BioWorld International Correspondent

Actelion Ltd. lost almost one-quarter of its value Monday following news that it halted a Phase III trial of its drug for acute heart failure, Veletri, after an interim analysis indicated that it would fail to attain its primary endpoints.

More than 2.25 million Actelion shares changed hands during trading on the Swiss Stock Exchange Monday. By the close, Actelion had dropped CHF37.50 to CHF115.50 (US$97.79).

An independent safety committee met Saturday for a second interim analysis of data from the so-called Veritas (Value of Endothelin Receptor Inhibition with Tezosentan in Acute Heart Failure Study) trial. It was designed to assess the efficacy of Veletri (tezosentan) with respect to both mortality/morbidity and dyspnea. By early October, about 1,300 patients had enrolled in the study, all of whom received standard therapy plus either Veletri or placebo. Although positive hemodynamic effects were observed in the treatment arm, the committee concluded that the possibility of the study attaining at least one of the primary endpoints with statistical significance was too remote to justify its continuation.

Speaking on a conference call Monday, Actelion officials were at a loss to explain what happened.

"Here we have a clear hemodynamic benefit, without tachycardia, without increased myocardial oxygen consumption and without any visible side effects, and we cannot see a benefit," said CEO Jean-Paul Clozel. "I really think it's a unique case, and I think it's very surprising."

Sally Bennett, senior biotechnology analyst at ING's London office, had been skeptical.

"We only had a 30 percent probability factor for this product," she told BioWorld International. "Acute heart failure is a notoriously difficult condition. I think no drug has ever shown a survival advantage."

The company plans to complete analysis of the data it has generated, but, said Head of Clinical Development Isaac Kobrin, it does not plan to continue development of Veletri in acute heart failure or in other indications on the basis of its hemodynamic activity.

The failure of Veletri will give a short-term boost to the company's bottom line, as it saves on additional trial costs and pre-marketing spending, but it must now look elsewhere for additional growth.

"Veletri would have given them growth well beyond 2007, but there are other things in the pipeline that could secure that long-term growth," Bennett said.

The results of six late-stage clinical trials are due to be reported during the next 15 months. Most represent line extensions to its two marketed products, Tracleer and Zavesca, which, respectively, are approved for treatment of pulmonary arterial hypertension and Type I Gaucher's disease. A Phase IIb/III trial of clazosentan in subarachnoid hemorrhage is about to get under way in Europe, as well.

"We expect to see first patients in the trial by the end of the year," Kobrin said. "We are still discussing wording issues with the FDA in order to proceed with the trial also in the U.S."

Bennett remains cautious on the program, too, as the target indication there also is very difficult.

"You shouldn't be buying into the stock on the basis of clazosentan alone," she said.