BioWorld International Correspondent

Swiss drugmaker Actelion Ltd. is seeking a second orphan designation for its flagship product, Tracleer (bosentan), having obtained positive safety and efficacy data in a clinical study of scleroderma patients suffering from digital ulcerations.

Allschwil-based Actelion performed a double-blind, placebo-controlled trial of 122 patients in 14 centers in the U.S., Canada, France, Germany, Italy and the UK. Two-thirds of the subjects received 62.5 mg of drug for four weeks followed by 125 mg of drug for 12 weeks, while the rest received placebo. A three-month, open-label, follow-up treatment is ongoing. According to a preliminary analysis of the data, the primary endpoint of the study - prevention of new ulcer formation - was achieved. The result, the company said, is highly statistically significant. "When I say highly statistically significant,' I mean a p' value of less than 0.01," Michael Gaitonde, head of medical marketing for Europe, told a conference call audience.

Tracleer, an endothelin receptor antagonist, gained FDA approval last November as the first oral treatment for pulmonary arterial hypertension, a condition that can arise independently or in association with the connective tissue disorder scleroderma (see BioWorld International, Nov. 28, 2001). About 25 percent of scleroderma patients, according to Actelion, suffer from ischemic digital ulceration, which arises due to blockage of small blood vessels on the fingers and toes. These painful, slow-to-heal open sores impair patient function and quality of life and can give rise to secondary complications such as infection and, if untreated, gangrene. Current therapy, Actelion said, consists of prophylactic intravenous infusion of prostacyclins such as Flolan or Iloprost.

Several scientific observations underpinned the rationale for the study, including an increase in endothelin concentration in Raynaud's phenomenon and systemic sclerosis; the involvement of endothelin in vascular fibrosis and vasoconstriction; and the release of endothelin by scleroderma fibroblasts in vitro. Moreover, individual case reports from the study of Tracleer in pulmonary arterial hypertension patients indicated a potential benefit for those with digital ulcers.

The company plans to communicate the complete results of the digital ulceration study, Rapids-1, shortly. Meanwhile, it is entering talks with the FDA and other regulatory authorities on how to proceed with a regulatory filing. "If we are allowed to file with one trial and get an indication, this would be great," Head of Clinical Development Isaac Kobrin said in the conference call. However, Actelion plans to be ready to commence a second trial this winter, if required to do so. "What is clear is we wish to pursue an indication," Head of Corporate Communications Roland Haefeli told BioWorld International.

The Rapids-1 trial is the first additional indication Actelion has explored for Tracleer. "It is clear these are highly important findings because they help us to grow into the secondary market as fast as possible," Haefeli said.

Actelion is lining up additional clinical projects for Tracleer, including a study of the drug in pulmonary fibrosis in scleroderma, which may commence by year's end or early in 2003, Haefeli said. It is designing a protocol for a trial of Tracleer in idiopathic pulmonary fibrosis, although that will not get under way until data from a Phase III trial of Actimmune (interferon gamma-1b) in the same condition, which is being conducted by InterMune Pharmaceuticals Inc., of Brisbane, Calif., becomes available.

It also is evaluating the potential of Tracleer in metastatic malignant melanoma, a move that would take it outside its core areas of expertise in endothelin-related disorders and cardiovascular disease. That may involve a collaboration with a third party. "That is definitely one of the questions we are evaluating," Haefeli said.