Encysive Pharmaceuticals Inc. set its lead drug candidate, Thelin (sitaxsentan), on the pathway toward approval for pulmonary arterial hypertension by filing a new drug application with the FDA.
"We're submitting this NDA and we hold worldwide rights," Encysive President and CEO Bruce Given told BioWorld Today, noting that the submission represents a clear transition from the company's past as a research and development shop designed for out-licensing. "So we really are in the driver's seat here."
Two years ago, the Houston firm paid $10 million to reacquire all rights to the drug from a joint venture through which its initial development had progressed. And continuing its advancement since then, Encysive has moved Thelin to its pivotal moment.
The company is applying to market a 100-mg dose of the small molecule as a once-daily oral treatment for PAH, a condition that involves high blood pressure and structural changes in the walls of the pulmonary arteries that causes shortness of breath, limits activity and eventually is fatal unless treated with heart or lung transplantation. Given said patient morbidity was as high as 50 percent before injectable prostacyclin drug treatments came on the market a decade ago, and Thelin, an endothelin antagonist, could represent a new complement to some of those existing therapies.
Encysive's application, for which it has requested a priority review, includes a database on about 900 PAH patients who received Thelin. And largely contributing to that body of support are findings from a pair of randomized, placebo-controlled Phase III studies.
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 its would-be competition Tracleer (bosentan, from Actelion Ltd.). Specifically, 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, which is considered a first-generation oral therapy for PAH. (See BioWorld Today, Feb. 15, 2005.)
"Ultimately, what the world wants is a drug that's more selective," Given said. "And we will fill that need, so we feel very comfortable with the competitive situation."
Another differentiating factor between Thelin and Tracleer is the latter's interaction with sildenafil (Viagra, from Pfizer Inc.), a PDE5 inhibitor that increasingly is seeing use off label as another component in treating PAH.
"Everybody is looking to combination therapy," Given added, noting myriad data on such treatments reported during this week's American Thoracic Society meeting in San Diego. "It's similar to all the other chronic cardiovascular diseases, and most other chronic diseases in general such as diabetes and asthma. They're all multiple-drug, multiple-target diseases."
Down the road, he said PAH therapy could include an endothelin antagonist, a PDE5 inhibitor and a prostacyclin product. Among prostacyclins on the market are the injected Remodulin (treprostinil sodium, from United Therapeutics Corp.) and the inhaled Ventavis (iloprost, from CoTherix Inc.).
Encysive said PAH afflicts about 100,000 to 200,000 people around the world, and its Phase III program is designed to support worldwide product registrations.
"We've said that we'll sell the drug ourselves in North America," Given said, "and remained noncommittal about what we'll do in Europe and the Asian-Pacific markets. We think we have the luxury of time in making that decision."
He added that Encysive would outline any future research plans at an analyst/investor gathering next month, including discussions about its evaluations of an earlier-stage clinical candidate, TBC3711, as a next-generation endothelin receptor antagonist, given that such compounds could prove effective in treating a variety of diseases in which the regulation of vascular constriction is important. That compound's rights also were brought fully on board when the company, then called Texas Biotechnology Corp., opted out of its joint venture agreement with ICOS Corp., of Bothell, Wash. (See BioWorld Today, Feb. 3, 2003, and April 24, 2003.)
In addition to such development programs, Encysive already has one FDA-approved drug in its portfolio, Argatroban, a product marketed by London-based GlaxoSmithKline plc for heparin-induced thrombocytopenia.
On Wednesday, Encysive's stock (NASDAQ:ENCY) lost 19 cents to close at $10.31.