MORE CARDIOVASCULAR SAFETY DATA REQUESTED FOR PARGLUVA
Merck and Bristol-Myers Squibb (BMS) must submit additional safety data to the FDA before their jointly developed diabetes drug Pargluva can gain final approval, the firms said recently.
The FDA issued Merck and BMS an approvable letter for Pargluva (muraglitazar), requesting additional safety information from ongoing clinical trials, or those completed since the safety data from the last formal regulatory submission, to more fully address the drug's cardiovascular safety profile.
Merck and BMS are "eager to begin discussions with the FDA to address this issue and to determine what additional information may be necessary," the companies said in a joint statement. However, there is currently no timetable to begin the discussions, a BMS spokesman told FDAnews.
The data request could delay Pargluva's launch by at least a year, according to financial analysts. "Pargluva appears to have a less favorable safety profile than currently marketed products," Friedman Billings Ramsey analyst David Moskowitz writes in a recent research note. "Given that the ongoing safety studies will not be complete until mid-2006," Moskowitz said he is now forecasting a U.S. launch for Pargluva in the fourth quarter of next year.
The FDA's request for additional safety data comes roughly one month after the agency's Endocrinologic and Metabolic Drugs Advisory Committee voted 8-1 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 the FDA advisers agreed that Pargluva has a favorable risk-benefit profile, the panel noted that the drug, a dual alpha/gamma PPAR (peroxisome proliferator-activated receptor) activator, is not without safety risks. Many trial subjects, for example, have experienced elevated fluid retention while taking Pargluva and other dual-PPAR agonists, a condition that could lead to edema or potentially aggravate pre-existing heart conditions.
"Muraglitazar, like other PPAR gamma agonists, was found to cause fluid accumulation and as such to precipitate congestive heart failure in susceptible individuals," David Orloff, director of the FDA's Division of Metabolic and Endocrine Drug Products, states in review documents for Pargluva. Orloff also noted there is an "imbalance in the incidences of cardiovascular deaths and of serious cardiovascular adverse events (other than congestive heart failure) relative to placebo and [Actos] has arisen in the muraglitazar clinical trial experience." However, the differences were based on a very small number of adverse events, he adds.
FDA reviewers had difficulty determining the overall extent of Pargluva's cardiovascular risks, in part because the clinical data submitted by Merck and BMS weren't consistent. The agency's analysis was further complicated by the fact that cardiovascular events are common in patients with Type 2 diabetes, writes Orloff. Additionally, imbalances across randomized treatment groups in level of cardiovascular risk are possible, which can further complicate clinical assessment, he notes.