Editor

Flashback to June: Pfizer Inc.'s Revatio - based on sildenafil, the same active ingredient that made Viagra such a winner for males with erectile problems - wins FDA clearance for pulmonary arterial hypertension.

Industry observers begin speculating about Revatio's chances against, or with, Actelion Ltd.'s Tracleer (bosentan), a dual endothelin receptor antagonist and the only other approved oral therapy for PAH. (See BioWorld Financial Watch, June 13, 2005.)

A rare but aggressive and deadly disorder afflicting about 100,000 people worldwide, PAH brings symptoms that include difficulty breathing, dizziness and fatigue. Without treatment, sufferers survive an average of less than three years after diagnosis.

Revatio, at 20 mg three times daily, became the first oral treatment for PAH to be approved in patients with an early stage of PAH. Tracleer, cleared for marketing in November 2001 and given twice a day at 125 mg, is indicated for worsening PAH patients.

Other drugs on the market included the much-liked Ventavis (iloprost), an inhaled prostacyclin from CoTherix Inc., which in-licensed the compound from Schering AG in 2003. It won approval at the end of 2004. Prostacyclins are often considered good for use with endothelin drugs.

Numbering among the more invasive PAH therapies on the market was United Therapeutics Corp.'s prostacyclin Remodulin (treprostinil), cleared in 2002 as a continuous subcutaneous infusion. Late last year, the FDA extended the Remodulin label to include an I.V. formulation and help the most severely ill patients. Even with its "subcue" route of administration, Remodulin tended to be favored over GlaxoSmithKline plc's I.V. drug, Flolan (epoprostenol), for PAH.

Analyst Ruth Brown at Decision Resources praised Revatio for its side effect profile and predicted the drug might challenge bosentan in patients who are less sick, while possibly finding use in combination with other PAH therapies. But she said the major growth is likely to show up in the endothelin class.

Jump ahead to last week. That's when Myogen Inc.'s Phase III data with its oral endothelin, ambrisentan, surprised even the more optimistic observers, and sent firm's stock on a ride that added more than 40 percent in value.

The ARIES-2 trial proved that ambrisentan boosted patients' exercise capacity, the primary efficacy endpoint, while improving a key secondary endpoint of time to clinical worsening, along with hitting several other secondary efficacy endpoints.

More specifically, ambrisentan at 5 mg once daily gained 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 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).

Martin Auster, analyst with Wachovia Securities, wrote in a research note that he expects ambrisentan to become the endothelin of choice for PAH physicians, in a market that will grow to $750 million or more by 2010. He modeled $380 million in worldwide sales of ambrisentan 2011.

Will Myogen seek a partner? The company is "not particularly forthcoming with their strategy," Auster told BioWorld Financial Watch, but like any other company would no doubt entertain the right offer.

"They're in the driver's seat," he said.

ARIES-2 is the first of two pivotal trials testing the Myogen drug. Top-line results from ARIES-1, which Myogen said in February would be delayed for six months, due to problems finding enough treatment-na ve patients, are due late in the second quarter.

"Our confidence in ambrisentan would be enforced by results of a similar magnitude in ARIES-1, though we expect it will be near impossible for [Myogen] to top ARIES-2's outcome," Auster wrote.

After the Myogen news, fallout for Actelion proved swift. Overseas analysts at Helvea promptly cut their price target from CHF115 (US$88.89) to CHF95, reporting that ambrisentan - targeted for a 2007 launch date - could "seriously undermine the future sales of Tracleer."

The ARIES-2 news didn't help Encysive Pharmaceuticals Inc., either. Shares plummeted 33 percent, with investors nervous about chances for the company's Thelin (sitaxsentan), in what suddenly became an even tougher field.

Encysive submitted a new drug application for Thelin in May, with paperwork that includes a database of about 900 PAH patients.

The second of the pivotal trials, 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). Also in that 18-week study, conducted under a special protocol assessment with the FDA, Encysive said Thelin proved to be safer than Tracleer. That is, 100 mg of Thelin produced a 3 percent rate of liver function abnormality, defined as an elevation in liver enzymes to levels greater than three times the upper limit of normal, compared to 6 percent for placebo and 11 percent for Tracleer.

Auster, who also covers Encysive, maintained his "outperform" rating on the stock, but was "less enthusiastic" in light of the Myogen data, which suggest greater efficacy in the walk test and the lack of drug interaction with the anti-clotting agent warfarin.

Ahead of the coming PAH "marketing war," he revised downward his worldwide sales estimates for Thelin in 2009 (likely the third full year that drug is on the market) to $147 million from $270 million. Weakness in Encysive shares after the ambrisentan news possibly overcompensates for the latter's impact on Thelin's prospects, he said.

"We would advocate sticking with [Encysive] at its current $7.50 share price ahead of the projected launch" in the first half of 2006, Auster said.