STUDY: PARGLUVA POSES SAFETY RISKS

If approved by the FDA, Merck and Bristol-Myers Squibb's (BMS) highly anticipated diabetes treatment Pargluva would "constitute an unacceptable patient hazard," according to an independent clinical analysis that shows the drug poses significant safety risks.

The analysis, recently published online by the Journal of the American Medical Association (JAMA), suggests Pargluva (muraglitazar) is associated with an excess incidence of serious cardiovascular events, including death, myocardial infarction (MI), transient ischemic attack and congestive heart failure, compared with placebo.

The study, conducted by researchers at the Cleveland Clinic Foundation, was based on an analysis of clinical trial information released by the sponsors and the FDA prior to last month's meeting of the agency's Endocrinologic and Metabolic Drugs Advisory Committee.

The advisory panel voted 8-1 Sept. 9 to recommend approval of Pargluva as a stand-alone therapy for Type 2 diabetes. The panel also voted 7-2 in favor of approving the drug in combination with metformin, which is marketed by BMS as Glucophage, and is available in generic form.

While FDA reviewers concluded Pargluva's benefits outweigh its risks, the Cleveland Clinic researchers had a much different opinion of the drug after reviewing the safety data submitted by Merck and BMS. "From these public disclosure documents, we observed a numerical excess of adverse cardiovascular events for patients treated with muraglitazar compared with controls (patients treated with either placebo or pioglitazone)," writes Steven Nissen, a physician in the Cleveland Clinic's department of cardiovascular medicine, and lead author of the study.

Most troubling, the researchers said, was that Pargluva had a risk ratio of 2.23 for the most widely accepted composite endpoint of death, MI and stroke — meaning the drug more than doubled patients' chances of experiencing such adverse events.

Pargluva's safety profile was also questioned in a JAMA editorial that accompanied the Cleveland Clinic study. The editorial, written by James Brophy, a physician at McGill University Medical Center in Montreal, Quebec, suggests there were specific methodological decisions in the sponsors' application that "may foster an illusion of safety."

Brophy pointed to a number of "disingenuous" study methods employed by the sponsors during Pargluva's trials, including: selecting a study population unlikely to have adverse outcomes; conducting "underpowered" studies increasing the failure rate to detect meaningful safety differences; and limiting preapproval peer-review publication of results so as to minimize scrutiny and debate of both methods and results.

While Brophy acknowledged that Pargluva might ultimately prove to be a valuable drug, he urged the FDA to proceed cautiously. "A new drug for a uniformly fatal disease with no other treatment options is likely, even in the presence of some treatment risks, to be approved by regulators and accepted by patients," he writes. "Conversely for muraglitazar, for which no meaningful outcome benefits have been demonstrated and other treatments exist, the safety standards should be proportionally higher and importantly less uncertainty should be tolerated about suspected risks."

Although the FDA's advisory panel recommended approval of Pargluva, the agency recently issued Merck and BMS an approvable letter for the drug, requesting additional cardiovascular safety data.