By Randall Osborne
West Coast Editor
Despite unhappy news from animal testing with high doses of its oral p38 MAP kinase inhibitor VX-745 ¿ news that is causing Vertex Pharmaceuticals Inc. to suspend Phase II development of the rheumatoid arthritis drug ¿ the company said it¿s confident about second-generation compounds and will march ahead with them.
Vertex¿s stock (NASDAQ:VRTX) closed Monday at $17.74, down $5.73, or 24.4 percent.
¿This is somewhat of a development setback, but we think we¿ve lost a year or less in terms of getting a product to market in [the oral p38 MAP kinase] area,¿ said Michael Partridge, associate director of corporate communications for Cambridge, Mass.-based Vertex.
VX-745 showed proof of principle that correlated the inhibition of p38 MAP kinase with anti-inflammatory effects but, at the same time, in animal studies the drug also apparently crossed the blood-brain barrier, making its way into the central nervous system.
Partridge declined to describe the unfavorable effects on animals, but said the ¿chemically distinct¿ second-generation compounds already have been shown in pharmacokinetic studies not to cross the barrier.
The blood levels that caused CNS effects in animals given high-dose VX-745 measured about 10 times those obtained in human clinical trials so far, and no neurological side effects from VX-745 have arisen in clinical trials.
Still, Vertex is playing it safe.
¿This was a cautious and prudent decision, made in the interests of patients,¿ Partridge said. ¿It was also a commercial decision, based on the kind of data we¿ll need to generate on VX-745 in order to continue to develop it in RA.¿
Telling BioWorld Today there is ¿a case to be made for continued development on a different timetable in RA,¿ Partridge said it would take too long ¿ especially given that the second-generation compounds, or another drug entirely, might be developed quicker.
¿We don¿t just try and bring one compound into development, but look at multiple candidates representing different drug scaffolds,¿ he said. When you¿re leading in an area, we¿re able to recover quickly and bring another compound into clinical development. We still feel like we¿re in a very strong position.¿
Vertex is ¿not slamming the door on VX-745, because there is a possibility of doing further development down the road, probably for some other indication,¿ Partridge added.
Meanwhile, the company is moving forward with second-generation drugs VX-702 and VX-850, which are known not to cross the blood-brain barrier, and plans to start clinical studies with one or both in the first half of 2002.
Also next year, Vertex will offer data from its Phase II study of VX-745, which proved the drug well tolerated with no CNS effects at lower doses, and the primary endpoint of ACR 20, an RA scale, response indicated what the company called a ¿significant clinical effect,¿ and that was the point, Partridge said.
¿The results are encouraging, particularly on the clinical activity front,¿ he said. ¿The big question has been, can you achieve some kind of anti-inflammatory effect with an oral p38 MAP kinase inhibitor. Our goal was to be able to evaluate the effect, and we were able to do that.¿
The p38 MAP kinase regulates two inflammation-making cytokines, tumor necrosis factor alpha and interleukin-1, implicated in various inflammatory diseases. Vertex has development and commercial rights in the U.S. and Europe for its p38 MAP kinase inhibitors. Kissei Pharmaceutical Co., of Tokyo, has the rights in Japan and certain Asian countries for VX-745 and VX-702, with an option for VX-850.
Partridge noted that the latest news does not affect last year¿s potential $800 million collaboration with Novartis Pharma AG, of Basel, Switzerland, which was established for discovering kinase inhibitors through chemogenomics. He pointed out that yet another deal with Aventis AG, of Frankfurt, Germany, is for VX-740, an enzyme inhibitor separate from the p38 MAP kinase drugs. VX-740 is in Phase II studies. (See BioWorld Today, May 10, 2000.)
¿We¿ve got multiple bets on the table for RA,¿ Partridge said.