BioWorld International Correspondent

Shares in Actelion Ltd. dropped 12.1 percent Monday on the Swiss Stock Exchange, on news that its endothelin receptor antagonist bosentan (Tracleer) failed to meet primary endpoints in two Phase II/III trials in pulmonary fibrosis.

However, the company reported a positive mortality/morbidity trend in one of the studies, involving patients with idiopathic pulmonary fibrosis, and it intends to pursue a confirmatory Phase III clinical trial in that indication.

Bosentan already is approved for treating pulmonary arterial hypertension but, with competition from several new products looming in 2006, Allschwil, Switzerland-based Actelion has sought to lessen its dependence on that franchise by building line extensions to the product.

Although it said it had a scientific rationale underpinning a possible role for the product in treatment of pulmonary fibrosis - a progressive set of conditions characterized by irreversible scarring of lung tissue - in the absence of definitive efficacy data, it decided to first assess bosentan's efficacy in a relatively small patient population using what Isaac Kobrin, head of clinical development, called a "softer endpoint," that of performance in a six-minute walk test. It also looked at several secondary endpoints, including morbidity, as measured by several criteria, and mortality, but the studies were not powered to provide conclusive evidence of efficacy with respect to those parameters.

It conducted double-blinded, randomized, placebo-controlled studies on 163 patients with pulmonary fibrosis secondary to the connective tissue disorder scleroderma, and on 158 patients with idiopathic pulmonary fibrosis, that is pulmonary fibrosis of unknown origin. The former condition is characterized by slow progression, with death occurring on average 10 years after diagnosis. The latter progresses more rapidly - death occurs within an average of three years after diagnosis.

In the scleroderma patient study, called Build-2, no effect was observed on either primary or secondary endpoints. The six-minute walk test, Kobrin said, may not have been an appropriate primary endpoint. "It is possible the disease is progressing too slowly for detecting a difference on secondary endpoints," he told a conference call audience. CEO Jean-Paul Clozel said the company has no further plans to pursue that indication.

The idiopathic pulmonary fibrosis study, called Build-1, yielded more promising data. Although bosentan again failed to meet its primary endpoint, it demonstrated a positive trend in several predefined secondary endpoints related to morbidity and mortality. It disclosed data on one endpoint - combined incidence of death or treatment failure at 12 months. That occurred at a rate of 36.1 percent in the placebo group, whereas in the bosentan group, the equivalent figure was 22.5 percent.

"I would like to emphasize that these results have been obtained without any subgroup analysis. This is the full evaluation of all the patients included in Build-1," Clozel said. "Looking at these data now, we have a very strong rationale for pursuing a morbidity/mortality Phase III confirmatory trial in idiopathic pulmonary fibrosis," he added.

The response to the news was mixed, particularly as the market, according to a research note from Canaccord's London office, had priced expectations of a positive outcome into the stock.

"In the short term, of course, the disappointment is greater than the enthusiasm you can see in a potential drug for idiopathic pulmonary fibrosis," said one Swiss analyst who declined to be named. But the scleroderma indication could be revisited, he said, if the idiopathic pulmonary fibrosis program were successful. "For me, if it works in idiopathic pulmonary fibrosis, there's no reason why it shouldn't work in scleroderma," he said.