FDA's Endocrinologic & Metabolic Drugs Advisory Committee recommended use of Bristol-Myers Squibb/Merck's Pargluva with metformin and as monotherapy but voted seven to two against combination use with a sulfonylurea for the treatment of type 2 diabetes mellitus.

"If we say 'no,' then this drug will never be adequately tested with sulfonylurea in large enough numbers to know whether the cardiovascular indication is a problem, yet you do put people at risk if we say 'yes,'" committee consultant Lynne Levitsky (Massachusetts General Hospital) said.

"I will say 'no' but I do hope that a larger study will be done," Levitsky said.

The committee convened Sept. 9 to discuss approval of Pargluva (muraglitazar) as both monotherapy and combination therapy with metformin and a sulfonylurea for the treatment of type 2 diabetes.

The committee voted seven to two in favor of combination use with metformin and eight to one in favor of use as a monotherapy.

Safety data suggested a higher risk of death and non-congestive heart failure cardiovascular adverse events with muraglitazar than with placebo or active comparator, Lilly/Takeda's Actos (pioglitazone).

While a trial comparing muraglitazar plus metformin to pioglitazone plus metformin accounted for a majority of deaths, a muraglitazar plus glyburide vs. placebo study accounted for a majority of the non-CHF cardiovascular events.

Pargluva poses particular safety concerns in a number of patient groups, committee members noted.

Committee consultant Kenneth Burman (Washington Hospital Center) suggested that use of muraglitazar in patients with known cardiovascular disease, heart disease and bladder cancer may pose safety concerns.

Patients at risk for edema-related adverse events and hypertension may also pose safety concerns, other members said.

FDA suggested in its briefing documents that a 1.5 mg dose of Pargluva may be adequate for efficacy and lack the risk of higher doses (¹ Also see "Pargluva Fluid Retention, Cardiac Risk To Be Central Issues At Advisory Committee" - Pink Sheet, 8 September, 2005.). However the committee voted seven to two that there was not adequate evidence that the dose is effective.

The 1.5 mg dose "has only been studied in the [Phase II] dose ranging study by the sponsor and in that study it's important to remember that this was not really a study…of 1.5 [mg dose] but was a strategy to start at a dose of 1.5 [mg], increasing to a higher dose if necessary," committee member Dean Follmann (National Institutes of Allergy and Infectious Diseases) said.

"In that study…about 30% of the people ended up at a higher dose," Follmann said.

- Andrew Shelton

Bristol/Merck's Pargluva Combination Use With Sulfonylureas Not Recommended

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