By Kim Coghill

Washington Editor

Patients suffering from pulmonary arterial hypertension (PAH) will be one step closer to relief if the FDA¿s Cardiovascular and Renal Advisory Committee gives its stamp of approval to either of the two companies requesting recommended approval of its new drug application.

Silver Spring, Md.-based United Therapeutics Corp. (UTC) today will present data for Remodulin (formerly Uniprost and UT-15), a subcutaneous treatment for PAH, while Friday, Actelion Ltd., of Switzerland and South San Francisco, will present its case for Tracleer (bosentan), an oral treatment being developed with Genentech Inc. for the same indication. Both drugs have received orphan status.

The U.S. market is about 30,000 to 50,000 patients, and in other areas of the world, studies show there are another 50,000 patients. Simon Buckingham, Actelion¿s U.S. president, characterized PAH essentially as high blood pressure in the lungs. ¿These patients can¿t pump blood through their lungs sufficiently enough to get enough oxygen to be able to exercise sufficiently and to be able to do the normal daily things of life,¿ he told BioWorld Today. ¿Ultimately, the patients either have to go on intravenous therapy or they have a lung transplant.¿

Flolan, GlaxoSmithKline plc¿s continuous intravenous formulation of prostacyclin, is the only currently approved drug for PAH.

UTC submitted its new drug application (NDA) for Remodulin on Oct. 16, 2000, and pursuant to the Prescription Drug User Fee Act (PDUFA), FDA action was required no later than July 16. Initially, an advisory committee meeting to hear the application was scheduled Feb. 9, but in mid-December the FDA informed UTC that a hearing would not be necessary. (See BioWorld Today, Dec. 18, 2000.)

Sometime thereafter, a meeting was rescheduled and according to a prepared statement by the company, ¿The fact that the advisory committee meeting falls almost a month after the deadline, requires UTC to withdraw its NDA and resubmit it upon a favorable advisory committee recommendation the following day, Aug. 10.¿

UTC representatives could not be reached Wednesday for comment.

Remodulin (UT-15) is an analogue of prostacyclin, a molecule produced naturally within the body to keep blood vessels healthy. The company is expected to present data from two Phase III multicenter, double-blind, parallel-group trials. The primary endpoints of both studies were change in exercise capacity as measured by distance walked in six minutes.

A briefing document released Wednesday by the FDA said, ¿UT-15 did not meet its primary endpoint in the pivotal portion of its development program probably because its effects on exercise tolerance are smaller than expected. UT-15 doses rise progressively with time of exposure; the explanation for this is not known. The use of UT-15 is limited by tolerance to pain and local reaction at the site of infusion. There are no other safety issues, but UT-15 probably lacks Flolan¿s apparent benefits on mortality.¿

UTC¿s stock (NASDAQ:UTHR) closed Wednesday at $8.81, down $3.54, or 28.7 percent.

The company¿s past year has been marked by several ups and downs, including a 62 percent drop in stock in December after it released data saying revenues for UTC-15¿s first six months were expected to be $10 million to $20 million. Analysts had expected $80 million. (See BioWorld Today, Dec. 5, 2000.)

Actelion Expecting The Best

Two days before the Actelion hearing, Buckingham said he was feeling rather confident. ¿We¿re as confident as one can be. It¿s still up to the committee and the FDA to decide. If the committee votes in favor, we still have to work with the FDA. But we are going in with a strong case.¿

Buckingham hopes for a fourth-quarter launch.

Actelion has a partnership with South San Francisco-based Genentech for the co-promotion of Tracleer for pulmonary arterial hypertension and chronic heart failure in the U.S., with Actelion taking the lead in development and commercialization, Buckingham said. Tracleer is in Phase III trials for chronic heart failure.

Results from two successful Phase III pivotal studies of Tracleer in PAH will be presented at Friday¿s meeting, Buckingham said. In both studies, he said, the company met its endpoint of improving exercise capacity in participating patients.

The largest trial, called BREATHE-1 (Bosentan: Randomized Trial of Endothelin Receptor Antagonist Therapy for Pulmonary Hypertension), was a double-blind, placebo-controlled, multicenter study designed to evaluate the safety and efficacy of two twice-daily dose levels of Tracleer.

Patients receiving the medicine were able to walk statistically significantly greater distances in the six-minute walk test after 16 weeks, compared to placebo. The product also was well tolerated, according to the company.

The other study was a double-blind, placebo-controlled trial involving 32 patients at six centers (five in U.S. and one in France). At 12 weeks patients in the Tracleer group demonstrated a 20 percent increase in exercise ability compared to placebo in the standardized six-minute walk test (p=0.018). Tracleer patients improved their timed walk distance by a mean of 72 meters and there was a 40 percent net difference in cardiac output in favor of Tracleer compared to placebo.