# Presentation: 783076

## PARGLUVA® (Muraglitazar)Bristol-Myers Squibb and Merck & Co., Inc.New Drug Application 21-865 

**Clinical Safety**
**Julie Golden, M.D.**
**Medical Officer**
**Division of Metabolic and Endocrine Drug Products**
**September 9, 2005**
**Silver Spring, MD**

**Center for Drug Evaluation and Research**** **

## Outline

**Background**
**Subject Disposition**
**Safety Issues**
**Concerns/Points to Consider**
**Questions for Discussion**

## Regulatory Issues

**First PPAR-****γ**** (troglitazone) removed from the market in 2000 due to cases of idiosyncratic liver failure**
**PPARs and carcinogenicity: all clinical studies > 6 mo currently on clinical hold unless preclinical carcinogenicity studies submitted to the Agency**

## Background

**Safety profile of muraglitazar is generally consistent with PPAR-****γ**** and PPAR-****α**** pharmacology**
**Potential concerns with PPAR compounds**
**PPAR-****γ****: edema, weight gain, congestive heart failure, anemia, neutropenia**
**PPAR-****α****: myopathy, cholelithiasis**

## Clinical Safety Database

**22 Clinical Pharmacology Studies**
**6 Phase 2b and 3 Studies**
**5 Type 2 Diabetes Studies**
**2 Monotherapy**
**3 Combination Therapy**
**1 Mixed Dyslipidemia Study**

## Clinical Safety Database

**3226 subjects received at least one dose of muraglitazar in the Phase 2/3 studies**
**Type 2 diabetes: 2969**
**Monotherapy: 1560**
**Combination therapy: 1409**
**~ 2000 subjects received muraglitazar for at least 24 weeks**
**~ 700 subjects received muraglitazar for at least 104 weeks**

## Type 2 Diabetes Studies, Treatment Groups

## Pooling

**Muraglitazar ****≤ 5 mg: **
**CV168006: Mur 0.5 mg, 1.5 mg, 5 mg (titration possible)**
**Phase 3 Studies: Mur 2.5 and 5 mg**
**Pioglitazone ****≤**** 45 mg:**
**CV168006: Pio 15 mg (titration to 45 mg possible)**
**CV168025: Pio 30 mg**

## Pooling

**Monotherapy: CV168006 and CV168018**
**Combination therapy**
**CV168021: + glyburide**
**CV168022 and CV168025: + metformin**

## Subject Disposition 24 Weeks

**	**

|  | Mur ≤ 5 mg | Mur 10 & 20 mg | Pio ≤ 45 mg | Placebo |
| --- | --- | --- | --- | --- |
| Total Randomized | 2374 | 486 | 823 | 528 |
| Completed Trial | 1937 (82%) | 366 (75%) | 639 (78%) | 363 (69%) |
| Withdrew – Adverse Event | 78 (3%) | 52 (11%) | 20 (2%) | 11 (2%) |
| Withdrew – Lack of Efficacy | 181 (8%) | 27 (6%) | 94 (11%) | 106 (20%) |

## AEs Leading to Discontinuation,Type 2 Diabetes Studies 24 Weeks

## Safety Issues

**Deaths**
**Edema Events**
**Heart Failure Events**
**Weight Gain**
**Cardiovascular Events**

## Deaths

## Deaths, Type 2 Diabetes StudiesAll Data

## Cardiovascular Deaths

**52 yo male (****Mur 2.5 + Met****): myocardial infarction**
**54 yo male (****Mur 5 + Met****): myocardial infarction***
**67 yo male (****Mur 5 + Met****): sudden death**
**53 yo male (****Mur 5 + Met****): stroke**
**56 yo female (****Mur 5 + Gly****): myocardial infarction**
**66 yo female (****Mur 5 + Met****): sudden death***
**61 yo male (****Mur 5 + Met****): “found dead”**
**60 yo female (****Mur 5 + Met****): stroke**
**59 yo male (****Mur 20****): myocardial infarction***
**62 yo male (****Placebo + Gly****): pulmonary embolism**

## Subject CV168022-153-2Muraglitazar 5 mg + metformin

**54 year-old white male with 6-year history of type 2 diabetes, obesity, hypertension, coronary artery disease, and coronary thrombosis**
**Day 115:  CHF symptoms **
**1 day hospitalization, single dose of furosemide 40 mg I.V.**
**Day 117: normal chest x-ray**
**Day 118: **
**body weight increase of 10 lbs. from Day 90**
**elevated NT-proBNP (1236 pg/mL; screening 548 pg/mL)**
**physical exam and outpatient cardiac exam refused**
**Day 125: found dead in home**
**death certificate: myocardial infarction and occult coronary artery disease**

## Subject CV168025-193-9Muraglitazar 5 mg + metformin 

**66 year-old white female with 4-year history of type 2 diabetes, CHF, hypertension, peripheral vascular disease, transient ischemic attack, bilateral lower extremity fluid retention, atrial flutter, mitral insufficiency, obesity, and tobacco use  **
**Day 201: dyspnea; reported as CHF**
**Day 202: sudden death**
**autopsy not performed; cause of death reported as myocardial infarction**

## Subject CV168006-11-8Muraglitazar 20 mg

**59 year old white male with 2-year history of type 2 diabetes, previous tobacco use, hypertension, iron overload with fatty liver, and psoriasis  **
**Day 43: bilateral pitting edema in ankles**
**Day 49: admitted with myocardial infarction and CHF**
**increasing exertional dyspnea for the previous month**
**markedly elevated cardiac enzyme levels **
**clinical deterioration; intubation**
**Day 50: **
**cardiac catheterization: 99% left main arterial distal stenosis**
**echocardiogram: moderately dilated left ventricle with severe global hypokinesis; ejection fraction 15 - 20%**
**Day 60:  life support withdrawn; patient died**

## Cancer Deaths

**69 yo male (****Mur 1.5****): lung cancer**
**69 yo female (****Mur 1.5****): acute myeloid leukemia**
**49 yo male (****Mur 2.5 + Met****): hepatocellular carcinoma**
**56 yo female (****Mur 5 + Met****): breast cancer**
**70 yo female (****Mur 5****): lung cancer**
**63 yo female (****Mur 5 + Met****): lung cancer**
**50 yo female (****Mur 5 + Met****): pancreatic cancer**
**66 yo male (****Pio 15****): throat cancer**

## Deaths

| Study CV168025 |  |  |
| --- | --- | --- |
|  | Muraglitazar 5 mg + Metformin | Pioglitazone 30 mg + Metformin |
| N | 587 | 572 |
| Total Deaths | 6 (1.02%) | 1 (0.17%) |
| Cardiovascular Deaths | 5 (0.85%) | 0 (0.0%) |

**5 cardiovascular deaths from 3 sites (out of 234):**
**Site 193 = Netherlands, 2 deaths, 8 randomized subjects**
**Site 241 = Russia, 2 deaths, 38 randomized subjects**
**Site 314 = Finland, 1 death, 2 randomized subjects**

## Edema

## Edema-Related Predefined Preferred Terms

**Fluid retention/overload**
**Generalized edema**
**Peripheral edema**
**Swelling**
**Hypervolemia**

## Edema Adverse Events, CV16800624 Weeks

## Edema Adverse Events Phase 3 Studies24 Weeks

## Edema Adverse Events Phase 3 Studies24 Weeks

## Congestive Heart Failure

## CHF Adverse Events, CV16800624 Weeks

## CHF Adverse EventsPhase 3 Studies24 Weeks

## Congestive Heart Failure: Monotherapy vs. Combination TherapyType 2 Diabetes Studies24 Weeks

## CHF Adjudication Committee:Predefined Preferred Terms

**Cardiac failure**
**Pulmonary edema**
**Ventricular failure**
**Dyspnea**
**Edema (moderate or greater intensity)**

## CHF Adjudication Committee Results Phase 3 Studies24 Weeks

## Weight Gain

## Weight Change: Type 2 Diabetes, 24 Weeks

## Cardiovascular Events

## Cardiovascular Adverse Events: Predefined Preferred Terms

**Myocardial infarction**
**Coronary revascularization**
**Coronary artery disease**
**Angina/myocardial ischemia**
**Cardiac death**
**Stroke**
**Transient ischemic attack**
*** NOT congestive heart failure**

## Cardiovascular Adverse Events Type 2 Diabetes Studies24 Weeks

## Cardiovascular Events: Monotherapy vs. Combination TherapyType 2 Diabetes Studies, 24 Weeks

## Cardiovascular Events: Phase 3 Combination Studies24 Weeks

## Cardiovascular Events: Study CV16802124 Weeks

**Muraglitazar 2.5 mg:**
**64 yo M:  Non-Q wave MI, day 85**
**52 yo F:  TIA, day 31**
**64 yo M:  Unstable angina, day 11**
**59 yo F:  Stroke, day 9**

**Muraglitazar 5 mg:**
**68 yo M:  MI, day 1 (prior to first dose)**
**54 yo F:  Stroke, d26; Brain tumor, day 43**
**62 yo M:  Coronary artery disease, day 111**
**70 yo M:  Angina, days 17, 37, 56, and 66**
**52 yo F:  TIA, day 78**
**46 yo M:  Myocardial ischemia, day 85**
**60 yo M:  Stroke, day 139**

## Inclusion/Exclusion CriteriaBaseline Characteristics

## Inclusion/Exclusion Criteria

**No history of MI, coronary angioplasty or bypass graft(s), valvular disease or repair, unstable angina pectoris, TIA or cerebrovascular accidents within 6 months prior to entry into the study**
**Monotherapy:  No antihyperglycemic therapy more than 3 consecutive or a total of 7 non-consecutive days 4-6 weeks prior to Screening**
**Combination Therapy:  Receiving treatment with sulfonylurea (CV168021) or metformin (CV168022, CV168025) for at least 6 weeks prior to Screening**

## Baseline Characteristics

|  | Monotherapy |  | Combination Therapy |  |
| --- | --- | --- | --- | --- |
| Characteristic | Any Mura | Non-Mur | Any Mur | Non-Mur |
| Age: ≥ 65 years | 13.9% | 10.4% | 16.1% | 14.3% |
| Gender: Male | 56.4% | 54.1% | 51.4% | 50.8% |
| Mean BMI (kg/m2) | 31.1 | 31.6 | 31.3 | 31.7 |
| Diabetes: ≥ 5 years | 23.8% | 21.9% | 52.7% | 48.0% |
| Mean HbA1c (%) | 8.17 | 8.24 | 8.07 | 8.12 |
| Use of Statins | 20.1% | 17.5% | 24.3% | 24.2% |
| Use of Diuretics | 18.3% | 16.4% | 19.9% | 20.7% |
| Metabolic Syndrome | 67.1% | 65.6% | 66.8% | 67.9% |

**a Includes all doses of muraglitazar except OL**

## Baseline Coronary Artery Disease Phase 3 Studies

|  | Mur 2.5 mg | Mur 5 mg | Pio 30 mg | Placebo |
| --- | --- | --- | --- | --- |
| CV168018 Monotherapy | 8/111 (7.2%) | 2/114 (1.8%) | - | 2/115 (1.7%) |
| CV168021
+ glyburide | 13/191 (6.8%) | 7/193 (3.6%) | - | 8/199 (4.0%) |
| CV168022
+ metformin | 11/233 (4.7%) | 10/205 (4.9%) | - | 11/214 (5.1%) |
| CV168025
+ metformin | - | 77/587 (13.1%) | 78/572 (13.6%) | - |

## Concerns/Points to Consider

## Deaths

**Most deaths in the muraglitazar-treatment group were due to cardiovascular events and cancer**
**Congestive heart failure may have contributed to the cardiac event leading to death in 3 subjects on muraglitazar**
**No clear pattern has emerged**

## Deaths

**Most cardiovascular deaths were from one study**
**CV168025: metformin add-on, active control**
**5 cardiovascular deaths from 3 study sites**

## Cardiovascular Events

**Diverse events with no clear pattern**
**Increased incidence in combination studies**
**Imbalance driven by one study **
**CV168021: glyburide add-on, placebo-controlled study**

## Cardiovascular Events

**When combination studies pooled, events were not dose-related**
**Inconsistent rate of events in placebo groups from combination studies**
**Low number of events, particularly in comparator groups, make incidence rates unstable**

## Questions for Discussion

**Is it likely that the excess of cardiovascular deaths and events in the muraglitazar group are related to the dose-related fluid retention?**
**If not, is there a plausible pharmacological explanation?**
**Are subjects on combination therapy (i.e., longer history of diabetes) or with a relevant medical history more vulnerable to the adverse effects of muraglitazar? **
**Cardiovascular events**
**Fluid-related events**

## Acknowledgements

**Medical Review Team**
**Robert Misbin, M.D.**
**Eric Colman, M.D.**
**David Orloff, M.D.**
**Statistical Review Team**
**Lee Ping Pian, Ph.D.**
**J. Todd Sahlroot, Ph.D.**
**Project Management**
**Jena Weber**

**Pharmacology/Toxicology Review Team**
**John Colerangle, Ph.D.**
**Jeri El Hage, Ph.D.**
**Biopharmaceutics Review Team**
**Jaya Vaidyanathan, Ph.D.**
**Hae Young Ahn, Ph.D.**