Reanalysis of Pargluva data questions safety
Steven Nissen, M.D., and Eric Topol, M.D., of the Cleveland Clinic, conducted the analysis on Pargluva (muraglitazar), a diabetes drug which is under FDA review and which BMS wants to co-market with Merck. Designed as the first in a new class of diabetes medicines, the drug has shown promise in regulating blood glucose levels among patients with type 2 diabetes while also improving blood cholesterol levels.
BMS and Merck said in a statement that they are "eager to begin discussions with the FDA to address more fully the cardiovascular safety profile of the compound and to determine what additional information may be necessary."
A BMS spokesperson subsequently told MM&M the company has not had the opportunity to thoroughly review the new analysis, adding, "there are many different and appropriate ways to analyze data."
An FDA advisory panel that met in September recommended Pargluva's approval by an 8-to-1 vote. And last week the agency issued an approvable letter, indicating the drug could be cleared for marketing once additional information to be provided by BMS is received and reviewed.
James Brophy, a cardiologist at McGill University in Montreal, wrote in an editorial accompanying the study that muraglitazar may yet prove to be a valuable drug but that potential cardiovascular risks as well as safety concerns about carcinogenicity must be resolved first. JAMA said it posted the study and editorial on its website due to their "timeliness and potential importance for public health."
Nissen and Topol, who are the same researchers who pointed out heart risks of Vioxx in 2001, said they obtained data for their analysis from FDA briefing documents.
In patients treated with muraglitazar, death, MI (heart attack) or stroke occurred in 1.47 percent of patients compared with .67 percent of patients treated with either placebo or pioglitazone, another drug, the researchers wrote.
They noted that the results are of particular concern, because adverse events were observed after study participants had only limited drug exposure ranging from 24 to 104 weeks.
While the numbers of analyzed events were small, and data for their analysis was pooled from publicly disclosed regulatory documents rather than from original trial databases, the two are calling for BMS to do a large study to examine Pargluva's long-term effect on the heart.
BMS said it presented a plan for a clinical outcomes trial, and that "the timing of this trial will depend on our discussions with the FDA."
In a statement last week, the company said the FDA had requested "additional safety information from ongoing trials, or those completed since the safety data from the last formal regulatory submission, to address more fully the cardiovascular safety profile of the drug."
The request comes as a set back for BMS and Merck, as analysts have predicted it could delay Pargluva's approval for at least a year.