Figuring out the pulmonary arterial hypertension race is like betting on horses, but a trio of leading PAH doctors who dined with C.E. Unterberg, Towbin in San Francisco earlier this month seemed to agree on Encysive Pharmaceuticals Inc.'s endothelin receptor antagonist (ETRA) Thelin.

And Unterberg has advice for would-be investors in Encysive shares, ahead of June 15, Thelin's potential approval date. The advice is: Buy stock.

Physicians predicted only "modest" use of Thelin (sitaxsentan), but noted that price-watching prescription writers will be eager for a cheaper drug in the class with a more favorable liver toxicity profile than Actelion Ltd.'s strong-selling Tracleer (bosentan). Actelion hit the headlines in November when the firm entered an agreement to buy out CoTherix Inc. for $13.50 per share, or about $420 million. CoTherix has an inhaled PAH drug, Ventavis (iloprost), on the market.

Thelin's PDUFA date falls just a business day behind the date for Gilead Sciences Inc.'s priority-review PAH therapy ambrisentan, another ETRA. Docs on the Unterberg panel said they expect the FDA to demand liver monitoring for ambrisentan, and only the 5 mg dose will win clearance, though the filing also included a 10 mg dose.

Whither Flolan (epoprostenol), the prostacyclin from GlaxoSmithKline plc? That's the approved compound for which Myogen Inc. bagged a potential $100 million marketing deal last spring. Opinions of Flolan remained low because of safety risks, and physicians downplayed any of threat of a generic version - Flolan's patent expired in April - since making the drug requires a laborious, 16-step process.

Then there's Remodulin (treprostinil), the FDA-cleared tricyclic benzidine analog of epoprostenol from United Therapeutics Inc., which entered a deal last June for the development of oral treprostinil with Supernus Pharmaceuticals Inc., which is giving UTC access to technology for making tablets. UTC wants to lure doctors away from Flolan, which took a blow last year as investors learned of a "dear doctor" letter that pointed out cases of central venous line-associated Gram-negative sepsis in patients on intravenously given Remodulin (a condition Flolan's label also warns about).

PAH is just what it sounds like: high blood pressure in arteries that carry oxygen to the lungs - constricted pathways that make the heart pump harder, until the patient turns woozy, weary and gasping. It comes in two forms, primary (rare) of unknown cause, and secondary, where the underlying culprit can be such diseases as emphysema, bronchitis, or congenital heart disease.

Doctors often miss it. By the time the right diagnosis is made, patients often face a rather bleak prognosis - though the Pulmonary Hypertension Association finds survival is continuing to lengthen, with some patients lasting as long as 15 to 20 years before they succumb. A better treatment could mean big revenue for its inventors.

Almost inevitably, the pharma giant Pfizer Inc. has entered the space with Revatio (sildenafil), which uses the same active ingredient as the blockbuster erectile dysfunction drug Viagra. Getting more attention, though, is an inhaled form of United Therapeutics' Remodulin in the works with Aradigm Corp., which could dodge the infection problem of the injected form. Enrollment in the TRIUMPH-1 study could finish by the end of June, and might yield top-line data this fall. Unterberg believes the trial had about 195 patients last week, and if five more can be enrolled this month and another 10 in June, then the sought number will be reached.

Observers say the odds are better than 50/50 that inhaled Remodulin will end up with a 6-minute walk distance (6MWD) improvement of greater than 35 meters, with p=<0.02, which means the trial likely could serve as the registration trial. But if the p=0.03 or more, regulators probably would need a second study in 40 patients.

Also on the horizon are EPIX Pharmaceuticals Inc.'s PRX-08066, a 5HT2B antagonist undergoing a Phase IIa trial in PAH related to chronic obstructive pulmonary disease. The 72-patient trial started last summer, testing the drug's effect on systolic pulmonary artery pressure after two weeks of therapy.

A year ago, EPIX said a Phase Ib trial boosted pulmonary artery pressures in subjects by exercising them at high altitudes. Given PRX-08066 or placebo twice a day for three days in three separate periods, the patients showed in a preliminary analysis a statistically significant drop in systolic pressure during hypoxia. At 200mg, subjects gained a 40 percent reduction in blood pressure as compared to placebo, with no effect on cardiac index or exercise capacity.

Preparing to enter the clinic is aviptadil, the vasointestinal peptide from Biogen Idec Inc., a 1-adenosine receptor antagonist that was licensed last year from the Swiss firm mondoBiotech AG. That's good news for Biogen investors, as the drug has languished for a while. In the deal, Biogen agreed to pay mondoBiotech $7.5 million up front, up to $30 million in milestones, as well as royalties and a potential $5 million equity investment upon an initial public offering by mondoBiotech.

Unterberg's physician dinner happened in conjunction with the American Thoracic Society conference in San Francisco, where United Therapeutics offered posters with early data on yet another version of Remodulin, too - an oral form, albeit apparently at levels below therapeutic.

Also at the meeting, Gilead unveiled long-term follow-up data for 383 patients in its ARIES-E extension study of ambrisentan, showing maintenance of improvements in 6MWD and the Borg dyspnea score over an entire year, plus 95 percent survival for the period. Gilead scientists also disclosed a year's follow-up from the ambrisentan switching study, called AMB-222, that showed patients who quit Tracleer or Thelin due to abnormalities in liver-function tests gained benefit ambrisentan. One in 31 patients had LFT jumps above the triple-normal limit, and this was fixed by adjusting the dose.

As ambrisentan runs its approval race with Thelin, CIBC World Markets puts chips on the former, calling approval in June "highly likely" and predicting that the compound will become the best-in-class ETRA for PAH.