By Cormac Sheridan

BioWorld International Correspondent

Swiss biopharmaceutical firm Actelion Ltd. reached a significant milestone last week, receiving its first FDA approval as it gained marketing clearance for Tracleer (bosentan) in pulmonary arterial hypertension (PAH).

The decision also marks the coming of age of a new drug category, endothelin receptor antagonists. They act by blocking the uptake by endothelin receptors of the peptide hormone endothelin. Levels of endothelin, a potent vasoconstrictor, are elevated in the plasma and lung tissue of PAH patients and are thought to limit normal blood flow, leading to severe shortness of breath, chest pain and fainting. In untreated patients, life expectancy can be as short as two years from the onset of symptoms.

Allschwil-based Actelion said the true incidence of PAH is unknown, but it cites one study that estimates a total of just 100,000 sufferers in the U.S. and Europe. Tracleer, which Actelion originally licensed from F. Hoffmann-La Roche Ltd., of Basel, Switzerland, is indicated to improve exercise ability and decrease the rate of clinical worsening in PAH patients with significant limitation of physical activity. Because of liver toxicity effects and potential fetal damage during pregnancy, it will be available only through a direct distribution program run by Actelion Pharmaceuticals US Inc., of South San Francisco.

¿We do expect that next year we should be able to access 3,000 to 3,500 [patients] on a full-year-equivalent basis,¿ said company spokesman Roland Haefeli. Tracleer is the subject of additional reviews in the European Union, Canada, Switzerland and Australia. ¿We expect to have peak sales of 30,000 at around 2006,¿ Haefeli said.

The company has priced the drug at US$28,500 per patient per annum in the U.S., ¿which was higher than we expected,¿ said analyst Markus Metzger at the Cologne office of Bank Vontobel AG, of Zurich. Metzger said he had anticipated a price of around CHF30,000 (US$18,000) per patient. However, total sales will be offset by Actelion¿s undertaking to provide Tracleer for free to patients who cannot procure reimbursement. ¿What you have to keep in mind, the reimbursement will only be in the range of 70 [percent] to 80 percent,¿ Metzger said.

The only other FDA-approved treatment, London-based GlaxoSmithKline plc¿s formulation of epoprostenol (Flolan), has considerable delivery disadvantages. It requires continuous intravenous infusion and, Haefeli said, costs an average of US$100,000 per patient per annum.

Tracleer also is undergoing Phase III clinical trials in congestive heart failure (CHF), and is in clinical development for additional undisclosed indications. Actelion is due to report on the CHF study, called Enable, in the first quarter next year.

Genentech Inc., of South San Francisco, has an option to become Actelion¿s co-marketing partner for Tracleer in all indications. But that is linked to the outcome of the CHF study. ¿In order for the option to be exercisable at all, Enable must be positive,¿ Haefeli said.

Actelion has forecast peak annual sales of about US$450 million for Tracleer in PAH. Just over 10 percent of this figure would flow to Roche and Genentech. However, Genentech will shift to a shared-cost, shared-revenue model should it decide to exercise its option.

Actelion currently has CHF170 million in cash and a monthly burn rate of CHF10 million, Haefeli said. ¿With the sustained revenue stream that is coming online now, our cash position is sufficient to finance all current projects,¿ he said. ¿In 2003 we are getting very close to breakeven and in 2004 it is a full year of profit.¿

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