BioWorld International Correspondent

Shares in Actelion Ltd. dropped 12.5 percent Monday on news that clazosentan failed to demonstrate clinical benefit in patients who had experienced subarachnoid hemorrhage, despite attaining its primary endpoint of reducing cerebral vasospasm in a Phase IIb trial.

A preliminary analysis of the dose-finding study, which recruited 413 patients in 52 treatment centers located in 11 countries, demonstrated that all three intravenous doses - 15 mg/hour, 5 mg/hour and 1 mg/hour - reached statistical significance for the primary endpoint vs. placebo. The effect was dose-dependent. The highest dose led to a 65 percent risk reduction of cerebral vasospasm occurring vs. placebo.

Preventing cerebral vasospasm - or uncontrollable tightening of the brain blood vessels - is an accepted clinical intervention following hemorrhage and it is currently targeted by approved and unapproved treatments, some of which are highly invasive. "It is assumed that having vasospasm is bad," Isaac Kobrin, clinical director at Allschwil, Switzerland-based Actelion, said in a conference call.

However, the risk reduction following clazosentan infusion did not translate into any morbidity/mortality benefit, as measured in a secondary composite endpoint, which comprised death, the occurrence of new cerebral infarcts, development of delayed ischemic neurological deficit and a requirement for rescue therapy for vasospasm. There was no difference between placebo and any of the treatment groups for those parameters six weeks after the original event. Moreover, treatment with clazosentan, an endothelin receptor A antagonist, led to an elevated number of adverse events, such as hypotension and fluid retention.

"This is something that is puzzling. We have to look at the data, really analyze all aspects, in order to decide how to proceed. This is, in fact, what we are going to do in the next three to four weeks," Kobrin said. "Only then will we know whether we can continue or not."

The news increases the risk profile attached to Actelion, because the company still is largely dependent on its Tracleer (bosentan) franchise in pulmonary arterial hypertension.

"I think it's a combination of lack of apparent clinical benefit and a side-effect profile that tips the balance to the negative at the moment," Karl Heinz Koch, analyst at Geneva-based Lombard Odier Darier Hentsch, told BioWorld International. "They could have potentially filed on the basis of the Phase II study if they had shown a clinical benefit."

Actelion obtained clazosentan when it acquired neighboring firm Axovan AG in September 2003, in a cash deal worth up to CHF252 million (US$202.8 million), that was linked to certain milestones. Lombard Odier had forecast risk-adjusted revenues for the product of CHF400 million five years after approval.

"It's an area without many alternatives. Reducing a surrogate marker is potentially a valuable treatment option," Koch said. (See BioWorld International, Oct. 1, 2003.)

Karl Keegan, analyst at Canaccord Capital's London office, had forecast sales of CHF200 million for the product by 2011, which would have represented 15 percent of the company's turnover. Canaccord, accordingly, cut its target price Tuesday on the share from CHF135 to CHF118. Because of the recent share price drop, it is maintaining a hold recommendation on the stock.

Actelion has suffered several other late-stage disappointments. Efforts to pursue line extensions for Tracleer have failed so far, although several other studies in a range of indications are under way. Veletri failed in studies for acute heart failure and hepato-renal syndrome, and Palosuran failed in diabetic nephropathy.

The company has two products in early clinical development, one of which remains undisclosed. The compound, code-named Actelion-1, is in development for cardiovascular indications. Results from a Phase II trial are expected in the second half of the year.

"I suspect it's a Tracleer follow-on, without potential liver toxicity, which is the main risk to the existing franchise," Koch said.