Myogen Inc. had hoped to complete enrollment in its Phase III trials of ambrisentan in pulmonary arterial hypertension by mid-year, but the company reported a six-month delay in enrollment due to difficulties finding the right patients.

Shares of Myogen (NASDAQ: MYOG) fell $1.92 Thursday, or 21.3 percent, to close at $7.08.

Myogen began enrollment in January 2004 for its two 186-patient Phase III trials of ambrisentan, a Type A selective endothelin receptor antagonist. The ARIES-2 trial, being conducted in Europe and South America, remains on schedule, with enrollment to be completed in the middle of the year and results available around the end of 2005. But enrollment in ARIES-1 is "going more slowly than we hoped," said Joe Turner, Myogen's chief financial officer and senior vice president of finance, attributing the delay to a decline in available treatment-na ve patients.

The Denver-based company said it now expects to complete enrollment in the ARIES-1 trial in North America and Australia by the end of the year, with results to be available six months later, Turner said.

"What we're seeing is that fewer patients are coming in to the tertiary referral centers without already being on a drug," he told BioWorld Today. "There are oral drugs that are coming into this market, like Tracleer, which is increasing its penetration."

Tracleer, a dual endothelin antagonist receptor developed by Allschwil, Switzerland-based Actelion Inc., received FDA approval in late 2001. Turner added that the expanding indications for sildenafil, marketed as Viagra, include PAH and the drug is "being used off-label fairly extensively." He added that other products were either on the market or in development for "this relatively restricted patient population, and that's affected our goal at this point."

Remodulin (treprostinil sodium) from United Therapeutics Corp., of Silver Spring, Md., received marketing approval in 2002 for PAH. Last month, the FDA granted approval to CoTherix Inc., of South San Francisco, for its inhaled product, Ventavis, for PAH. CoTherix intends to launch the product next quarter. Another product, Thelin (sitaxsentan), by Houston-based Encysive Pharmaceuticals Inc., is in Phase III development. (See BioWorld Today, Jan. 4, 2005.)

Encysive's stock (NASDAQ:ENCY) jumped $1.17 Thursday, or 12.4 percent, to close at $10.59.

Despite the competition, Turner said Myogen is "excited about this market, which may be small in terms of the number of patients," but is "critically important" in terms of patient need.

Turner said ambrisentan is designed as a selective endothelin receptor antagonist to target only the endothelin A receptor, as opposed to Tracleer, which targets both endothelin A (ETA) and endothelin B (ETB).

The binding of endothelin to ETA receptors promotes vasoconstriction, while the binding of endothelin to ETB receptors causes vasolidation. Turner said ambrisentan also is designed to metabolize in a way that helps prevent drug interaction.

"We're hoping to confirm that in our Phase III trials, and that will distinguish us from other drugs," he said.

Both ARIES trials will evaluate two dosage groups of patients and one placebo group. Myogen said the primary endpoint is exercise capacity, measured as the change from baseline in the six-minute walk test distance compared to placebo. Secondary endpoints include the Borg dyspnea index, WHO functional class and a quality-of-life assessment.

ARIES-1 will evaluate the orally administered ambrisentan doses of 5 mg and 10 mg once a day for 12 weeks in patients in North America and Australia, while the ARIES-2 trial is to test doses of 2.5 mg and 5 mg in patients in Europe and South America.

Pending regulatory approval, Turner said the company would consider partnering the drug outside the U.S., but he "expects we'll take it forward to the market on our own here."

Abrisentan is one of three drugs in Myogen's development pipeline to treat cardiovascular disorders. The company completed in November a large Phase III trial with enoximone capsules to treat chronic heart failure. Results are expected around mid-year. A third drug, darusentan, also an endothelin receptor antagonist, is in Phase IIb trials for systolic-resistant hypertension.

Myogen is collaborating with Novartis Institutes for Biomedical Research Inc., an affiliate of Novartis AG, of Basel, Switzerland, on a target and drug discovery research program focused on the development of small-molecule therapeutics for chronic heart failure and related cardiovascular disorders. Novartis obtained the exclusive rights to license new drug targets and product candidates developed, and also will fund further development, as well as make milestone and royalty payments to Myogen on commercialized products.

Myogen has one marketed product: Perfan, an intravenous form of enoximone sold in Europe for acute decompensated heart failure. Turner said the company anticipates 2004 Perfan sales to be between $3.1 million and $3.3 million. Myogen expects to release its fourth-quarter and full-year earnings later this month. As of the quarter ending Sept. 30, the company had $132 million in cash.