Washington Editor

Positive Phase III news sent Myogen Inc.'s stock soaring 40.5 percent, with top-line data demonstrating ambrisentan's ability to improve symptoms of pulmonary arterial hypertension.

The trial showed that the small molecule bettered patients' exercise capacity, the primary efficacy endpoint, improved a key secondary endpoint of time to clinical worsening and several other secondary efficacy endpoints. The study, named ARIES-2, is the first of two pivotal trials evaluating the oral endothelin receptor antagonist in that indication, a disease that causes constriction of the blood vessels in the lungs and leads to high pulmonary arterial pressures.

"The results were nothing short of remarkable," said Louis Lemos, an analyst with Variant Research Corp. "They've exceeded our bullish expectations."

While that good news boosted Denver-based Myogen's shares (NASDAQ:MYOG) $7.80 to close at $27.07, it drove down the stock Encysive Pharmaceuticals Inc., which is developing a potential competitor. Its shares (NASDAQ:ENCY) plummeted 33 percent Monday, or $3.69, to close at $7.49.

Specific findings from ARIES-2 showed that once-daily dosing of 5 mg of ambrisentan led to a 59.4-meter improvement in the placebo-corrected mean change in six-minute walk distance at 12 weeks, compared to baseline (p=0.0002), the study's primary endpoint. A dose of 2.5 mg improved that same measure by 32.3 meters (p=0.0219), while placebo patients experienced a mean decrease from baseline by 10.1 meters. Improvements in time to clinical worsening compared to placebo were observed for both the 5-mg dose group (p=0.0076) and the 2.5-mg dose group (p=0.0048).

"Clearly, the drug works exceedingly well," Lemos said, later adding that "we knew [the data] would be good, but not this good."

Although headaches were the most common side effect seen in the study, occurring in a higher number of 5-mg patients than those on 2.5 mg, the company said safety results showed ambrisentan to be generally well tolerated. Perhaps more notably, it showed no effect on the activity or dosage of warfarin-type anticoagulants commonly prescribed for those patients, which has been a problem with other endothelin receptor antagonists. Also importantly, no patients treated with ambrisentan developed serum aminotransferase concentrations greater than three times the upper limit of the normal range, an absence of liver toxicity that Lemos said differentiates the investigational drug from the only approved endothelin receptor antagonist in that indication, Tracleer (bosentan, from Actelion Ltd.).

"Some of the doctors that we have spoken with indicated that they believe endothelin receptor antagonists work well," he added, "but in the back of their minds, they're always thinking about liver toxicity and potential warfarin interactions. It appears at this point that ambrisentan is not going to have an issue with this."

ARIES-2, which was conducted in Europe, Israel and South America, enrolled 186 patients (62 in each dose group). Full data eventually will be unveiled at a still-undetermined scientific meeting. Top-line results of the other pivotal trial, ARIES-1, are due late in the second quarter.

Both randomized, double-blinded studies began nearly a year ago and follow identical designs except for the doses studied and locations. ARIES-1 is being conducted in North America and Australia to evaluate 5-mg and 10-mg doses of ambrisentan compared to placebo. In a conference call, Myogen President and CEO William Freytag indicated that the company would file for approval of all three doses if data from ARIES-1 also support the 10-mg dose.

"In all likelihood," Lemos said, "it's our anticipation that the next Phase III data that we see will be equal, if not better, than what we saw today."

He said FDA approval would come in 2007, most likely after Houston-based Encysive's Thelin (sitaxsentan), which is expected to receive clearance in March. Both ambrisentan and Thelin are selective endothelin receptor antagonists.

Thelin's new drug application was filed earlier this year, based largely on a pair of randomized, placebo-controlled Phase III studies. One of them, called STRIDE-2, met its primary objective of improved six-minute walk with a statistically significant increase of 31.4 meters compared to placebo (p=0.03), and also showed Thelin to have less hepatic toxicity than Tracleer. (See BioWorld Today, May 26, 2005.)

Lemos, who predicted that Thelin would fare well against Tracleer initially, added that because "ambrisentan clearly seems to be differentiating itself" in terms of efficacy and safety, it could end up generating in excess of $400 million in annual U.S. sales by 2009. "We fully expect it to get quite a bit of use right out of the gate."

Earlier this year, the company's stock received a 60 percent boost on positive Phase IIb data with darusentan, a type-A selective endothelin receptor antagonist for high blood pressure. Soon after, Myogen raised net proceeds of about $101 million through a public offering. (See BioWorld Today, Aug. 19, 2005, and Sept. 19, 2005.)

The company's recent crest is a nice contrast to a trough it fell into earlier this summer when its then-lead drug candidate for heart failure, enoximone, failed in top-line data from two Phase III trials, echoing earlier disappointing results from another Phase III study. (See BioWorld Today, June 28, 2005.)