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Results of Short-Term Phase II Studies of Sitagliptin --MK-0431--, Merck's Investigational Treatment for Type 2 Diabetes, Presented at ADA

Posted on: Saturday, 11 June 2005, 15:00 CDT

Results from three recent Phase II studies announced today showed that sitagliptin phosphate (MK-0431), Merck's investigational medicine in a potentially new class of agents for the treatment for diabetes called DPP-IV (dipeptidyl peptidase IV) inhibitors significantly improved glycemic control in patients with type 2 diabetes compared to placebo. In addition, sitagliptin was generally well tolerated, with overall adverse events similar to placebo.

These data in more than 1,000 patients from two short-term, twelve-week, placebo-controlled, dose-range finding studies and one small short-term study of sitagliptin in combination with metformin, were presented today at the 65th Annual Meeting of the American Diabetes Association in San Diego.

"Results from the studies conducted to date are very interesting," said John M. Amatruda, MD, vice president, Metabolism/Clinical and Quantitative Sciences at Merck & Co., Inc. "These studies demonstrate proof of concept for sitagliptin in short-term clinical studies. Longer term-trials, such as those now underway in Phase III, should provide greater insight into the efficacy, the ability to maintain glycemic control over a longer period of time, and the tolerability profile of sitagliptin."

Designs and Results of Studies

In a double-blind, placebo-controlled, parallel group study, 552 patients with type 2 diabetes were randomized to one of five treatment groups: placebo; sitagliptin (25 mg, 50 mg, or 100 mg) once daily; or sitagliptin 50 mg twice daily. Prior to randomization, patients were enrolled in a diet and exercise regimen and, if taking other anti-hyperglycemic agents, a drug wash off period was conducted. Patients had predominantly mild to moderate hyperglycemia. The mean baseline HbA1c (A1C) was approximately 7.7 percent to 7.8 percent, with 28.8 percent of patients having a baseline A1C at or less than 7.0 percent.(1)

After 12 weeks, treatment with sitagliptin led to a significant mean reduction in A1C from baseline as compared to placebo with an average reduction of 0.6 percent observed in the sitagliptin 100 mg once daily group of which the majority of these patients had mild to moderate hyperglycemia. Observed differences in A1C between patients taking sitagliptin and patients administered placebo were greatest in those patients with higher baseline A1C at randomization. In patients with a A1C baseline of between 8.5 and 10 percent, a mean reduction of 0.8 percent, relative to placebo, was seen in patients randomized to the 100 mg once daily dose of sitagliptin using data carried forward, that is including patients whether they completed the study or not. A mean 1.1 percent reduction in A1C relative to placebo was observed in patients taking sitagliptin 100 mg using data from patients who completed the study as per study protocol.

Treatment with sitagliptin was well tolerated and resulted in no significant weight gain. One adverse event of hypoglycemia was reported in each of the four sitagliptin treatment groups, compared to no adverse events of hypoglycemia reported in the placebo group.

The second dose finding study presented was a randomized, double-blind, placebo-controlled study, which evaluated the efficacy and tolerability of sitagliptin in 743 patients with type 2 diabetes. In this study, patients were randomized to one of six treatment groups: placebo; sitagliptin (5 mg, 12.5 mg, 25 mg, or 50 mg twice daily); or the sulfonylurea glipizide 5 mg titrated to 20 mg daily. Prior to randomization, patients were enrolled in a diet and exercise regimen and, if taking other antihyperglycemic agents, a drug wash off period. Patients were characterized as having predominantly mild to moderate hyperglycemia. The mean A1C baseline was 7.8 percent to 7.9 percent, with 20.8 percent of patients having a baseline A1C at or less than 7.0 percent.

After a 12-week treatment period, sitagliptin significantly reduced A1C from baseline compared to placebo. The largest mean reduction in the patients treated with sitagliptin was 0.77 percent, in the 50 mg twice-daily treatment group. Patients taking glipizide showed a 1.0 percent reduction from baseline in A1C. At week 12, placebo subtracted A1C results did not appear to reach a plateau in the active treatment groups.

Treatment with sitagliptin was well tolerated and, like placebo, resulted in no significant weight gain. Patients treated with glipizide had an average weight gain of 1.1 kilogram relative to placebo. Adverse event reports of hypoglycemia were observed in four percent of patients taking sitagliptin, 17 percent of patients taking glipizide and two percent of patients taking placebo.

Also presented at the meeting were results from a Phase II randomized, double-blind, placebo-controlled, four-week crossover study, which evaluated the efficacy and tolerability of sitagliptin in combination with metformin versus metformin plus placebo. In the United States, metformin is the most commonly used oral antihyperglycemic agent in patients with type 2 diabetes.(2)

Twenty-eight patients with a mean baseline A1C of 7.7 percent receiving metformin were randomized into one of two treatment groups following a five-week diet and exercise run in period; they received metformin plus placebo or metformin plus sitagliptin 50 mg twice daily. At the end of the first four-week treatment period, patients given metformin plus placebo were then given sitagliptin 50 mg twice daily and vice versa. After the first four-week treatment period, results of the 24-hour weighted mean glucose for patients taking metformin plus sitagliptin 50 mg twice daily was 125 mg/dL as compared to 158 mg/dL in patients taking metformin plus placebo. This corresponds to a mean glucose reduction of 33 mg/dL.

The combination of sitagliptin and metformin was generally well tolerated with no clinically meaningful differences in the occurrence of adverse events when compared to metformin alone.

About sitagliptin

Sitagliptin is an investigational medicine now under development by Merck & Co., Inc. for the treatment of type 2 diabetes. If approved, sitagliptin would be a member of a potentially new class of antihyperglycemic agents called DPP-IV inhibitors, which block the DPP-IV enzyme that normally inactivates the incretin gut hormones GLP-1 and GIP. Sitagliptin is thought to lower blood glucose levels by enhancing the level of active incretin hormones which increase insulin from pancreatic beta-cells and decrease glucagon from pancreatic alpha cells in a glucose-dependent manner (when blood glucose is elevated and not when blood glucose is low).

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck discovers, develops, manufactures and markets vaccines and medicines in more than 20 therapeutic categories. The company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also published unbiased health information as a not-for-profit service. For more information, visit www.merck.com.

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.

(1) American Diabetes Association Clinical Practice Guidelines. Jan 2005

(2) IMS - NPA Plus audit, as of Dec 04

Source: Business Wire

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