Bristol-Myers Squibb remains in discussions with FDA about what clinical studies would be required to address concerns about the cardiovascular safety profile of its type 2 diabetes treatment candidate Pargluva (muraglitazar).

The scope of the additional trials that are needed has prompted Merck to drop out of the co-development partnership for the dual peroxisome proliferators-activator receptor agonist.

The two drug makers announced Oct. 27 that they would begin discussions to terminate the collaborative agreement after determining that regulatory approval and commercial success of muraglitazar would require additional clinical trials that could take up to five years to complete.

Although the partnership with Merck will be ended, Bristol is leaving open the possibility of pursuing Pargluva approval. Bristol stated that it will continue discussions with FDA and "will consider a range of options including additional studies or terminating further development of muraglitazar."

The termination of the collaboration appears to be an abrupt turnaround: As recently as the day before the companies announced the end of their agreement, both said they were prepared to discuss the timing and design of a clinical outcomes trial addressing Pargluva's cardiovascular safety profile.

"We are eager to begin discussion with the FDA to address more fully the cardiovascular safety profile of the compound and to determine what additional information may be necessary," Merck said in a statement Oct. 26.

However, it appears FDA asked for more data than expected. In announcing the developments Oct. 27, Bristol said that "ongoing trials were not designed to answer questions raised by FDA."

The statement stands in direct contrast to the companies' comments following the receipt of an "approvable" letter from FDA earlier in the month.

FDA's action letter called for additional information on Pargluva's cardiovascular safety. However, a joint statement from Bristol and Merck on Oct. 18 reported that "FDA has requested additional safety information from ongoing trials, or those completed since the safety data from the last formal regulatory submission."

Pargluva is not the first PPAR agent to succumb to safety issues - several other competing PPAR programs have been delayed or dropped due to safety concerns (¹ Also see "AstraZeneca Galida NDA Delayed Until 2007 Due To PPAR Safety Concerns" - Pink Sheet, 11 October, 2004., p. 24).

Bristol/Merck's announcement of the termination of the collaboration closely follows the online publication of a data analysis and accompanying editorial in the Journal of the American Medical Association Oct. 20, calling for a delay in the approval of Pargluva due to safety concerns.

"This agent should not be approved to treat diabetes based on laboratory end points until safety is documented in a dedicated cardiovascular events trial," Steven Nissen, Kathy Wolski and Eric Topol (all of the Cleveland Clinic Foundation) conclude.

The JAMA analysis evaluates the incidence of death, myocardial infarction, stroke, congestive heart failure and transient ischemic attack in diabetic patients treated with muraglitazar compared with controls.

Although based on the same Phase II/III trial results of Pargluva in diabetic patients presented to the FDA advisory committee, the JAMA analysis yielded a different, higher risk rate.

Committee members noted potential cardiovascular safety risks with the therapy, but were mollified by the firms' plans for a pharmacovigilance program with a 15,000 patient cohort and an outcomes trial. The advisory panel ultimately issued a favorable recommendation (² [A#00670380005], p. 11).

Nissen et al. conclude that in comparison with placebo or pioglitazone (Lilly/Takeda's Actos ), muraglitazar is "associated with an excess incidence of the composite end point of death, major adverse cardiovascular events (MI, stroke, TIA) and CHF."

In contrast, the sponsor's presentation at the advisory committee concluded there was "no significant excess risk of deaths or cardiovascular events" with Pargluva.

The JAMA review included an analysis of four Phase III trials and one Phase II trial evaluating the effects of muraglitazar on various measures of glycemic control and lipids and reporting on major adverse events, including cardiovascular outcomes.

The design, which was restricted to patients receiving muraglitazar doses of 5 mg/day, yielded 2,374 patients treated with muraglitazar and 1,351 who were given comparator agents (823 pioglitazone and 528 placebo).

The authors describe the results of the analysis as "concerning." For the primary outcome measure (all-cause mortality, nonfatal MI or nonfatal stroke) the relative risk for muraglitazar was 2.23.

"Other endpoints using narrower definitions (including only cardiovascular death) or broader composites (including CHF and TIA events) showed similar risks," the article states. The widest endpoint (all-cause mortality, nonfatal MI, stroke, TIA and CHF) "showed a highly significant increase in RR for muraglitazar-treated patients (2.62; p=0.004)."

"Furthermore, there was a highly consistent pattern of excess morbidity for all of the components of the major outcome measure with all RRs exceeding 2.1," the authors note. "The consistency in magnitude and direction of the adverse effects across multiple cardiovascular endpoints reduce the likelihood that these findings result from chance alone."

The authors also point out that the clinical trial population is often the "lowest-risk strata of patients" and that "real world exposure would likely substantially amplify the risk." They additionally note that atherosclerotic disease is common in diabetics.

"Taken as a whole, these data demonstrate that it is likely that muraglitazar, if approved by the FDA, would constitute an unacceptable patient hazard."

In conclusion, "muraglitazar appears to increase the risk for morbidity and mortality in diabetic patients during relatively short-term treatment. The estimated magnitude of this risk is substantial, with RRs indicating a doubling for irrevocable, major endpoints and composite outcomes," Nissen et al. state.

"Accordingly, muraglitazar should not be used or approved to treat patients with diabetes until an appropriate dedicated trial to assess cardiovascular outcomes is performed."

In response to the JAMA study, Bristol said its trials "were designed like any other clinical trial for a diabetes drug" and were conducted by outside experts and thought leaders in diabetes treatment.

Nissen et al. note some limitations to their analysis, including the fact that because they did not have access to the original trial databases, they used a proportional analysis to determine risk rather than "the more powerful time-to-event" methods.

In comparison to the JAMA analysis, the data used in the sponsors' analysis included six Phase II/III studies including 4,640 subjects, 3,226 of whom were treated with Pargluva - the results showed a "low incidence" of investigator-diagnosed heart failure events.

An FDA analysis, presented at the advisory committee, determined that a low number of cardiovascular events made incidence rates unstable. The analysis showed nine cardiovascular deaths in the Pargluva arm (n=3,226) compared to one in the placebo group (n=591) and none (n=823) in the Actos arm.

An analysis of the five studies in Type 2 diabetes showed non-CHF cardiovascular events were seen in 40 Pargluva patients (1.4%), six Actos patients (0.7%) and four placebo patients (0.8%); the imbalance was attributed to a sulfonylurea add-on in the study.

In a JAMA editorial accompanying the study, James Brophy (McGill University) says that despite disagreement between the JAMA review and the companies' analysis, "a consensus should exist that these differences indicate less than robust data."

The sponsors' application includes methodological decisions that "foster an illusion of safety," he says, calling such decisions "perhaps unintended but nevertheless disingenuous."

For example, Brophy notes that the sponsor's analysis includes patients receiving "subtherapeutic" doses of 2.5 mg or less. "Since FDA approval was not sought for these small doses of muraglitazar, the inclusion of these data in the safety analysis for the proposed marketed doses may be questioned," Brophy says.

"Because there were no associated cardiovascular events among these patients, the effect is a dilution of the clinically pertinent risk estimate," he adds. Recalculated to include only the proposed marketed doses of Pargluva, the sponsor event rate is 97 events per 2,447 patient-years, an excess of 20% compared with placebo alone and 67% compared to the combined placebo-pioglitazone control group.

Brophy concludes that while a pharmacovigilance study may provide "useful information," a large premarketing safety trial will provide more secure evidence and limit risk.

Pargluva Panic: Need For Additional Trial Prompts Merck To Drop Partnership

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