Aventis Pharma and Vertex Pharmaceuticals to Expand Development of Pralnacasan, Oral Cytokine Inhibitor for Inflammatory Diseases
BRIDGEWATER, N.J., and CAMBRIDGE, Mass., April 24 /PRNewswire-FirstCall/ - Aventis Pharma (NYSE: AVE - news) and Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX - news) today announced that they are expanding clinical development of the interleukin-1 beta converting enzyme inhibitor pralnacasan, based on clinical proof-of-mechanism data obtained in a recently-completed Phase II clinical trial in rheumatoid arthritis (RA). Pralnacasan is an oral, small molecule drug candidate licensed for development by Aventis from Vertex. In this Phase II clinical trial, proof-of-mechanism for pralnacasan as a novel anti-inflammatory drug candidate was obtained based on an assessment of the compound's clinical activity and tolerability. With this result, pralnacasan has met Aventis' criteria for expanded clinical development.
The data from the Phase II clinical trial in RA supports further clinical development of pralnacasan in RA, as well as initial Phase II clinical trials in osteoarthritis and other potential indications. Aventis will evaluate the timing of initiating such trials.
``These results demonstrate that pralnacasan, an oral cytokine inhibitor, has anti-inflammatory effects in rheumatoid arthritis,'' said Frank Douglas, executive vice president and head of Drug Innovation & Approval at Aventis. ``We and Vertex look forward to completing our analysis of this trial and designing additional rheumatoid arthritis studies. At the same time, we will consider initiating clinical studies in osteoarthritis and other indications, if appropriate. This will allow us to define fully the clinical applications and market opportunity for pralnacasan.''
Pralnacasan is an orally administered inhibitor of interleukin-1 beta converting enzyme (ICE), an important enzyme regulating inflammatory processes. ICE regulates the production of interleukin-1 beta (IL-1 beta) and IL-18, key proinflammatory cytokines that initiate and sustain the progression of inflammation. Inhibiting ICE may be a useful strategy for curtailing damaging inflammatory processes common to a number of acute and chronic conditions.
Study Design
The Phase II clinical trial was designed to evaluate the safety, efficacy and pharmacokinetics of pralnacasan alone and in combination with other treatments in patients with active RA. The clinical trial was conducted in Europe and enrolled adult patients diagnosed with mild to moderate RA at least 6 months prior to the start of the study. Patients in the study were able to continue their treatment with anti-inflammatory therapies. Upon study entry, patients were required to have received either: 1) a fixed dosage regimen of RA therapies that included one or more disease-modifying anti-rheumatic drugs (DMARDs) and/or corticosteroids for at least three months, or 2) no additional RA drug therapy. The clinical trial was a 12-week, double blind, randomized, placebo-controlled study. After the initial 12 weeks of the trial, patients had the option of extending treatment for an additional 12 weeks. In the study, patients were randomized to receive one of two doses of pralnacasan or placebo, in addition to any other RA therapies they were receiving. There were 285 adult patients enrolled in the study, of which 224 patients in the pralnacasan dose groups and 55 in the control group were available for evaluation. Approximately 80% of patients were taking concomitant DMARDs and approximately 55% were taking concomitant corticosteroids at study entry.
``This trial was designed to collect information about the activity of pralnacasan alone and in combination with other RA treatments in a diverse patient population,'' commented Dr. Douglas. ``We believe that the study design and the data will facilitate the design of a focused development plan.''
Study Results
A broad range of clinical and pharmacodynamic measures was used to assess pralnacasan's anti-inflammatory activity. Results showed that patients receiving pralnacasan had a strong trend toward a dose-dependent improvement in signs and symptoms of disease, as measured by ACR20 response rates after 12 weeks (p=0.076). Patients are considered to have an ACR20 response if they achieve at least a 20% improvement in their tender-joint and swollen-joint counts in addition to 20% or more improvement in a minimum of three additional criteria set by the American College of Rheumatology (ACR). Analyses of patient sub-groups not receiving concomitant DMARDs, methotrexate or corticosteriods showed similar strong trends indicative of pralnacasan's anti- inflammatory effect. Patients receiving the high dose of pralnacasan in the intention-to-treat population exhibited ACR20 response rates greater than 40%. In addition, the high dose of pralnacasan induced significant decreases in the inflammatory biomarkers C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and serum amyloid A (SAA).
In the study, pralnacasan demonstrated good tolerability alone and in combination with other RA therapies when administered for up to 24 weeks.
Based on the demonstrated anti-inflammatory effects, Aventis and Vertex conclude that clinical proof-of-mechanism for pralnacasan as a novel, first- in-class therapy for inflammatory diseases has been obtained.
``We and Aventis have pioneered the scientific development of ICE inhibitors, starting with innovative early drug design efforts. This research provided the framework for demonstrating that oral ICE inhibitors can lead to clinical benefit in inflammatory diseases like rheumatoid arthritis,'' said Vicki Sato, Ph.D., President of Vertex. ``Pralnacasan is an example of our focus on unmet medical needs and providing the next generation of first-in- class therapeutics for patients seeking safer, more effective treatments.''
Final data analysis is continuing, and the companies anticipate that additional data from this study will be provided during Aventis' R&D Day presentations in June.
Vertex and Aventis began collaborating in 1993 to discover and develop orally available inhibitors of ICE. Their intensive design efforts were based on the three-dimensional molecular structure of ICE, solved by Vertex researchers in 1994. In 1998, pralnacasan became the first ICE inhibitor to enter clinical development. In September 1999, Vertex and Aventis expanded their original agreement. Under this agreement, Aventis funds development of pralnacasan and will pay Vertex up to $62 million for the successful development of pralnacasan in RA, the first targeted indication. Aventis has retained the rights to develop pralnacasan for additional indications and Vertex will receive similar milestones on these indications. Vertex has co- promotion rights in the United States and Europe and will receive royalties on global sales, as well as a co-promotion royalty and reimbursement of co- promotion costs... |
