Actelion’s efforts to build a new drug portfolio that can ease the company’s dependence on its mainstay Tracleer (bosentan) have hit another snag after a Phase III clinical trial with the endothelin receptor antagonist clazosentan failed to meet its primary endpoint.
Initial results from the CONSCIOUS-2 (Clazosentan to Overcome Neurological iSChaemia and Infarct OccUrring after Subarachnoid haemorrhage) study showed a non-significant relative risk reduction of 17% versus placebo for the primary endpoint of vasospasm-related morbidity and all-cause mortality in clipped patients following aneurysmal subarachnoid hemorrhage (aSAH).
The safety profile of clazosentan in CONSCIOUS-2 was comparable to that seen in previous studies with the compound in aSAH, Actelion noted. But the disappointing efficacy outcome of what chief executive officer Jean-Paul Clozel described as “such a complex study, both in terms of design and execution” sent Actelion’s shares tumbling by around 8%. It also cast doubt both on another late-stage trial with clazosentan and the wider development programme for the drug.
“Actelion will continue to focus on growing its existing business,” Clozel stated. With four marketed products, he added, the Swiss biopharmaceutical company is “generating the necessary revenues to continue to invest appropriately in clinical studies for our more than 10 development compounds”.
In March, Actelion abandoned the clinical development of bosentan as a potential treatment for idiopathic pulmonary fibrosis when results from the BUILD-3 (Bosentan Use in Interstitial Lung Disease) trial fell short of the primary endpoint of reducing morbidity/mortality.
CONSCIOUS programme
CONSCIOUS-2 was a global study involving more than 1,150 patients from over 100 centres with aSAH and aneurysmal surgical clipping. Participants were randomised 2:1 to either 5 mg/hour of clazosentan or placebo.
The trial followed CONSCIOUS-1, a multi-centre, randomised, placebo-controlled study that assessed the efficacy of clazosentan 15mg/hour, 5mg/hour and 1mg/hour in preventing cerebral vasospasm following aSAH in patients who had undergone either clipping or coiling to stop initial bleeding.
In CONSCIOUS-1, Actelion pointed out, clazosentan significantly reduced moderate/severe vasospasm at all the doses tested, with a relative risk reduction of 65% versus placebo at the highest dose. Treatment with clazosentan was, however, associated with a higher rate of adverse events than placebo, mainly related to vasodilatory effects such as hypotension and fluid retention.
The company must now decide whether to carry on with the CONSCIOUS-3 trial, which has an identical primary endpoint to CONSCIOUS-2. This is a Phase III study evaluating the efficacy and safety of two doses of clazosentan (5mg/hour or 15mg/hour) against placebo in patients post-aSAH who have been treated with endovascular coiling. As of the end of September 2010, CONSCIOUS-3 had enrolled close to 600 patients out of a target of 1,500.
Actelion said it would “discuss the appropriate course of action” with the steering committee for the trial. It would provide an update on the clazosentan development programme when third-quarter results are presented on 21 October 2010.
Reuters quoted Sarasin analyst David Kaegi as saying that CONSCIOUS-2 had been “potentially the most important catalyst for Actelion shares this year”, citing prospective sales of SwFr 500 million to SwFr 1 billion for the drug.
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