West Coast Editor

As ICOS Corp. works to resolve issues with the FDA related to its erectile dysfunction treatment, the company's partnership effort with Texas Biotechnology Corp. has stopped an extension trial of sitaxsentan, its endothelin receptor antagonist for pulmonary arterial hypertension, because of liver abnormalities in patients.

Enrollment is complete in the Phase IIb/III trial with sitaxsentan, and patients from this trial had been eligible for the extension study.

Shares of ICOS (NASDAQ:ICOS) were not hit hard by the news, closing Tuesday at $15.01, down 49 cents, but Texas Biotechnology's stock (NASDAQ:TXBI) fell 24.6 percent, ending the day at $2.45, down 80 cents.

"For ICOS investors, it's a pretty small part of the story," said Philip Nadeau, vice president of SG Cowen in New York. "When I talked to the company, they were careful to say you couldn't draw any conclusions about the potential of the drug from this decision," he added.

"At a gross level, it doesn't really change too much about our impression of the drug," Nadeau told BioWorld Today. "These side effects have been known for this class of drug for quite some time."

Initial safety and efficacy results for the 12-week, Phase IIb/III trial are expected in the second half of this year, probably around October, but since that trial is still ongoing and the results are blinded, the risk-benefit profile of the drug can't be determined. Liver damage was seen in both trials, but in both trials was reversible.

"They know there's a certain risk of liver injury, and they want to be prudent and careful and not expose too many patients to the risk without being certain they're also conferring benefit," Nadeau said.

Bruce Given, president and CEO of Texas Biotechnology, told BioWorld Today that halting the extension trial "was the more appropriate way to go, even knowing it would probably be misread and misinterpreted, and was feeding into an environment where it's hard not to have news like this greeted rather harshly."

He added, "From a development program perspective, I don't think this means much of anything at all. We still don't know what the dose-response relationship is for safety or efficacy. Investors don't know any more today than they did six months ago."

ICOS and Texas Biotechnology said earlier that another, confirmatory pivotal trial would likely be necessary after this one, which is called the Sitaxsentan To Relieve Impaired Exercise in Pulmonary Arterial Hypertension, or STRIDE, trial.

Lacy Fitzpatrick, associate director of investor relations at ICOS, told BioWorld Today the results from the STRIDE trial "will enable us to make decisions on the next study."

In late April, the FDA sent Bothell, Wash.-based ICOS an approvable letter for its erectile dysfunction drug, Cialis, which asked for more pharmacology studies, sought talks on labeling matters and wanted ICOS partner Eli Lilly and Co.'s manufacturing deficiencies fixed. (See BioWorld Today, May 1, 2002.)

Cialis, which is a phosphodiesterase type 5 blocker like New York-based Pfizer Inc.'s popular Viagra (sildenafil citrate), provides the ability to achieve an erection some 24 to 36 hours after dosing, whereas Viagra works for only eight hours after dosing.

Meanwhile, the erectile dysfunction market threatens to grow more crowded. Bayer AG, of Leverkusen, Germany, has another PDE5 inhibitor, vardenafil, under review at the FDA. The 12-month deadline for action on vardenafil under the Prescription Drug User Fee Act guidelines is not until September, but Nadeau said he would not be surprised if Bayer got word from the agency before then - maybe as early as today.

"We can't be sure the FDA is going to give them the letter [today] but they gave ICOS the letter at 10 months," he said, noting that the agency apparently has been trying to make the 10-month "action date" when possible.

The question is whether the FDA will ask for more data from Bayer about vardenafil, as it did from ICOS regarding Cialis. ICOS's drug has a longer half-life than Bayer's, but the FDA's request for more studies with Cialis may have been based on more than that, so vardenafil could be in line for the same request, Nadeau said.

Fitzpatrick noted an approval application also has been filed in Europe.

"We could have a regulatory decision [in Europe] by the end of this year," she said.

For its part, Houston-based Texas Biotechnology has Argatroban (formerly Novastan, a small-molecule inhibitor of thrombin) being marketed by GlaxoSmithKline plc, of London, for heparin-induced thrombocytopenia. Studies are under way with the drug in ischemic stroke, angioplasty and hemodialysis.