Aventis and Vertex Pharmaceuticals Incorporated announced voluntary discontinuation of phase IIb clinical trials of pralnacasan, an oral interleukin-1 beta converting enzyme (ICE) inhibitor, in rheumatoid arthritis. This decision is based on results from an animal toxicology study that showed liver abnormalities after a nine-month exposure to pralnacasan at high doses. There have been no significant adverse events associated with liver toxicity in subjects and patients who participated in pralnacasan studies to date.

The decision was confirmed following a discussion with the Food and Drug Administration (FDA) that Aventis and Vertex had requested. During this discussion, the FDA supported the decision of Aventis and Vertex to discontinue present phase IIb clinical trials in rheumatoid arthritis.

Also during this discussion, it was determined that two, shorter-term on-going phase I trials will continue as planned, as the FDA agreed with Aventis and Vertex that the toxicity findings based on longer-term regimens in animals did not imply safety concerns in the significantly shorter phase I trials.

"This is an unexpected toxicology finding, and the prudent action is to discontinue the ongoing phase II clinical studies, and fully evaluate the toxicology results before moving ahead," said Frank Douglas, executive vice president of Drug Innovation & Approval and Member of the Aventis Management Board. "We are committed to working with Vertex to better understand and hopefully resolve this issue."

"Pralnacasan is the subject of an extensive phase II clinical program, reflecting the promise of oral ICE inhibitors as a breakthrough strategy to treat a range of inflammatory diseases. Although we are disappointed with the results of the toxicology study, we support the decision to fully analyze the toxicology data, and we will work diligently with Aventis to evaluate the results to determine the appropriate path forward," said Vicki Sato, president of Vertex. "Both we and Aventis continue to believe that modulation of the ICE enzyme with an oral therapy holds the potential to change the way in which debilitating inflammatory diseases are treated."

The purpose of toxicology studies is to help define potential target organ toxicity and to determine and confirm the therapeutic window for the safe dosing of investigational therapeutic agents in clinical trials and ultimately, clinical practice. Today's decision is based on the results from a 9-month animal toxicology study.

The findings observed in the 9-month toxicology study were not observed in prior toxicology studies conducted with pralnacasan, including 6-month studies in two different species. Decisions on further clinical trials of pralnacasan will be made after the final analysis of the nine-month toxicology study and data from an on-going 12-month toxicology study are available.

In July 2003, Vertex and Aventis announced the initiation of a phase IIb randomized, placebo-controlled, double-blind, multi-center clinical trial to evaluate the safety and efficacy of pralnacasan in patients with RA. During this study, patients were permitted to continue background methotrexate therapy, the industry standard treatment for rheumatoid arthritis, which also can induce liver toxicity. Patients completing this trial were allowed to roll over to an extension trial where they were treated with pralnacasan or standard of care therapy. The discontinued phase IIb studies were to evaluate 340 patients treated with pralnacasan or placebo for 12 weeks.

Approximately 330 patients had been randomized prior to the decision to discontinue the study, and approximately 50 had completed treatment.

Rheumatoid Arthritis is a progressive, systemic autoimmune disease characterized by the inflammation of the membrane lining in joints. This inflammation causes a loss of joint shape and alignment, resulting in pain, stiffness and swelling, ultimately leading to joint destruction and disability.