Shares in Switzerland’s Actelion took another battering after the company announced that a clinical trial aimed at expanding the indications for the company’s mainstay drug bosentan (Tracleer) had failed to meet its primary endpoint.

Actelion said it would no longer be pursuing development of bosentan as a potential treatment for idiopathic pulmonary fibrosis (IPF), a progressive and usually fatal lung disease.

The company’s shares dropped by more than 18% on the news, which was a marked setback in Actelion’s efforts to broaden the Tracleer palette and ease its reliance on the core indication of pulmonary arterial hypertension (PAH). According to Reuters, Actelion had expected approval of Tracleer for IPF to double sales of the drug, currently running at SwFr 1.51 billion a year.

The company’s shares had already been hit hard last December when Actelion unveiled mixed data, including safety concerns, from a Phase III clinical trial of its investigational insomnia drug, almorexant.

The latest announcement concerned BUILD-3 (Bosentan Use in Interstitial Lung Disease), a 616-patient trial looking at the safety and efficacy of the dual endothelin receptor antagonist in IPF patients. Initial results showed that, while there was a consistent trend in favour of bosentan, BUILD-3 did not meet its primary endpoint of reduction in morbidity/mortality.

Jean-Paul Clozel, chief executive officer of Actelion, confirmed that the findings “do not support initiating regulatory proceedings”. Helvea analyst Olav Zilian was cited by Reuters as noting that “the reported trend is so weak that we do not believe doctors will consider using the drug off-label in these severely sick patients”.

According to Clozel, Actelion remains convinced that endothelin receptors “are important targets for potential future treatments in this poorly understood and rapidly progressing form of pulmonary fibrosis. The results of BUILD-3 suggest that a more complete blockade of both endothelin receptors – as potentially achieved with macitentan – might be needed”.

Macitentan is a “highly potent”, tissue-targeting endothelin receptor antagonist discovered in-house at Actelion. The drug is in a Phase III study (SERAPHIN) for symptomatic PAH but is also being investigated as a potential treatment for IPF. A 10-patient exploratory study of macitentan in IPF is expected to be fully enrolled later this year, reporting data in the second half of 2001.

In the meantime, Clozel underlined Actelion’s strong commitment both to PAH and “innovation in general”, with a total of 11 compounds in various stages of clinical development. In the second half of this year, the company is expecting results from the late-stage CONSCIOUS-2 trial, evaluating the safety and efficacy of clazosentan in non-traumatic subarachnoid haemorrhage following aneurysmal clipping.