By Aaron Lorenzo

Actelion Ltd. celebrated Thanksgiving with the news that the FDA approved its active endothelin receptor antagonist Tracleer (bosentan) for the treatment of pulmonary arterial hypertension (PAH).

¿For a biotech company that started less than four years ago and [with] our first product on the market, it¿s a very significant day for us,¿ said Simon Buckingham, the president of South San Francisco-based Actelion Pharmaceuticals U.S. ¿This is a first-in-class drug. It¿s an orally active, endothelin receptor antagonist. It is, in fact, the first oral drug approved for treating pulmonary arterial hypertension.¿

Tracleer is designed to improve exercise ability and decrease the worsening rate of PAH patients with significant limitation of physical activity. Levels of endothelin, a blood vessel constrictor, are elevated in the plasma and lung tissue of patients with PAH, suggesting a pathogenic role for endothelin in the progression of this condition. Tracleer blocks the binding of endothelin to its receptors, preventing the effects of endothelin upon blood vessels.

Current treatment involves an exhaustive, cumbersome option.

¿Pulmonary arterial hypertension is a severe, life-threatening disease that can really cripple patients¿ hearts and lungs,¿ Buckingham said. ¿Up until now, the only approved therapy has involved a continuous intravenous infusion of a drug called Flolan (epoprostenol), which has to be administered directly through a central line into a patient¿s heart and has a lot of side effects, and also a lot of inconvenience.¿

Taken twice a day at 125mg, Tracleer is expected to be available to U.S. patients in early December.

¿We expect, potentially worldwide, that we¿ll be able to treat upwards of 20,000 to 30,000 patients on this medication,¿ Buckingham said. ¿We believe that that¿s feasible with the size of this indication and the lack of alternative therapies. Having said that, we believe that by peak, say, five years from now, I think this drug has the potential to do anywhere from $400 [million] to perhaps even $500 million.¿

The drug is also in Phase III trials to investigate its potential as a possible treatment of chronic heart failure (CHF).

¿We¿ve got a very large trial, a morbidity and mortality trial, in chronic heart failure,¿ Buckingham said. ¿We¿ll have the results in the first quarter of next year. That¿s obviously a larger target population, but again, we¿re looking at a very severely ill group of heart failure patients.

¿I think even beyond heart failure, this is real proof that the concept of antagonizing endothelin ¿ particularly its vasoconstrictive effects, potentially also its fibrotic effects ¿ has real promise in other areas as well,¿ he said.

As part of a deal signed a year ago, South San Francisco-based Genentech Inc. now has the option to become a co-promotion partner for Tracleer in both indications in the U.S., though Genentech will be more involved in the CHF indication.

¿The real economic value for Genentech of its partnership with Actelion lies in the much larger market opportunity in CHF,¿ Dennis Harp, an analyst for Deutsche Banc Alex. Brown, said in a written statement.

The companies will develop and co-promote Tracleer in the U.S. The deal included an up-front payment of $35 million from Genentech, plus additional milestone payments that could increase the total to $140 million for Actelion, of Allschwil, Switzerland. (See BioWorld Today, Dec. 14, 2000.)

¿The relationship that we have with Genentech is primarily directed toward the chronic heart failure indication,¿ Buckingham said. ¿The pulmonary hypertension application, we will launch that ourselves. Genentech is still involved in some aspects of marketing program development, but essentially this is an Actelion launch in relation to sales and distribution.¿

The FDA approval to treat PAH is based on two pivotal trials, the larger of which was called BREATHE-1. In the 213-patient trial, twice-daily Tracleer (125 mg and 250 mg) showed statistically significant improvements versus placebo in the primary efficacy endpoint of exercise capacity. The overall treatment effect was a 44-meter improvement in walking distance as measured by a six-minute walk test (p=0.0002). Treatment with Tracleer also was associated with a significant delay in the time to clinical worsening, defined as death, hospitalization, worsening PAH or initiation of intravenous therapy (p=0.0015), as well as significant improvement in functional status and breathlessness.

A 32-person study recently published in The Lancet demonstrated that patients receiving Tracleer had significant improvements in exercise capacity and hemodynamics (blood circulation). Studies showed approximately 11 percent of Tracleer patients experienced abnormal but reversible liver enzyme elevations, meaning patients must undergo monthly liver monitoring. Due to the risk of birth defects, women who are or may become pregnant cannot take the drug.

Actelion submitted an NDA for pulmonary arterial hypertension to the FDA last November and to the European authorities in February. Tracleer also is under review in Switzerland, Canada and Australia. Authorities in the United States, the European Union and in Australia have granted Tracleer orphan drug status in PAH. The company also is studying Tracleer for children under the age of 12 suffering from PAH, as well as the concomitant use of Tracleer in patients who receive intravenous prostacyclin therapy.

Actelion is publicly traded on the Swiss Stock Exchange (SWX:ATLN). Genentech¿s stock (NYSE:DNA) dropped 25 cents Wednesday to close at $55.15.