By Matthew Willett

ICOS Corp. and partner Texas Biotechnology Corp. began recruiting patients in a pivotal Phase II/III trial of their oral endothelin A receptor antagonist, sitaxsentan.

The trial, named STRIDE (sitaxsentan to relieve impaired exercise in pulmonary hypertension), is designed to be a randomized, double-blind, placebo-controlled evaluation of sitaxsentan¿s efficacy and safety. The 180-patient trial¿s primary endpoint is a change in exercise capacity over a 12-week span, and also will measure improvements in six-minute walking distance, cardiopulmonary hemodynamics and quality of life.

¿Endothelin receptors are the subject of considerable interest in the vascular research community and the cardiovascular research community,¿ Michael Stewart, ICOS¿ vice president of clinical affairs, told BioWorld Today. ¿The A¿ receptor mediates vascular tone. It really affects the musculature of the small muscles in the artery that are responsible for vascular tone. In this particular disease, pulmonary arterial hypertension, it¿s believed there is an excessive vascular tone, and using a molecule like this that blocks the receptor for endothelin A is one way to interfere with high arterial pressure.¿

Previous trials have shown an improvement, Stewart said, in exercise capacity. A 20-patient trial the company reported on last year indicated sitaxsentan improved patients¿ ability to exercise, as measured by walking distance, by more than 10 percent (p=0.006).

ICOS, of Bothell, Washington, estimates pulmonary arterial hypertension affects about 100,000 people worldwide.

ICOS agreed to co-develop sitaxsentan with Texas Biotechnology Corp., of Houston, just under a year ago in a joint venture deal that included a $2 million up-front payment to Texas Biotechnology. All told, the deal could be worth up to $55.5 million to Texas Biotechnology. (See BioWorld Today, June 7, 2000.)

The move to a pivotal trial does trigger a milestone payment for Texas Biotechnology, ICOS¿ vice president of business development, Clifford Stocks, said. That payment¿s size is undisclosed, he said.

¿It¿s a 50-50 worldwide joint venture to develop the endothelin antagonist class, of which this therapeutic is a part,¿ Stocks said. ¿The commitment that we¿ve made to Texas to form the joint venture, which occurred about a year ago, was that we would give them a $2 million up-front fee and commit to further milestone payments of about $53.5 million directly to Texas based on events, including multiple indications.¿

Stewart said he couldn¿t estimate when ICOS might be in position to submit data for regulatory approval. That, he said, will depend on the data from the pivotal trial. ¿That will certainly depend on the results and the magnitude of the results and how quickly we come to a conclusion,¿ he said. ¿If we find out we have a drug that benefits patients with this life-threatening disease, we¿ll move as rapidly as possible to try and submit.¿

In other areas in the ICOS pipeline the company is focused on development of Cialis, a PDE5 inhibitor, and Pafase, a therapeutic candidate under investigation in sepsis.

Cialis, under development in a joint venture with Eli Lilly & Co., of Indianapolis, named Lilly ICOS LLC, proved effective in a Phase III trial evaluating the erectile dysfunction therapeutic in men with diabetes-associated erectile dysfunction.

Pafase (rPAF-AH), under joint development with Suntory Ltd., of Japan, entered a Phase III trial in severe sepsis in April.

At the end of the first quarter ICOS reported $216.2 million in cash, cash equivalents and investment securities available for sale. It reported $18.9 million in revenues, and a net loss of $15.2 million, or 29 cents per share.

ICOS¿ shares (NASDAQ:ICOS) fell $1.25 Wednesday to close at $62.15. Texas Biotechnology¿s stock (AMEX:TXB) fell 55 cents to close at $8.15.

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