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.
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