New Study Shows Investigational Compound Muraglitazar Significantly Lowered Blood Glucose Levels As Measured By A1C Reduction in Patients With Type 2 Diabetes

PRINCETON and WHITEHOUSE STATION, N.J., May 20 /PRNewswire-FirstCall/ -- Results from a Phase III study presented today at the 14th Annual Meeting of the American Association of Clinical Endocrinologists (AACE) in Washington, D.C. indicated that muraglitazar, an investigational compound, significantly decreased hemoglobin A1C levels (a measure of average blood glucose over a two- to three-month time period) at 24 weeks versus placebo in patients with Type 2 diabetes. Additional effects were seen on triglycerides and HDL-C. Bristol-Myers Squibb Company and Merck & Co., Inc. are collaborators in the global development and commercialization of muraglitazar.

"This is the first time that Phase III data for muraglitazar have been presented in a scientific setting, and the study showed that muraglitazar had a glucose-lowering effect as measured by a significant reduction in A1C in patients with Type 2 diabetes," said Robert Frederich, M.D., Ph.D., Director, Metabolics, Global Clinical Research, Bristol Myers-Squibb Company. "In this study, muraglitazar decreased triglyceride levels and increased HDL cholesterol levels."

The New Drug Application (NDA) for muraglitazar is currently under review by the U.S. Food and Drug Administration (FDA). If approved, muraglitazar would become the first agent in a new class of investigational compounds called glitazars, a dual alpha/gamma PPAR (peroxisome proliferator-activated receptor) activator, available in the United States.

Muraglitazar decreased A1C levels

In this study there were two cohorts: a double-blind, placebo-controlled cohort with an entry A1C level between 7% and 10% (n=340) and an open-label cohort with entry A1C levels between 10% and 12% (n=109). In the double-blind study group, mean baseline A1C for all patient groups was 7.89% to 8.02%. At 24 weeks, mean changes in A1C versus baseline were -0.32%, -1.05%, and -1.23% in the placebo, muraglitazar 2.5 mg, and muraglitazar 5 mg groups, respectively (p-value less than 0.0001, placebo versus either muraglitazar group). In the open-label cohort (mean baseline A1C 10.68%), mean change in A1C versus baseline was -2.62% after 24 weeks of treatment with muraglitazar 5 mg once daily.

The AACE recommended A1C target level of less than or equal to 6.5% was achieved by 18%, 36%, and 58% of patients taking placebo, muraglitazar 2.5 mg, and muraglitazar 5 mg, respectively in the double-blind cohort.(i)

Results from secondary endpoints

In the subgroup of patients with baseline triglyceride levels of 150 mg/dL or more, changes in triglyceride levels were -13.2%, -24.8%, and -30.4% with placebo, muraglitazar 2.5 mg, and muraglitazar 5 mg (p-value equals 0.13 versus placebo for the muraglitazar 2.5 group and p-value equals 0.0002 versus placebo for the muraglitazar 5 mg group). Mean HDL-C levels increased 2%, 10%, and 16% from baseline in the placebo, 2.5 mg, and 5 mg groups of the double-blind study (p-value less than 0.0001 in both muraglitazar-treated groups versus placebo) and increased 12% from baseline in the 5 mg open-label group, respectively.

Other secondary endpoints showed that muraglitazar was associated with significant reductions from baseline in mean fasting plasma glucose (FPG), fasting plasma insulin, free fatty acid, apoB, and non-HDL cholesterol levels. Muraglitazar treatment was also associated with increased insulin sensitivity as measured by a decrease in homeostasis model assessment of insulin resistance (HOMA-IR).

Safety information

In the study, no cases of confirmed hypoglycemia were reported (confirmed hypoglycemia was defined as symptoms of hypoglycemia accompanied by a fingerstick glucose test result of less than or equal to 50 mg/dl). In the double-blind cohort, mean change in body weight versus baseline was -0.8, +1.1, and +2.1 kg in the placebo, muraglitazar 2.5 mg, and muraglitazar 5 mg groups, respectively, and was +2.9 kg in the open-label cohort taking muraglitazar 5 mg. Edema-related adverse events occurred in 8%, 8%, and 11% of patients taking placebo, muraglitazar 2.5 mg, and murgalitazar 5mg, respectively, in the double-blind study and 8% in patients taking muraglitazar 5 mg in the open-label cohort. All events were mild or moderate in severity in the muraglitazar-treated groups. Incidence of serious adverse events was 3% to 4% across all treatment groups. In the double-blind study, adverse events occurred in 69%, 71%, and 77% of the patients in the placebo, muraglitazar 2.5 mg, and muraglitazar 5 mg groups, respectively, and in 70% of the patients in the open-label cohort taking muraglitazar 5 mg.

Study Design

This Phase III trial was a randomized, double-blind, placebo-controlled, multicenter, parallel-group study of 340 men and women aged 18 to 70 years whose Type 2 diabetes was inadequately controlled (defined as having A1C values of 7% to 10% at screening) with diet and exercise and who had a body mass index (BMI) of less than 41. Patients received a once-daily regimen of muraglitazar 2.5 mg tablets (n=111), muraglitazar 5 mg tablets (n=114), or placebo (n=115) for 24 weeks. In addition, a cohort of patients (n=109) who met all other study criteria, but had higher A1C values at screening (A1C greater than 10% and up to and including 12%) were enrolled in a parallel 24- week open-label evaluation of a daily dose of muraglitazar 5 mg.

Exclusion criteria included triglyceride values greater than 600 mg/dL, symptomatic Type 2 diabetes, NYHA Class III/IV cardiac status, or treatment with non-statin cholesterol-lowering medications prior to randomization. Patients who were taking statins were allowed to continue taking statins if their regimens had been stable for at least 6 weeks prior to enrollment.

The primary endpoint was change in A1C from baseline. Secondary endpoints included changes from baseline in fasting plasma glucose, fasting insulin, free fatty acids, and fasting lipids (triglycerides, HDL cholesterol, non-HDL cholesterol, and apoB), and body weight; the proportions of patients reaching goal A1C levels; and assessment of HOMA-IR. Glucose-related results were assessed at week 24; lipid results were assessed using the average of lipid measurements taken at weeks 11 and 12. Last observation carried forward methodology was used to analyze the trial results.

Glitazar Class

Dual alpha/gamma PPAR activators belong to a new class called glitazars, which activate PPAR gamma lowering plasma glucose and free fatty acid concentrations and PPAR alpha lowering plasma triglyceride concentrations and increasing HDL cholesterol.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global pharmaceutical and related health care products company whose mission is to extend and enhance human life.

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first.

Bristol-Myers Squibb Forward-Looking Statement

This press release contains certain forward-looking information within the meaning of the Private Securities Litigation Reform Act of 1995 regarding a product in development and the potential efficacy of such product that involves substantial risks and uncertainties. Such risks and uncertainties include, among other things, the uncertainty of the success of the research and development activities; decisions by regulatory authorities regarding whether and when to approve any new drug application for a product candidate that may result from the research, as well as their decisions regarding labeling and other matters that could affect the commercial potential of such product candidate; and competitive developments. A further list and description of risks and uncertainties can be found in the Bristol-Myers Squibb's Annual Report on Form 10-K for the fiscal year ended December 31, 2004, and in its reports on Form 10-Q and Form 8-K. The Company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

Merck Forward-Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the cautionary statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31, 2004, and in its periodic reports on Form 10-Q and Form 8-K, which the company incorporates by reference.

(i) http://www.aace.com/clin/guidelines/diabetes_2002.pdf