Anything but Academic: Lessons From the PPAR Failures

Bristol and AstraZeneca lost major PPAR diabetes product development projects. Both companies got a nasty taste of a rapidly emerging force in the drug development process: the academic research organization. These academic centers are not shy about expressing their negative as well as positive opinions on drug development plans. Leading the pack is the Cleveland Clinic - the source of the safety questions that finished off the PPAR class.

Bristol and AstraZeneca lost their PPAR diabetes programs to the concerns of Cleveland Clinic cardiologists. Drug development teams need to watch their flanks.

Cole Werble

The pen is mightier than an FDA review—or at least it probably feels that way to PPAR drug developers.

AstraZeneca PLC and Bristol-Myers Squibb Co. officially cancelled their respective peroxisome proliferator activator receptor projects in May, ending drug development efforts that once looked like promising diabetes breakthroughs but were dropped suddenly to safety concerns.

Bristol lost muraglitazar (Pargluva) to a journal article based on an analysis of clinical trial data by a group of de facto safety reviewers operating outside FDA.

AstraZeneca lost tesaglitazar (Galida) to the fallout from the article and a private letter from one of the reviewers.

Both companies got a nasty taste of a rapidly emerging force in the drug development process: the academic research organization. Academic research centers are fighting back as competitors to the commercial clinical research organizations that pharma has been relying on for the past two decades.

With top researchers who have experience serving on FDA advisory committees and as consultants to the agency, a core of academic groups are beginning to act as self-designated surrogates for FDA. The Cleveland Clinic leads the pack among the most active centers and was the source of safety questions that finished off the PPAR class (See "Shadow FDA? Researchers Are Taking Approval Matters into their Own Hands," The RPM Report, December 2005 (Also see "Shadow FDA? Researchers Are Taking Approval Matters into their Own Hands" - Pink Sheet, 1 Dec, 2005.).)

The PPAR cancellations send a strong message to drug developers to pay careful attention to the emerging academic safety centers. Watching them closely is a minimum step for a drug development program; considering them as sites for sponsored research could take away some of the risk of an unexpected attack on a product under development.

Pargluva Gets Squeezed Out

Bristol officially pulled the plug on muraglitazar (Pargluva) on May 18, seven months to the day after receiving an "approvable" letter from FDA indicating that more data would be needed for approval despite a favorable advisory committee review of the product in September 2005.

Bristol’s analysis of FDA’s request for more information convinced the company that there would not be room for the product if and when it finally made it to the market circa 2011. The company said it faced "further long-term studies to clarify the cardiovascular profile."

But it was really an analysis of Bristol’s clinical trial data by a group from the Cleveland Clinic under department of cardiovascular medicine chairman Steven Nissen, MD, that sealed Pargluva’s fate. The company may have been able to work out a follow-up research program with FDA, but the publicity generated by the Cleveland Clinic team in an article in the October 20, 2005 issue of the Journal of the American Medical Association chilled Pargluva’s commercial prospects.

Nissen’s analysis got plenty of attention. But less visible was his continued involvement in questioning other research projects in the PPAR class.

Nissen was asked to explain the lessons from the Pargluva review at a meeting of the Institute of Medicine’s committee to assess drug safety in January. As part of his explanation, Nissen noted that he put AstraZeneca on notice that he was also watching the trials of tesaglitazar (Galida). In fact, he wrote to AstraZeneca urging them to prospectively determine the cardiovascular safety of the product.

"I wrote a letter to the sole remaining company that has a PPAR in development, which is AstraZeneca," Nissen said. "I suggested to them that they prospectively define cardiovascular safety and adjudicate the endpoints in their Phase III program." In the context of the Pargluva development failure, Nissen’s suggestion may have sounded more like a commercial death knell.

Nissen said that he hoped his contact with AstraZeneca might encourage the company to undertake further studies to prove that the Galida did not carry any cardiovascular risks. "My hope," Nissen said, was "that if this signal is not there, then that is good. And, if it is, they will find it out."

AstraZeneca Waits Seven Months: Refills Pipeline

AstraZeneca terminated its Galida program on May 4. In announcing the move, the company obliquely referred to the troubles caused for the class by the Nissen publicity: Galida "was in a class with a high degree of uncertainty," AstraZeneca observed.

AstraZeneca pointedly said that the decision was not based on cardiovascular risks. Central to the decision to cancel, the company said, was evidence of kidney issues—data showing elevations in serum creatinine.

AstraZeneca also said it was not ready to abandon all work in the area. The company claims to have other PPARs in development and that it may be able to apply lessons from the Galida failure to those projects.

Nevertheless, the PPAR class has a reputation for a wide range of effects during clinical trials. Nissen calls the class "unpredictable," telling the IoM meeting that "what is unusual about the PPARs is that they have all had a variety of toxicities—some of them completely unpredictable. Some of them are renally toxic. Some of them had hepatotoxicity."

By waiting for seven months after publicity on the Pargluva problems to cancel its PPAR project, AstraZeneca also gave its deal-making team time to replenish its pipeline. AstraZeneca signed at least a half-dozen product development and marketing deals between the Pargluva article in JAMA and the Galida announcement. Within 11 days of announcing the end of Galida, AstraZeneca made an additional purchase: a $1.07 billion offer for Cambridge Antibody Technology Group PLC .

But Nissen’s outspoken stance on PPARs carries a risk, since freelance safety reviews can affect the attractiveness of the Cleveland Clinic as a site for testing. To a question at the IoM meeting about career risks from taking negative positions on major products, Nissen quipped that he did not expect Bristol to "select my coordinating center to do future trials."

Cleveland Clinic: More Essential Because of Critical Posture?

But anger and retribution against a center for speaking out against a drug development project is not the only response to a cancelled project. The Cleveland Clinic’s reputation and clear interest in challenging projects may be making it that much more attractive as a site for studies.

AstraZeneca has had experiences both ways with the clinic. The company actually got a boost from work done by Nissen at the same time that he was writing to suggest more prospective safety work on Galida. Nissen was the principal investigator on a study demonstrating a positive effect on atherosclerosis from a high dose (40 mg daily) of the cholesterol reduction agent rosuvastatin (Crestor).

Nissen’s findings again drew a lot of public attention—his pronouncements are beginning to be recognized by health care writers as newsworthy, and the Crestor results were reported at the meeting where he took over the chairmanship of the American College of Cardiology. The Crestor findings were controversial as well as headline-grabbing: high-dose use of the newer statins has been a continuing issue since the market withdrawal of cerivastatin (Baycol).

Nissen’s findings on both Crestor and Pargluva illustrate one of the problems with safety pronouncements by groups working outside FDA: specialty bias, or the propensity for individual researchers to look for effects in areas where there interests are most keen.

Nissen’s focus on cardiovascular risks from drugs used primarily for other conditions (diabetes) is one side of the equation. His interest in examining high doses of the statins (to seek more activity against a cardiovascular risk) while overlooking concerns about the possible effects of the drug on other organs is the other side.

One of the important roles that FDA has attempted to fill over the years has been to wash out specialty biases by bringing multidisciplinary perspectives to new drug reviews. If academic research centers continue to flex their muscles in the drug safety arena, sponsors may have to rely on the agency to help maintain some balance. Support for broader and more open FDA safety reviews could be a deterrent to the highbrow hijacking of NDAs by academic groups.