BioWorld International Correspondent
Despite the apparent failure of clazosentan (Pivlaz) to demonstrate clinical benefit in a Phase IIb study last year, Actelion Ltd. is moving the endothelin receptor antagonist into a pivotal Phase III trial to evaluate its effect on reducing vasospasm-related morbidity and mortality in patients at risk of vasospasm following aneurysmal subarachnoid hemorrhage.
All three doses of the compound attained the primary endpoint of reducing cerebral vasospasm in the 413-patient Phase IIb trial last year, although, on initial reading, it failed to translate into the hoped-for clinical benefit. However, a subsequent analysis revealed that a failure to distinguish between vasospasm-related morbidity and morbidity arising from the initial hemorrhage was the problem. (See BioWorld International, June 21, 2006.)
"Absence of trend was not due to medical reasons but was due to the way the data were read," Actelion spokesman Roland Haefeli told BioWorld International. "We actually did see the benefit once we had the secondary analysis done."
The discrepancy arose, he said, because the trial data were interpreted in a decentralized fashion. When a centralized reading by key experts was conducted, "the variability disappeared," he said, although the study was not powered to demonstrate statistical significance.
Every year, more than 80,000 people in the U.S., the European Union and Japan have an aneurysmal subarachnoid hemorrhage, with bleeding into the area surrounding the brain. Some two-thirds of those, Actelion said, are at risk of experiencing vasospasm, an uncontrollable tightening of the brain blood vessels that can lead to permanent disability or death. Existing treatment options are limited.
The rationale for using an endothelin receptor antagonist is based on the fact that endothelin is a potent vasoconstrictor, and elevated levels of the compound have been observed in the cerebrospinal fluid of individuals who have experienced vasospasm.
The upcoming study, called CONSCIOUS-2 (Clazosentan to Overcome Neurological Ischemia and Infarct Occurring after Subarachnoid Hemorrhage 2), will recruit a minimum of 765 patients via 100 centers in the European Union, Canada, Asia, Australia and New Zealand. Discussions with the FDA are ongoing, Allschwil, Switzerland-based Actelion said, and the company hopes to add an additional 24 centers in the U.S.
Recruitment will be limited to what Actelion described as "a well-defined, homogenous population consisting of those who have had their aneurysm clipped" (that is, secured by surgery). Analyst Denise Anderson, of Kepler Equities in Zurich, said the overall morbidity and mortality data in the earlier Phase IIb study might have been influenced both by the diversity of the patients enrolled and by the diversity of treatments employed. So, for the Phase III trial, "they are going to narrow those parameters down," she told BioWorld International.
Patients will be randomized, in a 2-to-1 ratio, to receive 5 mg per hour of clazosentan - the middle dose from the Phase IIb study - or placebo, administered intravenously over 14 days following an episode of aneurysmal subarachnoid hemorrhage. Results from the study could become available by the second half of 2009.
As yet, Anderson is not attaching any value to the program, apart from its contribution to Actelion's overall pipeline valuation. "It is a very risky trial. It is a very difficult condition to treat," she said. Moreover, the fact that the "FDA is not on board yet" is "disappointing," she added.
"It's not about the analysis, but we have been in discussions with the FDA for a long time about the trial itself," Haefeli said.
The move triggers a milestone payment of CHF15 million (US$13.3 million) to former shareholders of Axovan AG, also of Allschwil, which Actelion acquired in 2003.
Shares in Actelion on the Swiss Stock Exchange (ATLN) closed at CHF50.80 Monday, the day the news was disclosed, down CHF1.20 from Friday's close of CHF51.60.