) – 50 WeeksTZD Comparator StudyTZD Comparator Study
A1CA1C(%)(%)
WeekWeek
7.397.39
6.996.99
(N = 550) (N = 550)
(N = 569)(N = 569)
52
MonotherapyMonotherapy[2.5 to 5 mg][2.5 to 5 mg]
Combination Combination TherapyTherapy
[2.5 to 5 mg][2.5 to 5 mg]
Other Efficacy Parameters Other Efficacy Parameters Muraglitazar 2.5 mg and 5 mgMuraglitazar 2.5 mg and 5 mg
Albumin/Creatinine ratio (median % change)
-20 to -25 -8 to -33
hs-CRP(mean % change)
-20 to -34 -12 to -33
PAI-1(mean % change)
-16 to -24 -11 to -30
Fibrinogen(mean % change)
-3 to -7 -2 to -6
Phase 3Phase 3
53
Summary of EfficacySummary of EfficacyMuraglitazar 2.5 mg and 5 mgMuraglitazar 2.5 mg and 5 mg
Dose-dependent, consistent, clinically meaningful Dose-dependent, consistent, clinically meaningful reductions in A1Creductions in A1C
– Up to 70% achieve A1C goals < 7%Up to 70% achieve A1C goals < 7%
– Durable glycemic effectDurable glycemic effect
Dose-dependent improvements in lipid parametersDose-dependent improvements in lipid parameters
– ↓↓TG, ↑HDL-CTG, ↑HDL-C
– ↓↓apoB, no deleterious effect on LDL-CapoB, no deleterious effect on LDL-C
Dose-dependent reductions in albumin/creatinine,Dose-dependent reductions in albumin/creatinine,hs-CRP, PAI-1 and fibrinogenhs-CRP, PAI-1 and fibrinogen
54
Clinical SafetyClinical SafetyRene Belder, M.D.Rene Belder, M.D.Vice President,Vice President,Muraglitazar Full DevelopmentMuraglitazar Full DevelopmentBristol-Myers SquibbBristol-Myers Squibb
55
Exposure by DoseExposure by Dose
0
200
400
600
800
1000
1200
1400
1600
0.5 1.5 5 10 20 15
Muraglitazar
Pat
ien
t Y
ears
Exp
osu
reP
atie
nt
Yea
rs E
xpo
sure
2.5
Pioglitazone
30 45Pbo
Additional Data IncludedAdditional Data Includedin Complete Datasetin Complete Dataset
NDANDA
Complete Dataset: Phase 2 and 3 Short-term and Long-termComplete Dataset: Phase 2 and 3 Short-term and Long-term
333333
7373
414414516516
15151515
623623
343343251251
440440
8080
56
Medical History and Concomitant MedicationsMedical History and Concomitant Medications
PboPboN = 528N = 528
MuraMuraN = 2969N = 2969
PioPioN = 823N = 823
Medical HistoryMedical History
HypertensionHypertension 5252 5454 6262
Atherosclerotic DiseaseAtherosclerotic Disease 1111 1212 1616
Concomitant MedicationsConcomitant Medications
StatinsStatins 2222 2222 2222
FibratesFibrates 0.40.4 0.80.8 0.40.4
Beta Blockers Beta Blockers 1313 1313 1616
Calcium Channel BlockersCalcium Channel Blockers 99 1010 1313
ACE InhibitorsACE Inhibitors 2828 2929 3737
DiureticsDiuretics 1919 1919 2020
Percent of SubjectsPercent of Subjects
Complete DatasetComplete Dataset
57
Presentation of Safety DataPresentation of Safety Data
Quantification of drug effects during 24-week Quantification of drug effects during 24-week (short-term) treatment presented by dose(short-term) treatment presented by dose
EdemaEdema
Weight gainWeight gain
Complete Dataset assessmentsComplete Dataset assessments
Heart FailureHeart Failure
CV EventsCV Events
CancerCancer
Hepatic SafetyHepatic Safety
Muscle SafetyMuscle Safety
58
Percent of Subjects Reporting Edema Events –Percent of Subjects Reporting Edema Events –24 Weeks24 Weeks
PboPboMuraMura
2.5 mg2.5 mgMuraMura5 mg5 mg
PioPio30 mg30 mg
MonotherapyMonotherapy 7.87.8 8.18.1 11.411.4 ––
Combo w/GlyCombo w/Gly 7.07.0 9.49.4 9.89.8 ––
Combo w/MetCombo w/Met 3.73.7 9.49.4 15.615.6 ––
TZD TZD ComparatorComparator(with Met)(with Met)
–– –– 9.29.2 7.27.2
Phase 3 Short-termPhase 3 Short-term
59
Percent of Subjects Discontinuing Due to Percent of Subjects Discontinuing Due to Edema Events – 24 WeeksEdema Events – 24 Weeks
PboPboMuraMura
2.5 mg2.5 mgMuraMura5 mg5 mg
PioPio30 mg30 mg
MonotherapyMonotherapy 1.71.7 00 00 ––
Combo w/GlyCombo w/Gly 00 0.50.5 0.50.5 ––
Combo w/MetCombo w/Met 00 00 0.50.5 ––
TZD TZD ComparatorComparator(with Met)(with Met)
–– –– 0.20.2 0.20.2
Phase 3 Short-termPhase 3 Short-term
60
Change from Baseline in Body Weight (kg)Change from Baseline in Body Weight (kg)at Week 24 (LOCF)at Week 24 (LOCF)
MonotherapyMonotherapyCombination Combination
w/Glyw/GlyCombination Combination
w/Metw/MetTZDTZD
ComparatorComparator
Pbo 2.5 5Pbo 2.5 5 Pio 30 5Pio 30 5
1.11.1
-0.8-0.8
2.12.1
2.62.6
0.40.4
4.14.1
1.41.4
-0.7-0.7
2.82.8
1.41.4
0.60.6
(kg)(kg)
Pbo 2.5 5Pbo 2.5 5 Pbo 2.5 5Pbo 2.5 5
88 91 8988 91 89 91 9091 9087 83 8387 83 83 89 90 8989 90 89Dose (mg)Dose (mg)
BL Mean (kg)BL Mean (kg)
Phase 3 Short-termPhase 3 Short-term
61
Heart Failure and PPARHeart Failure and PPAR Agonists Agonists
PPARPPAR agonists: reported hazard ratio for heart agonists: reported hazard ratio for heart failure of 1.2 to 1.8 compared to other oral failure of 1.2 to 1.8 compared to other oral antihyperglycemic therapyantihyperglycemic therapy1,21,2
Dose-related increase in plasma volume likely Dose-related increase in plasma volume likely responsible for increase in heart failureresponsible for increase in heart failure
– Heart failure more commonly reported in Heart failure more commonly reported in patients with pre-existing ventricular patients with pre-existing ventricular dysfunctiondysfunction
PPARPPAR agonists do not appear to directly affect agonists do not appear to directly affect myocardial functionmyocardial function
1. Karter AJ, 2005. Diabet Med;22(8):986-93. 1. Karter AJ, 2005. Diabet Med;22(8):986-93.
2. Delea TE, 2003. Diabetes Care;26(11):2983-9. 2. Delea TE, 2003. Diabetes Care;26(11):2983-9.
62
Incidence perIncidence per1000 Patient-years1000 Patient-years PboPbo Mura 2.5 mgMura 2.5 mg Mura 5 mgMura 5 mg Pio 30 mgPio 30 mg
MonotherapyMonotherapy 00 00 5.0 5.0
MetforminMetforminCombinationCombination 00 3.83.8 8.58.5 4.64.6
GlyburideGlyburideCombinationCombination 00 14.514.5 14.514.5
Investigator-Reported Heart FailureInvestigator-Reported Heart FailureComplete DatasetComplete Dataset
63
Kaplan-Meier Estimates for Time to First Heart Failure EventKaplan-Meier Estimates for Time to First Heart Failure Event
0.00
0.01
0.02
0.03
0.04
0.05
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150
Weeks
Mura Mura ≤≤ 2.5 mg 2.5 mg
Mura 5 mgMura 5 mg
Pro
po
rtio
n o
f P
atie
nts
P
rop
ort
ion
of
Pat
ien
ts
wit
h H
eart
Fai
lure
AE
wit
h H
eart
Fai
lure
AE
Mura Mura ≥ 10 mg≥ 10 mg
Complete DatasetComplete Dataset
64
Investigator-Reported Heart FailureInvestigator-Reported Heart FailureSubject IDSubject ID TherapyTherapy
Event Causing Heart Failure Event Causing Heart Failure (Adjudication Committee)(Adjudication Committee) Echo FindingsEcho Findings
Days to Days to resolutionresolution
022-255-11022-255-11 + Met+ Met -- LV hypertrophyLV hypertrophy 22
021-55-2021-55-2 + Gly+ Gly Myocardial infarctionMyocardial infarction LVEF 40%LVEF 40% CC
021-69-1021-69-1 + Gly+ Gly Heart block/bradycardiaHeart block/bradycardia -- 11
021-209-10021-209-10 + Gly+ Gly Probable myocardial ischemiaProbable myocardial ischemia LVEF 73%LVEF 73% CC
006-41-2006-41-2 MonoMono -- LVEF 55-60%LVEF 55-60% 1616
006-85-1006-85-1 MonoMono Atrial fibrillation Atrial fibrillation Normal LV functionNormal LV function 1616
006-245-27006-245-27 MonoMono Ischemic heart diseaseIschemic heart disease LVEF 41%LVEF 41% CC
006-419-4006-419-4 MonoMono -- -- 22
025-45-5025-45-5 + Met+ Met -- LVEF 40%LVEF 40% 77
025-48-6025-48-6 + Met+ Met Accelerated hypertensionAccelerated hypertension LVEF 50%LVEF 50% 44
025-193-9025-193-9 + Met+ Met Arrhythmia or cardiac Arrhythmia or cardiac ischemiaischemia -- Sudden deathSudden death
025-235-3025-235-3 + Met+ Met -- LVEF 57%LVEF 57% 66
025-236-7025-236-7 + Met+ Met Aortic stenosisAortic stenosis LVEF 51%LVEF 51% 1515
022-153-2022-153-2 + Met+ Met -- -- 11††
021-237-5021-237-5 + Gly+ Gly Myocardial infarctionMyocardial infarction -- Arrhythmia; deathArrhythmia; death
021-244-14021-244-14 + Gly+ Gly Atrial fibrillationAtrial fibrillation LVEF 67%LVEF 67% 3535
021-301-5021-301-5 + Gly+ Gly Adjustment of beta-blockerAdjustment of beta-blocker LVEF 72%LVEF 72% 5959
025-289-74025-289-74 + Met+ Met -- LVEF 30%LVEF 30% 99
025-337-5025-337-5 + Met+ Met -- LVEF 50%LVEF 50% 9696
5 mg1515 p y
2.5 mg516 p-y
Pio771 p-y
C = not resolved at time of study discontinuation C = not resolved at time of study discontinuation †† Heart failure resolved. Patient died 9 days later. Heart failure resolved. Patient died 9 days later.
Complete DatasetComplete Dataset
65
Heart Failure Adjudication in Phase 3Heart Failure Adjudication in Phase 3
Objective: to confirm investigator-reported cases and Objective: to confirm investigator-reported cases and to screen for potential undiagnosed heart failure eventsto screen for potential undiagnosed heart failure events
Methods: blinded assessment of patients with reported Methods: blinded assessment of patients with reported predefined adverse event termspredefined adverse event terms
ResultsResults
– All except one case of investigator-diagnosed heart All except one case of investigator-diagnosed heart failure confirmedfailure confirmed
– More than half of the heart failure events were due More than half of the heart failure events were due to intercurrent events to intercurrent events
– A small number of events of edema/dyspnea A small number of events of edema/dyspnea adjudicated as mild heart failure resolved with adjudicated as mild heart failure resolved with treatment while muraglitazar was continued in most treatment while muraglitazar was continued in most patientspatients
66
Heart Failure Risk FactorsHeart Failure Risk Factors
HistoryHistory
Incidence of Investigator-Reported Incidence of Investigator-Reported Heart Failure Heart Failure –– Phase 3 Phase 3
PatientsPatientswith Historywith History
% (n/N)% (n/N)
PatientsPatientswithout Historywithout History
% (n/N) % (n/N)
Congestive Heart FailureCongestive Heart Failure 8.0% (2/25)8.0% (2/25) 0.6% (11/1718)0.6% (11/1718)
Symptomatic Symptomatic Atherosclerotic DiseaseAtherosclerotic Disease
3.1% (7/227)3.1% (7/227) 0.4% (6/1516)0.4% (6/1516)
Beta-blocker UseBeta-blocker Use 2.4% (6/254)2.4% (6/254) 0.5% (7/1489)0.5% (7/1489)
Peripheral EdemaPeripheral Edema 1.9% (4/209)1.9% (4/209) 0.6% (9/1534)0.6% (9/1534)
HypertensionHypertension 1.2% (12/974) 1.2% (12/974) 0.1% (1/769)0.1% (1/769)
Phase 3 Short-term and Long-TermPhase 3 Short-term and Long-Term
67
Heart Failure SummaryHeart Failure Summary
Consistent with marketed PPARConsistent with marketed PPAR agonists, a low agonists, a low incidence of investigator-diagnosed events was incidence of investigator-diagnosed events was observed in muraglitazar-treated patientsobserved in muraglitazar-treated patients
Heart failure incidence Heart failure incidence – Dose dependentDose dependent– Higher in patients with a known AHA/ADA risk factor Higher in patients with a known AHA/ADA risk factor
for heart failurefor heart failure– Resolved with treatment and discontinuation of Resolved with treatment and discontinuation of
muraglitazarmuraglitazar
Infrequently, patients with moderate edema or dyspnea Infrequently, patients with moderate edema or dyspnea were adjudicated to have clinically unrecognized heart were adjudicated to have clinically unrecognized heart failure. Symptoms resolved with treatment while failure. Symptoms resolved with treatment while continuing on muraglitazar.continuing on muraglitazar.
68
Cardiovascular (CV) EventsCardiovascular (CV) Events
Imbalance in small numbers of non-fatal CV events in Imbalance in small numbers of non-fatal CV events in one study and fatal CV events in another studyone study and fatal CV events in another study
Analyzed taking into account differences in durationAnalyzed taking into account differences in durationof exposureof exposure
– Discontinued subjects were not followed long-termDiscontinued subjects were not followed long-term
CV events defined byCV events defined by
– 52 predefined terms from MedDRA 8.0 dictionary52 predefined terms from MedDRA 8.0 dictionary
– Acute and chronic cardiac and cerebrovascular Acute and chronic cardiac and cerebrovascular eventsevents
69
Predefined CV EventsPredefined CV Events
Acute atherosclerotic eventsAcute atherosclerotic events
Acute atherothrombotic cardiac eventsAcute atherothrombotic cardiac events(e.g., myocardial infarction, acute coronary (e.g., myocardial infarction, acute coronary syndrome, coronary occlusion)syndrome, coronary occlusion)
Acute atherothrombotic cerebrovascular events Acute atherothrombotic cerebrovascular events (e.g., stroke, TIA)(e.g., stroke, TIA)
CV death, including sudden or unwitnessed deathCV death, including sudden or unwitnessed death
Chronic atherosclerotic eventsChronic atherosclerotic events
Including angina, coronary artery disease, Including angina, coronary artery disease, myocardial ischemiamyocardial ischemia
70
Number of Subjects with CV EventsNumber of Subjects with CV EventsComplete DatasetComplete Dataset
PlaceboPlaceboN = 528N = 528
MuraglitazarMuraglitazarN = 2969N = 2969
PioglitazonePioglitazoneN = 823N = 823
Total Subjects with CV EventTotal Subjects with CV Event 1111 9797 1515
Acute Atherosclerotic EventsAcute Atherosclerotic Events 88 5555 66
Cardiovascular DeathCardiovascular Death 11 99 00 Myocardial Infarction (MI)Myocardial Infarction (MI) 0 0 1515 11 Acute MIAcute MI 22 44 00 Silent MISilent MI 00 00 11 Angina UnstableAngina Unstable 00 99 22 Coronary Artery OcclusionCoronary Artery Occlusion 33 77 00 Acute Coronary SyndromeAcute Coronary Syndrome 11 00 00 Cerebrovascular AccidentCerebrovascular Accident 00 1010 22 Transient Ischemic AttackTransient Ischemic Attack 11 66 00 Hemorrhagic StrokeHemorrhagic Stroke 00 11 00 Amaurosis FugaxAmaurosis Fugax 00 11 00
Chronic Atherosclerotic EventsChronic Atherosclerotic Events
Angina PectorisAngina Pectoris 22 2525 55 Coronary Artery DiseaseCoronary Artery Disease 33 1919 44 Myocardial IschemiaMyocardial Ischemia 00 77 44 Coronary Artery StenosisCoronary Artery Stenosis 00 44 00 Coronary Artery AtherosclerosisCoronary Artery Atherosclerosis 00 22 00
71
Patient-Patient-years of years of
ExposureExposure
Number of Number of Patients Patients
with Event with Event
IncidenceIncidenceper 1000 per 1000
Patient-yearsPatient-years
Patient-Patient-years of years of
ExposureExposure
Number of Number of Patients Patients
with Eventwith Event
Incidence Incidence per 1000 per 1000
Patient-yearsPatient-years
PlaceboPlacebo 330330 1111 33.3733.37 331331 88 24.2024.20
MuraglitazarMuraglitazar 34373437 9797 28.2228.22 34633463 5555 15.8815.88
PioglitazonePioglitazone 762762 1515 19.6819.68 766766 66 7.837.83
CV Events and Exposure to Study DrugCV Events and Exposure to Study Drug
CV EventsCV Events(Acute and Chronic)(Acute and Chronic)
Acute Atherothrombotic Acute Atherothrombotic CV EventsCV Events
Complete DatasetComplete Dataset
72
0
10
20
30
40
50
60
70
Pbo AnyMura
Mura 1.5 mg
Mura 2.5 mg
Mura 5 mg
Mura 10 mg
Mura 20 mg
Any Pio
CV Events by DoseCV Events by DoseComplete DatasetComplete Dataset
Inci
den
ce p
er 1
000
pat
ien
t-ye
ars
Inci
den
ce p
er 1
000
pat
ien
t-ye
ars
(95%
CI)
(95%
CI)
73
Kaplan-Meier Estimates for Time to First CV EventKaplan-Meier Estimates for Time to First CV Event
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150
Weeks
Mura Mura ≤≤ 2.5 mg 2.5 mg
Mura 5 mgMura 5 mg
Pro
po
rtio
n o
f P
atie
nts
wit
h C
V E
ven
tP
rop
ort
ion
of
Pat
ien
ts w
ith
CV
Eve
nt
Mura Mura ≥ 10 mg≥ 10 mg
Complete DatasetComplete Dataset
74
CV DeathCV DeathComplete DatasetComplete Dataset
3.0 2.6
0.0
5.0
10.0
15.0
20.0
PboPboN = 528N = 528
MuraMuraN = 3125N = 3125
PioPioN = 823N = 823
Incidence perIncidence per1000 patient-years1000 patient-years
(95% CI)(95% CI)
Patient-years ExposurePatient-years Exposure 332332 34853485 772772
Cardiovascular Deaths (n)Cardiovascular Deaths (n) 11 99 00
Myocardial InfarctionMyocardial Infarction 33
Sudden or UnwitnessedSudden or Unwitnessed 11 44
Cerebrovascular Accident Cerebrovascular Accident 22
75
Summary of CV Event AnalysisSummary of CV Event Analysis
Complete Dataset assessment of CV events indicates Complete Dataset assessment of CV events indicates comparable incidences of CV events and deaths for comparable incidences of CV events and deaths for muraglitazar and placebo when analyzed by patient year muraglitazar and placebo when analyzed by patient year of exposure of exposure
Lack of biologic plausibility for CV risk with muraglitazar Lack of biologic plausibility for CV risk with muraglitazar based onbased on
– Beneficial effects on markers of CV riskBeneficial effects on markers of CV risk
– Broad diversity among reported CV events Broad diversity among reported CV events
– No increase in CV events with increasing doseNo increase in CV events with increasing dose
– Absence of off-target CV toxicity in non-clinical or Absence of off-target CV toxicity in non-clinical or clinical studiesclinical studies
76
Patient-years ExposurePatient-years Exposure 332332 34713471 768768
Cancers (n)Cancers (n) 11 3434 99
CancerCancer
3.0
9.811.7
0
5
10
15
20
25
Complete DatasetComplete Dataset
PboPboN = 528N = 528
MuraMuraN = 3125N = 3125
PioPioN = 823N = 823
Incidence perIncidence per1000 patient-years1000 patient-years
(95% CI)(95% CI)
77
Patient-years ExposurePatient-years Exposure 332332 34853485 772772
Deaths (n)Deaths (n) 11 1818 22
CV CV 11 99 00
CancerCancer 00 77 11
Other Other 00 22 11
All Cause DeathAll Cause Death
3.05.2
2.60
5
10
15
20
25
Complete DatasetComplete Dataset
Deaths perDeaths per1000 patient-years1000 patient-years
PboPboN = 528N = 528
MuraMuraN = 3125N = 3125
PioPioN = 823N = 823
78
Liver ParametersLiver Parameters
PboPboN = 528N = 528
MuraMuraN = 2969N = 2969
PioPioN = 823N = 823
Baseline ALT (U/L)Baseline ALT (U/L) 31.0331.03 30.2030.20 32.2632.26
Mean Change from Mean Change from Baseline to Week 24Baseline to Week 24 -0.83-0.83 -7.13-7.13 -7.70-7.70
ALT > 3 x ULN, n (%)ALT > 3 x ULN, n (%) 5 (1.0)5 (1.0) 12 (0.4)12 (0.4) 7 (0.9)7 (0.9)
ALT > 5 x ULN, n (%)ALT > 5 x ULN, n (%) 1 (0.2)1 (0.2) 2 (0.1)2 (0.1) 3 (0.4)3 (0.4)
Phase 2 and 3 Short-term & Complete DatasetPhase 2 and 3 Short-term & Complete Dataset
79
CK EvaluationsCK Evaluations
PboPboMuraMura
≤ 5 mg≤ 5 mgMuraMura10 mg10 mg
MuraMura20 mg20 mg PioPio
With Statin, NWith Statin, N 131131 707707 7979 6666 232232
CK > 10 x ULN, n (%)CK > 10 x ULN, n (%) 00 1 (0.1)1 (0.1) 00†† 00 00
No Statin, NNo Statin, N 389389 17301730 166166 171171 580580
CK > 10 x ULN, n (%)CK > 10 x ULN, n (%) 2 (0.5)2 (0.5) 10 (0.6)10 (0.6)†††† 1 (0.6)1 (0.6) 1 (0.6)1 (0.6) 2 (0.3)2 (0.3)
†††† Investigator report of rhabdomyolysis associated with yard work;Investigator report of rhabdomyolysis associated with yard work; CK returned to below threshold while on treatment CK returned to below threshold while on treatment
No associated muscle symptoms on muraglitazarNo associated muscle symptoms on muraglitazar
†† One elevation occurred in a subject on Mura 5 / 10 mgOne elevation occurred in a subject on Mura 5 / 10 mg
Complete DatasetComplete Dataset
80
Summary of Muraglitazar SafetySummary of Muraglitazar Safety
Development program confirmed anticipated, Development program confirmed anticipated, dose-related, PPARdose-related, PPAR agonist-associated risks agonist-associated risks for edema, weight gain, and low incidence of for edema, weight gain, and low incidence of heart failure heart failure
Complete Dataset does not indicate increased Complete Dataset does not indicate increased risks for hepatotoxicity, myotoxicity, CV events risks for hepatotoxicity, myotoxicity, CV events or canceror cancer
Proposed post-approval pharmacovigilance Proposed post-approval pharmacovigilance program will enrich knowledge regarding safety program will enrich knowledge regarding safety of muraglitazarof muraglitazar
81
Pharmacovigilance,Pharmacovigilance,Ensuring Appropriate Use Ensuring Appropriate Use and Benefit / Risk Summary and Benefit / Risk Summary for Muraglitazarfor Muraglitazar
Fred T. Fiedorek, M.D.Fred T. Fiedorek, M.D.
82
Proposed PharmacovigilanceProposed Pharmacovigilance
Enhanced Pharmacovigilance PlanEnhanced Pharmacovigilance Plan
– Events of special interestEvents of special interest
– Unanticipated low frequency eventsUnanticipated low frequency events
– Targeted questionnaires to physiciansTargeted questionnaires to physicians
– Periodic, cumulative assessmentsPeriodic, cumulative assessments
Pharmacoepidemiology StudyPharmacoepidemiology Study
– Risk assessmentRisk assessment
– Monitor product education and Monitor product education and communication effectivenesscommunication effectiveness
83
Pharmacoepidemiology StudyPharmacoepidemiology Study ObjectivesObjectives
– To estimate relative incidences of safety events with To estimate relative incidences of safety events with muraglitazar relative to other T2DM treatments muraglitazar relative to other T2DM treatments
– To characterize T2DM treatment patternsTo characterize T2DM treatment patterns
Patient recruitment and follow up will be from a large US Patient recruitment and follow up will be from a large US managed care database (includes physician, pharmacy, and managed care database (includes physician, pharmacy, and hospital claims data)hospital claims data)
This cohort study will enroll a total of 15,000 patients This cohort study will enroll a total of 15,000 patients – 5000 Muraglitazar users5000 Muraglitazar users– 5000 TZD users5000 TZD users– 5000 Metformin, SU, Insulin5000 Metformin, SU, Insulin
Accrual into the study will depend on prescription ratesAccrual into the study will depend on prescription rates
Patient experience data will be reviewed quarterly for 1Patient experience data will be reviewed quarterly for 1stst year year
Active follow up of patients through annual questionnaires will Active follow up of patients through annual questionnaires will begin 1 year after database recruitment for next 5 yearsbegin 1 year after database recruitment for next 5 years
84
Plans for Ensuring Appropriate Plans for Ensuring Appropriate Use of MuraglitazarUse of Muraglitazar
85
Muraglitazar: Muraglitazar: Steps to Assure Appropriate UseSteps to Assure Appropriate Use
Key Communication PointsKey Communication Points Do not use in patients with NYHA Class III / IVDo not use in patients with NYHA Class III / IV
heart failureheart failure Evaluate and treat, if appropriate, patients developing Evaluate and treat, if appropriate, patients developing
edema or dyspneaedema or dyspnea
– Any patient developing severe edema, rapid weight Any patient developing severe edema, rapid weight gain or dyspnea should be evaluated and treated,gain or dyspnea should be evaluated and treated,if appropriate, for heart failureif appropriate, for heart failure
Heart failure education for muraglitazar tailored fromHeart failure education for muraglitazar tailored fromthe AHA/ADA Consensus Guidance publication the AHA/ADA Consensus Guidance publication
Communication Tools to Aid Appropriate UseCommunication Tools to Aid Appropriate Use Patient package insertPatient package insert Healthcare professional communication materialsHealthcare professional communication materials
86
Guiding Principles for Expanding Knowledge: Guiding Principles for Expanding Knowledge: Pharmacovigilance and Assuring Appropriate UsePharmacovigilance and Assuring Appropriate Use
Plans to enrich post-marketing product knowledgePlans to enrich post-marketing product knowledgefor muraglitazarfor muraglitazar
– Collection of post-launch safety dataCollection of post-launch safety data
– Collection of post-launch treatment experienceCollection of post-launch treatment experience
Glucophage (metformin) experience will help to guide Glucophage (metformin) experience will help to guide communication activities for assuring appropriate use communication activities for assuring appropriate use and tracking patient safety and tracking patient safety
As with all new BMS products, no branded direct to As with all new BMS products, no branded direct to consumer advertising for the first year consumer advertising for the first year
87
Benefit / Risk Benefit / Risk of Muraglitazarof Muraglitazar
88
Treatment of Type 2 Diabetes Treatment of Type 2 Diabetes
Need for treatment remains highNeed for treatment remains high
– Patients not at glycemic and/or lipid goalsPatients not at glycemic and/or lipid goals
– Low durability of efficacy for existing drugsLow durability of efficacy for existing drugs
No available single agent meets both glycemic No available single agent meets both glycemic and lipid (HDL-C, TG) treatment needsand lipid (HDL-C, TG) treatment needs
Outcomes trials show that meeting glycemic and Outcomes trials show that meeting glycemic and lipid goals reduces micro and macro vascular lipid goals reduces micro and macro vascular eventsevents
89
Mean Change Mean Change from Baselinefrom Baseline
MonotherapyMonotherapy[2.5 to 5 mg][2.5 to 5 mg]
Combination Combination TherapyTherapy
[2.5 to 5 mg][2.5 to 5 mg]
A1C (%)A1C (%) -1.05 to -1.23-1.05 to -1.23 -0.91 to -1.21-0.91 to -1.21
FPG (mg/dL)FPG (mg/dL) -26 to -40 -26 to -40 -26 to -44-26 to -44
% with A1C <7%% with A1C <7% 58 to 7258 to 72 52 to 6452 to 64
Muraglitazar – Proven Glycemic BenefitsMuraglitazar – Proven Glycemic Benefits
90
Mean Change Mean Change from Baselinefrom Baseline
MonotherapyMonotherapy[2.5 to 5 mg][2.5 to 5 mg]
Combination Combination TherapyTherapy
[2.5 to 5 mg][2.5 to 5 mg]
Muraglitazar – Proven Lipid BenefitsMuraglitazar – Proven Lipid Benefits
TG (%)TG (%) -18 to -27-18 to -27 -14 to -29-14 to -29
HDL-C (%)HDL-C (%) 10 to 1710 to 17 7 to 197 to 19
apoB (%)apoB (%) -7 to -12-7 to -12 -5 to -12-5 to -12
91
A1C: + 1% increaseA1C: + 1% increase11 CV Disease CV Disease + 18%+ 18%
Fatal / Non-fatal CHDFatal / Non-fatal CHD + 13%+ 13%
StrokeStroke + 17%+ 17%
PADPAD + 28%+ 28%
HDL-C: - 3.9 mg/dL decreaseHDL-C: - 3.9 mg/dL decrease22 CHDCHD + 15%+ 15%
TG: + 88 mg/dL increaseTG: + 88 mg/dL increase3 3 CHDCHD + 14% (men) + 14% (men)
+ 37% (women)+ 37% (women)
Muraglitazar 5 mg - 1.2%Muraglitazar 5 mg - 1.2%
Muraglitazar 5 mg + 6 mg/dLMuraglitazar 5 mg + 6 mg/dL
Muraglitazar 5 mg - 40 mg/dLMuraglitazar 5 mg - 40 mg/dL
Hazards of Inadequate Treatment in Type 2 DMHazards of Inadequate Treatment in Type 2 DMRelative Risk Associated with Change in Glycemic or Lipid Risk FactorsRelative Risk Associated with Change in Glycemic or Lipid Risk Factors
1. Selvin E: Ann Intern Med 2004;141:421-4312. Turner RC: BMJ 1998;316:823-8283. Hokanson JE: J Card Risk 1996;3:213-219
Change / ParameterChange / Parameter % Increase in Risk% Increase in RiskOutcomeOutcome
92
DCCT / EDIC: CV Outcomes Benefits withDCCT / EDIC: CV Outcomes Benefits withPast Intensive Glycemic ControlPast Intensive Glycemic Control
At completion of DCCT 1993At completion of DCCT 1993
Intensive control A1C = 7.2%Intensive control A1C = 7.2%vs.vs.
Conventional control A1C = 9.1%Conventional control A1C = 9.1%
Now, in 2005: Now, in 2005:
Nathan D. American Diabetes Association 2005 Scientific Sessions; June 10-14, 2005;San Diego, CA
Cardiovascular EventsCardiovascular Events 42% (19-63)42% (19-63)
Nonfatal MI, Stroke, and CV DeathNonfatal MI, Stroke, and CV Death 57% (12-79)57% (12-79)
OutcomeOutcomeRelative Risk ReductionRelative Risk Reduction
(95% CI)(95% CI)
93
Benefits of Treatment with a PPARBenefits of Treatment with a PPAR Agonist: Agonist: VA-HIT – Diabetes: Efficacy of Gemfibrozil in Preventing CV EventsVA-HIT – Diabetes: Efficacy of Gemfibrozil in Preventing CV Events
Rubins HB: Arch Int Med 2002;162:2597-2604
Major Cardiovascular EventsMajor Cardiovascular Events 0.68 (p = 0.004)0.68 (p = 0.004)
CHD DeathCHD Death 0.59 (p = 0.02)0.59 (p = 0.02)
Non-fatal Myocardial InfarctionNon-fatal Myocardial Infarction 0.78 (p = 0.17)0.78 (p = 0.17)
StrokeStroke 0.60 (p = 0.46)0.60 (p = 0.46)
OutcomeOutcome Hazard ratio (p-value)Hazard ratio (p-value)
(n = 769 subjects with diabetes)(n = 769 subjects with diabetes)
94
Planned Clinical Outcomes TrialPlanned Clinical Outcomes Trial
Rationale: To demonstrate benefits of dual PPAR Rationale: To demonstrate benefits of dual PPAR activation in T2DMactivation in T2DM
Large randomized controlled clinical trialLarge randomized controlled clinical trial
Adjudicated CV outcomes as primary endpointAdjudicated CV outcomes as primary endpoint
Duration of approximately 5 years, driven by Duration of approximately 5 years, driven by number of required eventsnumber of required events
Design to be finalized following results of ongoing Design to be finalized following results of ongoing trialstrials
– MuraglitazarMuraglitazar
– PROactive (pioglitazone)PROactive (pioglitazone)
– FIELD (fenofibrate)FIELD (fenofibrate)
95
Muraglitazar – PPARMuraglitazar – PPAR Agonist-associated Risk Agonist-associated Risk
Heart FailureHeart Failure
– Incidence is low and dose-dependentIncidence is low and dose-dependent
– Symptomatic and recognizable to both Symptomatic and recognizable to both patient and practitionerpatient and practitioner
– Manageable with treatment and Manageable with treatment and discontinuation of muraglitazardiscontinuation of muraglitazar
96
Dosing Recommendations:Dosing Recommendations:Muraglitazar 2.5 mg and 5 mgMuraglitazar 2.5 mg and 5 mg
Muraglitazar 2.5 mgMuraglitazar 2.5 mg
Appropriate starting dose in patients with mild Appropriate starting dose in patients with mild degrees of hyperglycemiadegrees of hyperglycemia
Appropriate starting dose in patients expectedAppropriate starting dose in patients expectedto be less tolerant of fluid retention, such as NYHAto be less tolerant of fluid retention, such as NYHAClass II heart failureClass II heart failure
Titration to 5 mg as necessary to achieveTitration to 5 mg as necessary to achieveADA goals ADA goals
Muraglitazar 5 mgMuraglitazar 5 mg
Appropriate starting dose for patients with more Appropriate starting dose for patients with more severe hyperglycemiasevere hyperglycemia
97
Proposed WarningsProposed Warnings
Muraglitazar should not be used in patients withMuraglitazar should not be used in patients with
NYHA Class III and IV heart failureNYHA Class III and IV heart failure
Moderate to severe hepatic insufficiencyModerate to severe hepatic insufficiency
Muraglitazar has not been studied and is thusMuraglitazar has not been studied and is thusnot indicatednot indicated
For use in combination with insulinFor use in combination with insulin
For use in pediatric patientsFor use in pediatric patients
Muraglitazar will also not be recommendedMuraglitazar will also not be recommended
For use with TZDs and fibratesFor use with TZDs and fibrates
98
ConclusionConclusion
Muraglitazar, the first dual PPARMuraglitazar, the first dual PPARαα//γγ agonist agonist
– Achieves and maintains glycemic goalsAchieves and maintains glycemic goals
– Improves diabetic dyslipidemiaImproves diabetic dyslipidemia
Muraglitazar has an acceptable safety and Muraglitazar has an acceptable safety and tolerability profiletolerability profile
– Events related to fluid retentionEvents related to fluid retentionwell-characterized and manageablewell-characterized and manageable
Muraglitazar offers a new treatment option for Muraglitazar offers a new treatment option for patients with type 2 diabetes with a favorable patients with type 2 diabetes with a favorable benefit / risk assessmentbenefit / risk assessment
99
Consultants Available to the CommitteeConsultants Available to the CommitteeRachel Bijou, M.D.Rachel Bijou, M.D.
Assistant Professor of Medicine Assistant Professor of Medicine Division of CardiologyDivision of CardiologyColumbia University, New York, NYColumbia University, New York, NY
Samuel Cohen, M.D., Ph.D.Samuel Cohen, M.D., Ph.D.
Professor and Chair, DepartmentProfessor and Chair, Departmentof Pathology & Microbiologyof Pathology & MicrobiologyUniversity of NebraskaUniversity of NebraskaMedical Center, Omaha, NEMedical Center, Omaha, NE
Ralph DeFronzo, M.D.Ralph DeFronzo, M.D.
Professor of MedicineProfessor of MedicineChief, Diabetes DivisionChief, Diabetes DivisionUniversity of Texas Health Sciences University of Texas Health Sciences Center, San Antonio, TXCenter, San Antonio, TX
Henry N. Ginsberg, M.D.Henry N. Ginsberg, M.D.
Irving Professor of Medicine Irving Professor of Medicine Director, Irving Center forDirector, Irving Center forClinical ResearchClinical ResearchColumbia University, New York, NYColumbia University, New York, NY
Robert Henry, M.D.Robert Henry, M.D.
Professor of MedicineProfessor of MedicineChief, Section of Endocrinology, Chief, Section of Endocrinology, Metabolism and Diabetes Metabolism and Diabetes University of California San DiegoUniversity of California San DiegoSan Diego, CASan Diego, CA
Anthony Keech, M.D.Anthony Keech, M.D.
Professor, Department of Medicine Professor, Department of Medicine Deputy Director, National Health Deputy Director, National Health Medical Research Council Clinical Medical Research Council Clinical Trials Centre,Trials Centre,The University of SydneyThe University of SydneyCamperdown, AustraliaCamperdown, Australia
100
Consultants Available to the CommitteeConsultants Available to the Committee
David M. Kendall, M.D.David M. Kendall, M.D.Associate Professor of Medicine Associate Professor of Medicine University of MinnesotaUniversity of MinnesotaChief, International Diabetes CenterChief, International Diabetes CenterMinneapolis, MNMinneapolis, MN
James D. Neaton, Ph.D.James D. Neaton, Ph.D.Professor, Biostatistics Division Professor, Biostatistics Division School of Public HealthSchool of Public HealthUniversity of Minnesota University of Minnesota Minneapolis, MNMinneapolis, MN
Brian Strom, M.D., M.P.H.Brian Strom, M.D., M.P.H.Professor of Medicine Professor of Medicine Chair, Department of Biostatistics Chair, Department of Biostatistics and Epidemiology and Epidemiology University of Pennsylvania University of Pennsylvania Philadelphia, PAPhiladelphia, PA
Alexander Walker, M.D., Dr.Ph.Alexander Walker, M.D., Dr.Ph.Senior Vice President for Senior Vice President for Epidemiology at i3 Drug Safety, Epidemiology at i3 Drug Safety, Ingenix, Newton, MAIngenix, Newton, MAFormer Professor and Chair, Former Professor and Chair, Department of Epidemiology Department of Epidemiology Harvard School of Public Health Harvard School of Public Health Boston, MABoston, MA
Top Related