Taking a pill reduces blood glucose of Diabetes 2 patients, muraglitazar

Main Category: Diabetes
Article Date: 13 Jun 2005 - 7:00 PDT

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Bristol-Myers Squibb Company and Merck & Co, Inc announced results from both a Phase III active-controlled study and a long-term Phase II dose-ranging study for the investigational oral medicine muraglitazar (now known under the registered trade name PARGLUVA™) during a late-breaking presentation of the 65th Annual Scientific Sessions of the American Diabetes Association (ADA). The primary endpoint of each study was reduction in A1C levels (a measure of a person's average blood glucose over a two- to three-month time period) in patients with type 2 diabetes. Lipid effects, a secondary endpoint of both studies, were also measured.

The Phase III study showed PARGLUVA 5 mg reduced A1C levels significantly more than pioglitazone1 30 mg in patients with type 2 diabetes. Both treatment groups were taking metformin (a drug used to treat type 2 diabetes). Significant effects were also seen on triglycerides and high-density lipoprotein cholesterol (HDL-C) levels. In the Phase II study at 104 weeks, patients who received PARGLUVA 5 mg had a change of -1.52 percent from baseline A1C (mean baseline of 7.92 percent) with a final mean A1C level of 6.4 percent.

Bristol-Myers Squibb and Merck are collaborators in the global development and commercialization of PARGLUVA. The New Drug Application (NDA) for PARGLUVA is currently under review by the U.S. Food and Drug Administration (FDA). If approved, PARGLUVA would become the first marketed agent in a new class of investigational compounds called glitazars. PARGLUVA is a dual alpha/gamma PPAR (peroxisome proliferator-activated receptor) activator.

Phase III Study: PARGLUVA Versus Pioglitazone

Study Design

This Phase III, double-blind, randomized, active-controlled trial was conducted in 1,159 patients with type 2 diabetes who had inadequate glycemic control on metformin alone. Patients were assigned to either a once-daily dose of PARGLUVA 5 mg (n=587) or pioglitazone 30 mg (n=572) for 24 weeks while continuing mean daily metformin doses of 1,854 mg and 1,851 mg in the PARGLUVA and pioglitazone groups, respectively. Starting at week 12, statin therapy could be initiated or adjusted as needed.

All analyses on mean change from baseline were adjusted for baseline level and used the last observation carried forward (LOCF) methodology. The mean baseline A1C value (8.1 percent) and other disease characteristics were comparable between the two groups.

PARGLUVA Significantly Reduced A1C and Fasting Plasma Glucose

At week 24, the addition of PARGLUVA 5 mg reduced mean A1C values from baseline by 1.14 percent compared with the addition of pioglitazone 30 mg, which resulted in a reduction of 0.85 percent (p-value less than 0.0001 between treatment groups). Sixty percent of patients taking PARGLUVA 5 mg attained the ADA recommended A1C goal (less than 7 percenti ), compared to 45 percent of patients taking pioglitazone 30 mg (p-value less than 0.0001 between treatment groups).

PARGLUVA 5 mg also reduced fasting plasma glucose, a secondary endpoint, more than pioglitazone 30 mg [-44 mg/dL from baseline versus -33 mg/dL from baseline, respectively (p-value less than 0.0001 between treatment groups)].

Results from Additional Secondary Endpoints

At week 12, triglyceride levels decreased 28 percent and 14 percent versus baseline in patients treated with PARGLUVA 5 mg and pioglitazone 30 mg, respectively (p-value equal to 0.0001 between treatment groups). In patients with a triglyceride level above 150 mg/dL at baseline, the reduction was 35 percent and 19 percent for PARGLUVA 5 mg and pioglitazone 30 mg, respectively (p-value less than 0.0001 between treatment groups). HDL-C levels increased 19 percent in the PARGLUVA 5 mg group and 14 percent in the pioglitazone 30 mg group (p-value equal to 0.0001 between treatment groups). In addition, non-HDL-C levels decreased 6 percent, apoB levels decreased 12 percent, and free fatty acids decreased 30 percent in the PARGLUVA 5 mg group compared to decreases of 1 percent, 6 percent and 21 percent, respectively, in the pioglitazone 30 mg group (all p-values less than or equal to 0.0001 between groups). There were no significant effects on LDL-C in either group.

At week 24, PARGLUVA 5 mg reduced fasting plasma insulin more than pioglitazone 30 mg [-5.0 microunits/mL from baseline versus -3.6 microunits/mL from baseline, respectively (p-value less than 0.0001 between treatment groups)]. Treatment with PARGLUVA 5 mg also increased insulin sensitivity more than pioglitazone 30 mg as measured by a decrease in homeostasis model assessment of insulin resistance (HOMA-IR) (p-value less than 0.0001 between treatment groups). Other secondary endpoints showed that CRP (C reactive protein) decreased 30 percent and PAI-1 decreased 30 percent in the PARGLUVA 5 mg group versus decreases of 24 percent and 22 percent, respectively, in the pioglitazone 30 mg group (p-value equals 0.04 for the CRP comparison and p-value equals 0.0002 for the PAI-1 comparison).

Safety Information

Discontinuation rates due to adverse events were 3 percent for PARGLUVA 5 mg and 2 percent for pioglitazone 30 mg. The incidence of serious adverse events was 4 percent for PARGLUVA and 3 percent for pioglitazone. Three deaths occurred during the 24 weeks of this study: two deaths in the PARGLUVA group (stroke and sudden cardiac death) and one death in the pioglitazone group (perforated ulcer). Investigators reported these cases not to be drug-related.

The rates of edema-related events for PARGLUVA versus pioglitazone were 9.2 percent and 7.2 percent, respectively, and weight gain was 1.4 kg vs. 0.6 kg, respectively. Investigator physicians reported that four patients developed events related to heart failure: three in the PARGLUVA group and one in the pioglitazone group, all of whom recovered with diuretic therapy and/or withdrawal of study drug. Confirmed hypoglycemia2 occurred in three patients taking PARGLUVA and one patient taking pioglitazone. There were no hypoglycemia-related serious adverse events or withdrawals.

Preliminary Information From Phase III Extension Study

The Phase III pioglitazone comparative study continued with a 26-week extension, and preliminary analyses indicate that glycemic and lipid efficacy differences between PARGLUVA 5 mg and pioglitazone 30 mg increased or were maintained after 50 weeks. In the preliminary analyses, the overall profile of adverse events in the long-term phase was similar to that seen in the short-term phase. Four additional deaths were reported for patients on PARGLUVA (stroke, myocardial infarction, sudden cardiac death, and previously diagnosed pancreatic cancer), which the investigators reported were not drug-related. There were an additional two cases of heart failure on PARGLUVA and one on pioglitazone. There were no deaths due to heart failure.

Phase II Extension Study: PARGLUVA Dose-Ranging Trial

Study Design

This Phase II, randomized, double-blind, dose-comparison-controlled study involved 1,477 patients with type 2 diabetes inadequately controlled with diet and exercise. Patients were assigned to one of five PARGLUVA doses (0.5 mg, 1.5 mg, 5 mg, 10 mg or 20 mg) or pioglitazone 15 mg at study initiation.

After the initial 24 week dose-ranging study, patients were continued into an ongoing long-term extension phase on their current dose of study medication, with two exceptions: patients who received PARGLUVA 0.5 mg in the short-term phase were increased to 1.5 mg, and patients who received PARGLUVA 20 mg in the short-term phase were decreased to 10 mg per a protocol amendment. The primary analysis presented was for the 24-week glycemic and safety data, as well as the week 11/12 lipid data for all doses in the short-term phase. The glycemic and safety data at 104 weeks for the PARGLUVA 5 mg dose (n=88) were also presented.

Concurrent fibrate therapy was excluded during the 24-week study, but could be initiated during the long-term phase. Treatment with statins was permitted, but the dose had to remain stable during the first 12 weeks of the short-term phase. Patients were not allowed to take a statin and a fibrate in combination at any time.

Glycemic Results

Patient groups had mean baseline A1C levels ranging from 8.13 percent to 8.31 percent at study initiation. At week 24, the changes in A1C from baseline were: -0.57 percent for PARGLUVA 1.5 mg, -1.18 percent for PARGLUVA 5 mg, -1.52 percent for PARGLUVA 10 mg, -1.76 percent for PARGLUVA 20 mg, and -0.57 percent for pioglitazone 15 mg.

At week 104, the 88 patients who received PARGLUVA 5 mg throughout the long term phase of the trial had a change of -1.52 percent from baseline A1C (baseline of 7.92 percent) with a final A1C level of 6.4 percent.

Secondary Endpoint Results

At week 104 of the study, mean changes in triglyceride levels frombaseline were -13 percent for PARGLUVA 1.5 mg (baseline 136 mg/dL), -22 percent for PARGLUVA 5 mg (baseline 156 mg/dL), -31% for PARGLUVA 10 mg (baseline 155 mg/dL), -39 percent for PARGLUVA 20 mg (baseline 138 mg/dL), and -12 percent for pioglitazone 15 mg (baseline 145 mg/dL). Mean increases in HDL cholesterol levels from baseline were 17 percent, 29 percent, 25 percent and 28 percent for PARGLUVA 1.5 mg (baseline 43 mg/dL), 5 mg (baseline 40 mg/dL), 10 mg (baseline 40 mg/dL), and 20 mg (baseline 42 mg/dL) respectively, and 18 percent for pioglitazone 15 mg (baseline 42 mg/dL) at week 104.

At week 104, mean changes in non-HDL cholesterol levels from baseline were -12 percent, -11 percent, -12 percent and -14 percent for PARGLUVA 1.5 mg (baseline 151 mg/dL), 5 mg (baseline 154 mg/dL), 10 mg (baseline 160 mg/dL), and 20 mg (baseline 158 mg/dL) respectively, and -9 percent for pioglitazone 15 mg (baseline 154 mg/dL). Mean changes in LDL cholesterol levels from baseline at week 104 were -10 percent, -6 percent, -5 percent and -7 percent for PARGLUVA 1.5 mg (baseline 118 mg/dL), 5 mg (baseline 116 mg/dL), 10 mg (baseline 123 mg/dL), and 20 mg (baseline 126 mg/dL), respectively, and -8 percent for pioglitazone 15 mg (baseline 123 mg/dL).

Safety Information

Study discontinuation rates attributed to adverse events in the non-titrated group ranged from 8-11 percent in patients taking PARGLUVA 10 mg or less and was 5 percent for the pioglitazone 15 mg group. The study discontinuation rate at 20 mg was 47 percent; this assessment excluded patients who had a forced-down titration to 10 mg.

By week 24, pioglitazone 15 mg was associated with a higher incidence of edema-related adverse events (14.3 percent) compared with PARGLUVA 5 mg (8.6 percent) and 1.5 mg (9.7 percent). By week 104, the cumulative incidences of edema-related events were 18.7 percent, 25.0 percent, 48.1 percent and 56.0 percent in the PARGLUVA 1.5 mg, 5 mg, 10 mg and 20 mg groups, respectively, and 30.8 percent in the pioglitazone 15 mg group. At any point of time in the study, the incidence of edema was less than 10 percent for the 5 mg dose of PARGLUVA.

Changes in mean body weight at week 24 were -0.22 kg, +1.60 kg, +3.19 kg and +4.85 kg in the PARGLUVA 1.5 mg, 5 mg, 10 mg and 20 mg groups, respectively, and +0.19 kg in the pioglitazone 15 mg group. Increases in mean body weight at week 104 were 0.56 kg, 5.86 kg, 8.94 kg and 9.01 kg in the PARGLUVA 1.5 mg, 5 mg, 10 mg and 20 mg groups, respectively, and 1.91 kg in the pioglitazone 15 mg group.

During the 104 weeks of treatment in this Phase II study, there was a similar incidence (0.4 percent) of death in both the PARGLUVA and pioglitazone patient groups (5/1226 and 1/251); none of these events was reported by the investigators to be drug-related. Investigators reported a total of 15 cases of heart failure -- three for PARGLUVA 5 mg, six for PARGLUVA 10 mg, and six for PARGLUVA 20 mg -- and all cases resolved with discontinuation of PARGLUVA and/or use of diuretic therapy. There were no deaths due to heart failure at any PARGLUVA dose. There were no cases of heart failure in the PARGLUVA 1.5 mg group or the pioglitazone 15 mg group.

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.

For more information, contact: Media - David M. Rosen, Bristol-Myers Squibb, 609-721-6155,
david.m.rosen@bms.com; or Tracy Ogden, Merck & Co., Inc., 484-686-4837,
tracy_ogden@merck.com; Investors - John Elicker, Bristol-Myers Squibb, 212-546-3775,
john.elicker@bms.com; or Graeme Bell, Merck & Co., Inc., 908-423-5185, graeme_bell@merck.com

1 ACTOS is the registered trade name for pioglitazone, which is marketed by Takeda Pharmaceuticals North America, Inc. and Eli Lilly and Company.

2 Confirmed hypoglycemia was defined as symptoms of hypoglycemia accompanied by a finger stick glucose test result of less than or equal to 50 mg/dl.

i American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care January 2005; 28 (Suppl. 1):S4-36S.

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