# Presentation: 779491

## FDA’s Endocrinologic and Metabolic DrugsAdvisory Committee Meeting

- MuraglitazarBMS-298585

- FDA’s Endocrinologic and Metabolic DrugsAdvisory Committee Meeting

- 9 September 2005

## Introduction

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

## 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

**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**

**BMS Presentation**

## Medical Need in Type 2 Diabetes Mellitus

- David M. Kendall, M.D.
- Associate ProfessorUniversity of MinnesotaChief, International Diabetes Center Minneapolis, MN

## 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**

## Microvascular Event Risk Reduction with Aggressive Glycemic Control in Patients with Diabetes

- 1. DCCT Research Group: NEJM 1993;329:977-986
- 2. UK Prospective Diabetes Study (UKPDS) Group: Lancet 1998;352:837-853

| Intensive versus conventional diabetes therapy - DCCT1 | Retinopathy (Primary) | 76% (62%-85%) |
| --- | --- | --- |
|  | Retinopathy Progression (Secondary) | 54% (39%-66%) |
|  | Neuropathy | 60% (38%-74%) |
|  | Albuminuria | 54% (19%-74%) |
|  | Microalbuminuria | 39% (21%-52%) |
| Intensive versus conventional diabetes therapy – UKPDS 332 | Microvascular Events (retinopathy, vitreous hemorrhage, fatal / non-fatal renal failure) | 25% (7%-40%) |
|  |  |  |

**Intervention**

**% Reduction in Risk**

**Outcome**

## Hazards of Inadequate Treatment in Type 2 DMRelative Risk Associated with Change in Glycemic or Lipid Risk Factors

- 1. Selvin E: Ann Intern Med* *2004;141:421-431
- 2. Turner RC: *BMJ *1998;316:823-828
- 3. Hokanson JE: J Card Risk 1996;3:213-219

| A1C:  + 1% increase1 | CV Disease  | + 18% |
| --- | --- | --- |
|  | Fatal / Non-fatal CHD | + 13% |
|  | Stroke | + 17% |
|  | PAD
 | + 28%
 |
| HDL-C:  - 3.9 mg/dL decrease2 | CHD | + 15% |
| 
TG:  + 88 mg/dL increase3 | 
CHD | 
+ 14% (men) 
+ 37% (women) |
|  |  |  |

**Change / Parameter**

**% Increase in Risk**

**Outcome**

## ADA 2005 Standards of Medical Care in Diabetes

| Glycemic Control
   A1C | 
< 7.0% |
| --- | --- |
| Lipids
   LDL-C
   Triglycerides
   HDL-C

Blood Pressure | < 100 mg/dL
< 150 mg/dL
> 40 mg/dL (men)> 50 mg/dL (women)
< 130/80 mmHg |

- American Diabetes Association: *Diabetes Care *2005 (suppl);28:S4-S36

**Goals**

## Reaching A1C, HDL-C, TG & LDL-C Targets in DiabetesNHANES (National Health and Nutrition Examination Survey) 1999-2000

- 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

**Percentage****at Target**

| ADA Targets |  |  |
| --- | --- | --- |
| A1C | < 7% |  |
| HDL-C | > 40 mg/dL> 50 mg/dL | (men)(women) |
| TG | < 150 mg/dL |  |
| LDL-C | < 100 mg/dL |  |

## Mechanism of Action of PPAR Agonists

**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**

## Muraglitazar Overview

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

## Muraglitazar

**Designed to simultaneously activate two PPARs**
**PPAR******** – target of thiazolidinediones (TZDs): rosiglitazone and pioglitazone**
**PPAR******** – target of fibrates: gemfibrozil****and 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**

## Muraglitazar Pharmacokinetics and Metabolism

**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**

## Muraglitazar Development Program

**Development program was designed to address benefits****and 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 with****Type 2 diabetes **
**Clinical Safety Evaluation**
**Muraglitazar’s safety profile is consistent with its PPAR******** activity**

## Proposed Indication for Muraglitazar

**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**

## MuraglitazarNon-Clinical Safety

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

## 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****γ**** 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**

## Muraglitazar: Non-clinical Cardiovascular Safety

**hERG and Purkinje assays **
**In vitro assessments of potential ****repolarization disturbances **
**No effects at 2200****x 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 AUC****at 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**

## 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**

## Muraglitazar: Mouse Carcinogenicity Study Results

**Muraglitazar: Mouse Carcinogenicity Study Results**

|  | MouseStudy I |  |  |  | Mouse Study IIa |  |
| --- | --- | --- | --- | --- | --- | --- |
| Dose (mg/kg) | 0 | 1 | 5 | 20 | 0 | 40 |
| Multiple of Human  5 mg AUC | 0 | 3x | 17x | 62x | 0 | 141x |
| Gallbladder Adenoma (Males)b | 0/83 | 0/42 | 0/42 | 1/38 | 0/44 | 2/32 |

- 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

## Muraglitazar: Rat Carcinogenicity Study Results

**Muraglitazar: Rat Carcinogenicity Study Results**

| Dose (mg/kg) | 0 | 1 | 5 | 30 | 50 |
| --- | --- | --- | --- | --- | --- |
| Multiples of Human  5 mg AUC |  | 1.3-1.8x | 7-8x | 37-45x | 48-59x |
| Subcutaneous Liposarcoma (Males) | 1/130 | 1/65 | 1/65 | 1/65 | 7/65* |
| Subcutaneous   Lipoma (Females) | 0/130 | 0/65 | 0/65 | 1/65 | 2/65* |
| Urinary Bladder Papilloma/Carcinoma (Males) | 5/130 | 3/65 | 9/65* | 26/65* | 38/65* |

- *	p < 0.025 (rare tumor) vs control

## 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**

## Incidence of Urinary Bladder Proliferative Lesions in Male Rats Treated with Muraglitazar for up to 15 Months

**Incidence of Urinary Bladder Proliferative Lesions in Male Rats Treated with Muraglitazar for up to 15 Months**

| Diet | Normal |  |  | Acidified |  |  |
| --- | --- | --- | --- | --- | --- | --- |
| Dose (mg/kg) | 0 | 1 | 50 | 0 | 1 | 50 |
| No. Examined (Months 6-15) | 59 | 60 | 75a | 54 | 56 | 63 |
| Transitional Cell Hyperplasia | 2 | 5 | 34 | 1 | 0 | 0 |
| Transitional Cell Papilloma | 0 | 0 | 3 | 0 | 0 | 0 |
| Transitional Cell Carcinoma | 0 | 1 | 19 | 0 | 0 | 0 |

- a higher number of rats examined because of premature deaths from urinary 	bladder tumors

## 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 year****at 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**

## Muraglitazar: Overall Carcinogenicity Risk Assessment

**Carcinogenicity hazard identified in lifetime studies****in 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**

## 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 indicate****a carcinogenic risk to humans**

## Clinical Efficacy

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

## 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**

## Key Enrollment Criteria

**Inclusion Criteria**
**A1C 7%–10% **
**Men and women, 18–70 years   **
**BMI ******** 41 kg/m****2**
**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**

## Demographics

|  | MonotherapyN = 1095 | Combination TherapyN = 2394 |  |
| --- | --- | --- | --- |
| Median Duration of Diabetes (yrs) | 1.5 |  | 5 |
| Mean age (yrs) | 53 |  | 55 |
| Age ≥ 65 yrs (%) | 12 |  | 15 |
| Gender (%)MaleFemale |                         5644                    |  |                              5149 |
| Race (%)White Black Other |                        816 (11 in US)13 |  |                              887 (13 in US) 5 |
| Ethnicity (%)Hispanic / Latino |                        19 |  |              29 |

## 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 **

## Study Design

**One-step rescue****begins at week 6**

**Double-blind**
**24 wks**

** ****Screening**

- Dose-Ranging Study

**(N = 1477)**

## Subject Disposition through 24 Weeks

|  | 
0.5 mg | 
1.5 mg | 
5 mg | 
10 mg | 
20 mg | Pio
15 mg |
| --- | --- | --- | --- | --- | --- | --- |
| Randomized	 | 236 | 259 | 245 | 249 | 239 | 251 |
| Data set for A1C analyses | 216 |  235 | 227 |    231 | 227 | 230 |
| Rescued |  93 |   82 |   48 |   24 | N/A |   79 |
| D/C due to AEs |   4 |   11 |    8 |   22 |   31 |   11 |

**Subject Disposition through 24 Weeks**

- Dose-Ranging Study

**Muraglitazar**

## Change from Baseline in A1C at Week 24 (LOCF)

**Change from Baseline in A1C at Week 24 (LOCF)**

**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**

**Pio****15 mg**
**230**
**8.3**

- Dose-Ranging Study

- * p < 0.001 vs Mura 0.5 mg

**Muraglitazar**

**Dose**
**n =**
**Baseline Mean (%)**

*****

*****

*****

*****

****** ****A1C (%)****with****95% CI**

**-0.25**

**-0.57**

**-1.18**

**-1.52**

**-1.76**

**-0.57**

## Percent of Subjects to A1C Goal at Week 24 (LOCF)

**Percent of Subjects to A1C Goal at Week 24 (LOCF)**

- Dose-Ranging Study

**0.5 mg**

**1.5 mg**

**5 mg**

**10 mg**

**20 mg**

**Pio 15 mg**

**% Subjects < 7.0%****% Subjects < 6.5%**

**Muraglitazar**

**%**

**Study 006 ST**

## Selected Safety Endpoints – 24 Weeks

|  | 0.5 mgN = 236 | 1.5 mgN = 259 | 5 mgN = 245 | 10 mgN = 249 | 20 mgN = 239 | Pio       15 mgN = 251 |
| --- | --- | --- | --- | --- | --- | --- |
| Mean Weight Change from Baseline at Week 24 (kg)  | -1.1 | -0.2 | 1.6 | 3.2 | 4.9 | 0.2 |
| Incidence of Edema Events (%) | 10.6 | 9.7 | 8.6 | 24.9 | 40.1 | 14.3 |
| Heart Failure Events (n) | 0 | 0 | 0 | 5 | 2 | 0 |

- Dose-Ranging Study

**Muraglitazar**

## 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**

## Clinical Efficacy

- Phase 3 Program
** ****Monotherapy Study**
** ****Combination with Glyburide**
** ****Combination with Metformin**
** ****TZD Comparator Study**

## Change from Baseline in A1C at Week 24 (LOCF)

**2.5 mg**
**105**
**8.0**

**5 mg**
**110**
**7.9**

**Pbo**
**111**
**8.0**

**5 mg OL**
**98**
**10.7**

**Change from Baseline in A1C at Week 24 (LOCF)**

- * p  0.001 vs. Pbo

**Dose**
**n =**
**Baseline Mean (%)**

- Monotherapy Study

****** ****A1C (%)****with****95% CI**

*****

*****

**Muraglitazar**

## 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 < 6.5%**

**30**

**14**

**58**

**31**

**72**

**58**

**Mura 5 OL**

**39**

**28**

- Monotherapy Study

**%**

## Lipid Parameters: % Change from Baselineat Week 12 (LOCF)

**Triglycerides**

**HDL-C**

**LDL-C**

**apo B**

-  * p < 0.001 vs Pbo

*****

*****

**% ******** **
**with **
**95% CI**

**Baseline Mean****(mg/dL)**

**187   193   194**

**45     44     42**

**132   130   124**

**104   103   102**

- Monotherapy Study

*****

*****

## Homeostasis Model Assessment (HOMA-IR)at Week 24 (LOCF)

- Monotherapy Study

**Pbo**

**Mura 2.5 mg**

**Mura 5 mg**

**Mura 5 mg OL**

**9.4**

**-23.9**

**-35.6**

**-37.9**

## Clinical Efficacy

- Phase 3 Program
** ****Monotherapy Study**
** ****Combination with Glyburide**
** ****Combination with Metformin**
** ****TZD Comparator Study**

## Change from Baseline in A1C at Week 24 (LOCF)

- *

- *

**Change from Baseline in A1C at Week 24 (LOCF)**

**2.5 mg**
**176**
**8.0**

**5 ****mg**
**189**
**8.2**

**Pbo****+ Gly**
**195**
**8.2**

- * p < 0.001 vs. Pbo + Gly

**Dose**
**n =**
**BL Mean (%)**

**Mura + Gly**

****** ****A1C (%)****With****95% CI**

- **

- **

- ** p < 0.001 vs. Pbo + Met

**2.5 mg**
**222**
**8.0**

**5 mg**
**198**
**8.0**

**Pbo****+ Met**
**197**
**8.0**

**Mura + Met**

- Combination Studies: Glyburide or Metformin

## Percent of Subjects to A1C Goal at Week 24 (LOCF)

**Percent of Subjects to A1C Goal at Week 24 (LOCF)**

**Pbo****+ Gly**

**Mura****2.5 mg****+ Gly**

**Mura**
**5 mg****+ Gly**

**% Subjects < 7.0%****% Subjects < 6.5%**

**%**

**27**

**10**

**54**

**27**

**64**

**38**

**Pbo****+ Met**

**Mura****2.5 mg****+ Met**

**Mura****5 mg****+ Met**

- Combination Studies: Glyburide or Metformin

## Lipid Parameters: % Change from Baselineat Week 12 (LOCF)

**Lipid Parameters: % Change from Baseline****at Week 12 (LOCF)**

**Triglycerides**

**HDL-C**

**LDL-C**

**apo B**

*****

*****

- Combination with Glyburide

**% ******
**with 95% CI**

**Baseline Mean****(mg/dL)**

**193   197   204**

**44    44    44**

**118   119   121**

**103   104   107**

-  * p < 0.001 vs Pbo

*****

*****

## Clinical Efficacy

- Phase 3 Program
** ****Monotherapy Study**
** ****Combination with Glyburide**
** ****Combination with Metformin**
** ****TZD Comparator Study**

## Mean Change from Baseline in A1C at Week 24 (LOCF)

- *

**Mean Change from Baseline in A1C at Week 24 (LOCF)**

**Mura 5 mg ****+ Met**
**569**
**8.1**

**Pio 30 mg ****+ Met**
**550**
**8.1**

- * p < 0.001 vs Pio + Met

- TZD Comparator Study

**Dose**
**n =**
**Baseline Mean (%)**

****** ****A1C (%)****with****95% CI**

## 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 < 6.5%**

**60**

**34**

**44**

**23**

- TZD Comparator Study

**%**

## Lipid Parameters: % Change from Baselineat Week 12 (LOCF)

**with 95% CI**

**Lipid Parameters: % Change from Baseline****at Week 12 (LOCF)**

**Triglycerides**

**HDL-C**

**LDL-C**

**apo B**

*****

*****

*****

-  * p < 0.001 vs Pio + Met

- TZD Comparator Study

**Baseline Mean****(mg/dL)**

**203      205**

**46      46**

**113      113**

**101      101**

## Mean A1C Over Time (LOCF) – 50 Weeks

**Mean A1C Over Time (LOCF) – 50 Weeks**

- TZD Comparator Study

****** ****A1C****(%)**

**Week**

**7.39**

**6.99**

**(N = 550)  **

**(N = 569)**

## Other Efficacy Parameters Muraglitazar 2.5 mg and 5 mg

|  | Monotherapy[2.5 to 5 mg] | Combination Therapy[2.5 to 5 mg] |
| --- | --- | --- |

**Other Efficacy Parameters ****Muraglitazar 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 3

## Summary of EfficacyMuraglitazar 2.5 mg and 5 mg

**Dose-dependent, consistent, clinically meaningful reductions in A1C**
**Up to 70% achieve A1C goals < 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,****hs-CRP, PAI-1 and fibrinogen**

## Clinical Safety

- Rene Belder, M.D.
- Vice President,Muraglitazar Full DevelopmentBristol-Myers Squibb

## Exposure by Dose

**0.5**

**1.5**

**5**

**10**

**20**

**15**

**Muraglitazar**

**Patient Years Exposure**

**2.5**

**Pioglitazone**

**30**

**45**

**Pbo**

**Additional Data Included****in Complete Dataset**
**NDA**

- Complete Dataset: Phase 2 and 3 Short-term and Long-term

**333**

**73**

**414**

**516**

**1515**

**623**

**343**

**251**

**440**

**80**

## Medical History and Concomitant Medications

|  | PboN = 528 | MuraN = 2969 | PioN = 823 |
| --- | --- | --- | --- |
|  |  |  |  |
| Medical History |  |  |  |
|    Hypertension | 52 | 54 | 62 |
|    Atherosclerotic Disease | 11 | 12 | 16 |
| Concomitant Medications |  |  |  |
|    Statins | 22 | 22 | 22 |
|    Fibrates | 0.4 | 0.8 | 0.4 |
|    Beta Blockers  | 13 | 13 | 16 |
|    Calcium Channel Blockers |   9 | 10 | 13 |
|    ACE Inhibitors | 28 | 29 | 37 |
|    Diuretics | 19 | 19 | 20 |

**Percent of Subjects**

- Complete Dataset

## 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**

## Percent of Subjects Reporting Edema Events –24 Weeks

|  | Pbo | Mura2.5 mg | Mura5 mg | Pio30 mg |
| --- | --- | --- | --- | --- |
| Monotherapy | 7.8 | 8.1 | 11.4 | – |
| Combo w/Gly | 7.0 | 9.4 | 9.8 | – |
| Combo w/Met | 3.7 | 9.4 | 15.6 | – |
| TZD Comparator
(with Met) | – | – | 9.2 | 7.2 |

- Phase 3 Short-term

## Percent of Subjects Discontinuing Due to Edema Events – 24 Weeks

|  | Pbo | Mura2.5 mg | Mura5 mg | Pio30 mg |
| --- | --- | --- | --- | --- |
| Monotherapy | 1.7 | 0 | 0 | – |
| Combo w/Gly | 0 | 0.5 | 0.5 | – |
| Combo w/Met | 0 | 0 | 0.5 | – |
| TZD Comparator
(with Met) | – | – | 0.2 | 0.2 |

- Phase 3 Short-term

## Change from Baseline in Body Weight (kg)at Week 24 (LOCF)

**Change from Baseline in Body Weight (kg)****at Week 24 (LOCF)**

**Monotherapy**

**Combination w/Gly**

**Combination w/Met**

**TZD****Comparator**

**Pbo   2.5    5**

**Pio 30     5**

**1.1**

**-0.8**

**2.1**

**2.6**

**0.4**

**4.1**

**1.4**

**-0.7**

**2.8**

**1.4**

**0.6**

****** ****(kg)**

**Pbo   2.5    5**

**Pbo   2.5    5**

**88    91    89**

**91       90**

**87    83    83**

**89    90    89**

**Dose (mg)****BL Mean (kg)**

- Phase 3 Short-term

## Heart Failure and PPAR Agonists

**PPAR******** agonists: reported hazard ratio for heart failure of 1.2 to 1.8 compared to other oral antihyperglycemic therapy****1,2**
**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 Med;22(8):986-93.
- 2. Delea TE, 2003. Diabetes Care;26(11):2983-9.

## Investigator-Reported Heart Failure

| Incidence per1000 Patient-years | Pbo | Mura 2.5 mg | Mura 5 mg | Pio 30 mg |
| --- | --- | --- | --- | --- |
| Monotherapy | 0 | 0 | 5.0  |  |
| Metformin
Combination | 0 | 3.8 | 8.5 | 4.6 |
| Glyburide
Combination | 0 | 14.5 | 14.5 |  |

**Investigator-Reported Heart Failure**

- Complete Dataset

## Kaplan-Meier Estimates for Time to First Heart Failure Event

**Mura ****≤**** 2.5 mg**

**Mura 5 mg**

**Proportion of Patients **
**with Heart Failure AE**

**Mura ****≥ 10 mg**

- Complete Dataset

## Investigator-Reported Heart Failure

**Investigator-Reported Heart Failure**

| Subject ID | Therapy | Event Causing Heart Failure 
(Adjudication Committee) | Echo Findings | Days to 
resolution |
| --- | --- | --- | --- | --- |
| 022-255-11 | + Met | - | LV hypertrophy | 2 |
| 021-55-2 | + Gly | Myocardial infarction | LVEF 40% | C |
| 021-69-1 | + Gly | Heart block/bradycardia | - | 1 |
| 021-209-10 | + Gly | Probable myocardial ischemia | LVEF 73% | C |
| 006-41-2 | Mono | - | LVEF 55-60% | 16 |
| 006-85-1 | Mono | Atrial fibrillation  | Normal LV function | 16 |
| 006-245-27 | Mono | Ischemic heart disease | LVEF 41% | C |
| 006-419-4 | Mono | - | - | 2 |
| 025-45-5 | + Met | - | LVEF 40% | 7 |
| 025-48-6 | + Met | Accelerated hypertension | LVEF 50% | 4 |
| 025-193-9 | + Met | Arrhythmia or cardiac ischemia | - | Sudden death |
| 025-235-3 | + Met | - | LVEF 57% | 6 |
| 025-236-7 | + Met | Aortic stenosis | LVEF 51% | 15 |
| 022-153-2 | + Met | - | - | 1† |
| 021-237-5 | + Gly | Myocardial infarction | - | Arrhythmia; death |
| 021-244-14 | + Gly | Atrial fibrillation | LVEF 67% | 35 |
| 021-301-5 | + Gly | Adjustment of beta-blocker | LVEF 72% | 59 |
| 025-289-74 | + Met | - | LVEF 30% | 9 |
| 025-337-5 | + Met | - | LVEF 50% | 96 |

**5 mg**
**1515 p****­****y**

**2.5 mg**
**516 p-y**

**Pio**
**771 p-y**

- C = not resolved at time of study discontinuation       † Heart failure resolved.  Patient died 9 days later.

- Complete Dataset

## 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**

## Heart Failure Risk Factors

| History | Incidence of Investigator-Reported Heart Failure – Phase 3 |  |
| --- | --- | --- |
|  | Patientswith History% (n/N) | Patientswithout History % (n/N) |
| Congestive Heart Failure | 8.0% (2/25) | 0.6% (11/1718) |
| Symptomatic Atherosclerotic Disease | 3.1% (7/227) | 0.4% (6/1516) |
| Beta-blocker Use | 2.4% (6/254) | 0.5% (7/1489) |
| Peripheral Edema | 1.9% (4/209) | 0.6% (9/1534) |
| Hypertension | 1.2% (12/974)  | 0.1% (1/769) |

- Phase 3 Short-term and Long-Term

## 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.**

## 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 duration****of 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**

## 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**

## Number of Subjects with CV Events

- Complete Dataset

**Placebo**
**N = 528**

**Muraglitazar**
**N = 2969**

**Pioglitazone**
**N = 823**

| Total Subjects with CV Event | 11 | 97 | 15 |
| --- | --- | --- | --- |

| Acute Atherosclerotic Events | 8 | 55 | 6 |
| --- | --- | --- | --- |
|      Cardiovascular Death | 1 | 9 | 0 |
|      Myocardial Infarction (MI) | 0  | 15 | 1 |
|      Acute MI | 2 | 4 | 0 |
|      Silent MI | 0 | 0 | 1 |
|      Angina Unstable | 0 | 9 | 2 |
|      Coronary Artery Occlusion | 3 | 7 | 0 |
|      Acute Coronary Syndrome | 1 | 0 | 0 |
|      Cerebrovascular Accident | 0 | 10 | 2 |
|      Transient Ischemic Attack | 1 | 6 | 0 |
|      Hemorrhagic Stroke | 0 | 1 | 0 |
|      Amaurosis Fugax | 0 | 1 | 0 |

| Chronic Atherosclerotic Events |  |  |  |
| --- | --- | --- | --- |
|      Angina Pectoris | 2 | 25 | 5 |
|      Coronary Artery Disease | 3 | 19 | 4 |
|      Myocardial Ischemia | 0 | 7 | 4 |
|      Coronary Artery Stenosis | 0 | 4 | 0 |
|      Coronary Artery Atherosclerosis | 0 | 2 | 0 |

## CV Events and Exposure to Study Drug

|  | Patient-years of Exposure |  | Number of Patients with Event  | Incidenceper 1000 Patient-years | Patient-years of Exposure | Number of Patients with Event | Incidence per 1000 Patient-years |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  |  |  |  |  |  |  |  |
| Placebo |  | 330 | 11 | 33.37 | 331 | 8 | 24.20 |
| Muraglitazar |  | 3437 | 97 | 28.22
 | 3463 | 55 | 15.88
 |
| Pioglitazone |  | 762 | 15 | 19.68
 | 766 | 6 | 7.83
 |

**CV Events and Exposure to Study Drug**

| CV Events(Acute and Chronic) |
| --- |

| Acute Atherothrombotic CV Events |
| --- |

- Complete Dataset

## CV Events by Dose

**CV Events by Dose**

- Complete Dataset

**Incidence per 1000 patient-years**
**(95% CI)**

## Kaplan-Meier Estimates for Time to First CV Event

**Mura ****≤**** 2.5 mg**

**Mura 5 mg**

**Proportion of Patients with CV Event**

**Mura ****≥ 10 mg**

- Complete Dataset

## CV Death

- Complete Dataset

| PboN = 528 | MuraN = 3125 | PioN = 823 |
| --- | --- | --- |

**Incidence per****1000 patient-years**
**(95% CI)**

| Patient-years Exposure | 332 | 3485 | 772 |
| --- | --- | --- | --- |
| Cardiovascular Deaths (n) | 1 | 9 | 0 |
|    Myocardial Infarction |  | 3 |  |
|    Sudden or Unwitnessed | 1 | 4 |  |
|    Cerebrovascular Accident  |  | 2 |  |

## 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**

## Cancer

| Patient-years Exposure | 332 | 3471 | 768 |
| --- | --- | --- | --- |
| Cancers (n) | 1 | 34 | 9 |
|  |  |  |  |

**Cancer**

- Complete Dataset

| PboN = 528 | MuraN = 3125 | PioN = 823 |
| --- | --- | --- |

**Incidence per****1000 patient-years**
**(95% CI)**

## All Cause Death

| Patient-years Exposure | 332 | 3485 | 772 |
| --- | --- | --- | --- |
| Deaths (n) | 1 | 18 | 2 |
|    CV  | 1 | 9 | 0 |
|    Cancer | 0 | 7 | 1 |
|    Other  | 0 | 2 | 1 |

**All Cause Death**

- Complete Dataset

**Deaths per****1000 patient-years**

| PboN = 528 | MuraN = 3125 | PioN = 823 |
| --- | --- | --- |

## Liver Parameters

|  | PboN = 528 | MuraN = 2969 | PioN = 823 |
| --- | --- | --- | --- |
| Baseline ALT (U/L) | 31.03 | 30.20 | 32.26 |
| 	Mean Change from     	Baseline to Week 24 | -0.83 | -7.13 | -7.70 |
| ALT > 3 x ULN, n (%) | 5 (1.0) | 12 (0.4) | 7 (0.9) |
| ALT > 5 x ULN, n (%) | 1 (0.2) | 2 (0.1) | 3 (0.4) |

- Phase 2 and 3 Short-term & Complete Dataset

## CK Evaluations

|  | Pbo | Mura≤ 5 mg | Mura10 mg | Mura20 mg | Pio |
| --- | --- | --- | --- | --- | --- |
| With Statin, N | 131 | 707 | 79 | 66 | 232 |
| 	CK > 10 x ULN, n (%) | 0 | 1 (0.1) | 0† | 0 | 0 |
| No Statin, N | 389 | 1730 | 166 | 171 | 580 |
| 	CK > 10 x ULN, n (%) | 2 (0.5) | 10 (0.6)†† | 1 (0.6) | 1 (0.6) | 2 (0.3) |

**††** Investigator report of rhabdomyolysis associated with yard work;    CK returned to below threshold while on treatment

**No associated muscle symptoms on muraglitazar**

**†** One elevation occurred in a subject on Mura 5 / 10 mg

- Complete Dataset

## 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**

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

- Fred T. Fiedorek, M.D.

## 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**

## 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 1****st**** year **
**Active follow up of patients through annual questionnaires will begin 1 year after database recruitment for next 5 years**

## Plans for Ensuring Appropriate Use of Muraglitazar

## Muraglitazar:  Steps to Assure Appropriate Use

**Key Communication Points**
**Do not use in patients with NYHA Class III / IV****heart 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 from****the AHA/ADA Consensus Guidance publication **
**Communication Tools to Aid Appropriate Use**
**Patient package insert**
**Healthcare professional communication materials**

## Guiding Principles for Expanding Knowledge: Pharmacovigilance and Assuring Appropriate Use

**Plans to enrich post-marketing product knowledge****for 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 **

## Benefit / Risk of Muraglitazar

## 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**

## Muraglitazar – Proven Glycemic Benefits

| Mean Change from Baseline | Monotherapy
[2.5 to 5 mg] | Combination Therapy
[2.5 to 5 mg] |
| --- | --- | --- |
| A1C (%) | -1.05 to -1.23 | -0.91 to -1.21 |
| FPG (mg/dL) |  -26 to -40  | -26 to -44 |
| % with A1C <7% |  58 to 72 | 52 to 64 |

**Muraglitazar – Proven Glycemic Benefits**

## Muraglitazar – Proven Lipid Benefits

| Mean Change from Baseline | Monotherapy
[2.5 to 5 mg] | Combination Therapy
[2.5 to 5 mg] |
| --- | --- | --- |

**Muraglitazar – Proven Lipid Benefits**

| TG (%) | -18 to -27 | -14 to -29 |
| --- | --- | --- |
| HDL-C (%) | 10 to 17 | 7 to 19 |
| apoB (%) | -7 to -12 | -5 to -12 |

## Hazards of Inadequate Treatment in Type 2 DMRelative Risk Associated with Change in Glycemic or Lipid Risk Factors

| A1C:  + 1% increase1 | CV Disease  | + 18% |
| --- | --- | --- |
|  | Fatal / Non-fatal CHD | + 13% |
|  | Stroke | + 17% |
|  | PAD | + 28% |
|  |  |  |
| HDL-C:  - 3.9 mg/dL decrease2
 | CHD
 | + 15%
 |
|  |  |  |
| TG:  + 88 mg/dL increase3  | CHD
 | + 14% (men) 
+ 37% (women) |

**Hazards of Inadequate Treatment in Type 2 DM****Relative Risk Associated with Change in Glycemic or Lipid Risk Factors**

- 1. Selvin E: Ann Intern Med* *2004;141:421-431
- 2. Turner RC: *BMJ *1998;316:823-828
- 3. Hokanson JE: J Card Risk 1996;3:213-219

**Change / Parameter**

**% Increase in Risk**

**Outcome**

## DCCT / EDIC: CV Outcomes Benefits withPast Intensive Glycemic Control

**At completion of DCCT 1993**
**Intensive control A1C = 7.2%****	****	****vs.****Conventional control A1C = 9.1%**
**Now, in 2005:  **

- Nathan D. American Diabetes Association 2005 Scientific Sessions; June 10-14, 2005;San Diego, CA

| Cardiovascular Events | 42% (19-63) |
| --- | --- |
| Nonfatal MI, Stroke, and CV Death | 57% (12-79) |

**Outcome**

**Relative Risk Reduction****(95% CI)**

## Benefits of Treatment with a PPAR Agonist: VA-HIT – Diabetes:  Efficacy of Gemfibrozil in Preventing CV Events

- Rubins HB: *Arch Int Med 2002*;162:2597-2604

| Major Cardiovascular Events | 0.68 (p = 0.004) |
| --- | --- |
| CHD Death | 0.59 (p = 0.02) |
| Non-fatal Myocardial Infarction | 0.78 (p = 0.17) |
| Stroke | 0.60 (p = 0.46) |

**Outcome**

**Hazard ratio (p-value)**

**(n = 769 subjects with diabetes)**

## 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)**

## Muraglitazar – PPAR 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**

## Dosing Recommendations:Muraglitazar 2.5 mg and 5 mg

**Dosing Recommendations:****Muraglitazar 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 expected****to be less tolerant of fluid retention, such as NYHA****Class II heart failure**
**Titration to 5 mg as necessary to achieve****ADA goals  **
**Muraglitazar 5 mg**
**Appropriate starting dose for patients with more severe hyperglycemia**

## Proposed Warnings

**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 thus****not indicated**
**For use in combination with insulin**
**For use in pediatric patients**
**Muraglitazar will also not be recommended**
**For use with TZDs and fibrates**

## Conclusion

**Muraglitazar, the first dual PPAR****α****/****γ**** agonist**
**Achieves and maintains glycemic goals**
**Improves diabetic dyslipidemia**
**Muraglitazar has an acceptable safety and tolerability profile**
**Events related to fluid retention****well-characterized and manageable**
**Muraglitazar offers a new treatment option for patients with type 2 diabetes with a favorable benefit / risk assessment**

## 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

## 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