Encysive Pharmaceuticals Inc. plans to file a new drug application in April based on pivotal Phase III data showing that Thelin met its primary endpoint in pulmonary arterial hypertension.

Not only did the drug, at a 100-mg dose, demonstrate a statistically significant improvement in six-minute walk distance, but it showed safety benefits, as well as a positive trend in the time to clinical worsening endpoint, compared with placebo and a control arm.

"I think it's really good news for the company," said Matt Kaplan, an analyst with New York-based Punk Ziegel & Co. "I think the clinical trial risk is out of the story now. Their second pivotal trial worked. It was clearly effective. They beat Tracleer numerically in terms of the six-minute workout, the time to clinical worsening, and Thelin appeared to have a better safety profile in terms of liver toxicities."

Tracleer (bosentan) therapy served as the control arm of the trial. Approved in 2001, the product was developed by Allschwil, Switzerland-based Actelion Ltd. and is the only approved oral agent for treating pulmonary arterial hypertension (PAH).

Encysive's 246-patient trial, known as STRIDE-2 (Sitaxsentan to Relieve Impaired Exercise), was a double-blind, randomized, placebo-controlled study of Thelin with an open-label bosentan arm. Patients received one of four treatments: Thelin at 50 mg or 100 mg once daily, placebo once daily, or bosentan twice daily. The study was conducted at 55 centers in North America, Europe, Israel and Australia.

"This trial was done under a special protocol assessment with the FDA," Encysive's president and CEO, Bruce Given, told BioWorld Today. "So the trial design, the endpoint, the statistics were all pre-negotiated with the agency. We think we hit all of our marks."

So did investors. The company's stock (NASDAQ:ENCY) rose about 12.3 percent Monday, or $1.29, to close at $11.80. Analysts agreed that the efficacy data were strong and that Thelin appeared to be superior to Tracleer in terms of safety.

"There's no reason, based on this data, that this drug shouldn't be approved," Kaplan said.

He estimated Thelin could bring by 2010 U.S. sales of $200 million-plus, or worldwide sales of $365 million, based on a conservative market of about 50,000 people each in the U.S. and in Europe.

STRIDE-2 data showed that Thelin, at the 100-mg dose, met the improvement in the six-minute walk distance primary endpoint, with a placebo-subtracted improvement of 31.4 meters (p=0.03). At the 50-mg dose, Thelin improved the walk distance by 24.2 meters, while bosentan improved it by 29.5 meters. Placebo patients did worse on the six-minute walk distance as the 18-week trial progressed.

While the 50-mg dose was not effective in adults, Given said it might be reconsidered in the future for a pediatric indication. Encysive plans to file the NDA in April, seeking an adult dose of 100 mg for approval of Thelin. The company will present detailed data in May at the American Thoracic Society meeting in San Diego, and it will file regulatory applications in Europe this summer.

"We own 100 percent of this compound," Given said. "No royalties, no residuals of any kind. A rarity in our industry."

Encysive plans to market the product in the U.S., but might partner it in Europe.

"The reality is, with a small sales force, you could very easily address the worldwide, or the U.S., market," Kaplan said, adding that Actelion markets Tracleer with about 150 people worldwide.

The top-line data of Thelin reported Monday also demonstrated an improved World Health Organization functional class when compared to placebo (p=0.04). The 50-mg dose of Thelin and bosentan did not reach statistical significance.

The bosentan group had more clinical worsening events, 15 total in nine patients, as compared to five events seen in four patients on 100 mg of Thelin. There were seven events in Thelin's 50-mg group and 13 events in the placebo group.

"The time to clinical worsening endpoint was not significant for any treatment," Given said, "although the Thelin 100-mg dose trended toward significance with a p' value of 0.08."

He said the collective data from three trials, STRIDE-1, STRIDE-2 and STRIDE-4, might help the company achieve a "p" value for the time to worsening endpoint, but Given is not sure whether that would be sufficient for the label.

Liver function abnormalities occurred in 3 percent of patients in Thelin's 100-mg group, 5 percent in the 50-mg group, 11 percent in the bosentan group and 6 percent in the placebo group. The largest elevations in liver enzymes occurred in placebo patients at 30.5 times the upper limit of normal, Given said, and in bosentan patients at 16.8 times the upper limit of normal.

Two patients in the 100-mg group, four in the 50-mg group and six in each the bosentan and placebo groups discontinued the trial due to adverse events. Premature discontinuations due to safety or efficacy occurred in four patients in the 100-mg group, eight in the 50-mg group, nine in the bosentan group and 11 in the placebo group.

"This is our third straight placebo-controlled trial where the 100-mg dose of Thelin yielded the smallest number of discontinuations in the overall trial," Given said.

A small molecule that blocks the action of endothelin, Thelin is a mediator of blood vessel constriction and growth of smooth muscle in vascular walls.

However, it does inhibit the metabolism of warfarin, a rat poison used as a blood thinner. When the two are co-administered, a decreased dose of warfarin is needed. Tracleer also interacts with warfarin, requiring an increased dose of the blood thinner, Kaplan said.

"In each case, patients have to be monitored," he said.

Other PAH products on the market are Silver Spring, Md.-based United Therapeutics Corp.'s Remodulin, which received approval in 2002, and South San Francisco-based CoTherix Inc.'s inhaled product Ventavis, which was approved last month.

If approved, Thelin would become Encysive's second approved product. The company gained approval in 2000 for Argatroban, which is marketed by London-based GlaxoSmithKline plc for heparin-induced thrombocytopenia.

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