By Karen Pihl-Carey

Vertex Pharmaceuticals Inc. partnered with Taisho Pharmaceutical Co. Ltd. to discover, develop and commercialize caspase inhibitors to treat cerebrovascular, cardiovascular and neurodegenerative diseases.

The deal potentially is worth $43 million in pre-market payments to Cambridge, Mass.-based Vertex, and gives Taisho rights in Japan and other Asian countries.

"We're very excited about it," said Richard Aldrich, Vertex's senior vice president and chief business officer. "We think Taisho will be a great partner on this program. It provides us with some significant financing near term to offset the costs of the program. I think they will be a very significant R&D partner, and more importantly, this is our third major collaboration in the caspase area."

The deal includes a $4 million up-front payment to Vertex, as well as development milestone payments and an expected $5 million in funding in 2000.

"The $43 million would be in research support and pre-commercialization milestones," Aldrich told BioWorld Today. "In addition to that, once we and Taisho have agreed on a development candidate, they will provide roughly one-third of the co-development costs."

If a candidate reaches the market, Vertex will supply the drug to Taisho in return for a supply royalty, which is a "significant double-digit royalty," Aldrich said.

Taisho, of Tokyo, will cover research funding and up to one-third of the cost of developing compounds in return for an option to obtain marketing rights for the compounds in Japan and certain Far East markets. Vertex will retain exclusive development and marketing rights in Europe, North America and other regions outside the Far East. Aldrich said there is a high level of interest in the caspase area from major pharmaceutical companies, and Vertex could establish additional partnerships.

Scientists have identified 11 human caspase enzymes known to play specific roles in apoptosis and inflammation. The Vertex and Taisho collaboration will focus on those related to apoptosis, which is implicated in stroke, myocardial infarction and a range of neurodegenerative diseases. While stimulation of apoptosis results in caspase activation within the cell, disruption of the caspase activity has been shown to block apoptosis in vitro and in vivo through gene knockout experiments and animal models.

Vertex scientists also have discovered the 3-dimensional atomic structures of four caspases and more than 50 enzyme/inhibitor complexes. They will use research from gene knockout studies to design with Taisho novel small-molecule caspase inhibitors for several indications.

"I think our whole effort in the caspase area and what we've been able to build in the last five or six years reflects Vertex's overall approach in taking success in one target and being able to expand it over a family of targets," Aldrich said.

Vertex now has collaborations in its caspase research worth $300 million, Aldrich said. A collaboration with Roussel Uclaf, of Paris, was signed in 1993 to develop inhibitors of caspase-1, also known as interleukin-1 beta converting enzyme (ICE). It gave Vertex U.S. rights and Roussel European rights, and both shared co-exclusive rights in Japan. Roussel later became part of Frankfurt, Germany-based Hoechst AG.

As Hoechst Marion Roussel, the company expanded the collaboration to continue developing HMR 3480/VX-740, an orally active inhibitor of ICE, for rheumatoid arthritis (RA), osteoarthritis and other inflammatory diseases. (See BioWorld Today, Sept. 2, 1999, p. 1.)

The VX-740 compound is in Phase II trials for RA. Vertex's collaboration with Taisho does not include any rights to the ICE inhibitors.

Vertex also has other candidates in the clinic to treat viral diseases, inflammation, cancer, autoimmune diseases and neurological disorders.

Its lead product, Agenerase (amprenavir), an HIV protease inhibitor co-promoted by London-based Glaxo Wellcome plc, was approved by the FDA in April to treat viral diseases. In October, Vertex's partner, Kissei Pharmaceutical Co. Ltd., of Matsumoto City, Japan, launched the product in Japan under the name Prozei.

Vertex's stock (NASDAQ:VRTX) closed Monday at $26.062, down 18.75 cents.