Encysive Dispute Resolution Request For Thelin Negged By FDA

Securing approval by conducting an additional Phase III study as requested by FDA would take years, CEO Cole tells “The Pink Sheet” DAILY.

Encysive Pharmaceuticals' clinical team is working with outside pulmonary arterial hypertension experts and statisticians to develop an additional Phase III study protocol for Thelin (sitaxsentan) to move forward if the firm determines that another study ultimately is required to secure FDA approval, the company said.

The Houston-based firm announced Sept. 5 that FDA had declined Encysive's request to enter into formal dispute resolution proceedings with the agency regarding its NDA for the PAH candidate. FDA agreed with the decision by the Division of Cardiovascular and Renal Products that, although the data provided in the NDA suggest the effectiveness of Thelin, they do not provide the substantial evidence of effectiveness needed for approval.

"We think there's really only a couple of options," CEO George Cole said in an interview with "The Pink Sheet" DAILY. "One is to gain approval via this appeal mechanism. We're still talking internally, and we're talking with outside experts about whether we should go to the next level or not and what is to be gained from that. And the other one is to do the clinical trial that the agency suggested."

Under FDA's dispute resolution proceedings, Encysive could appeal to a higher level within the agency if it chooses to do so. If Encysive decides to conduct the additional Phase III study instead, Cole said the timeline for completion has not been determined.

"It's not a short-term kind of thing," he stated. "This is an orphan disease, and we have to enroll patients. Even though it would only be probably a 12- to 16-week trial, we're probably talking years instead of months."

The latest review by FDA offered similar guidance to that already suggested by the agency, encouraging Encysive to conduct an additional Phase III study to evaluate the efficacy of sitaxsentan as measured by change in six-minute walk distance.

Encysive has been at odds with the agency on the efficacy of Thelin for over a year. The firm received a third "approvable" letter from FDA for the drug in June, which reiterated the agency's request for an additional Phase III study (¹ (Also see "Thelin's Third "Approvable" Letter Recommends Additional Clinical Trial" - Pink Sheet, 15 Jun, 2007.)).

After submitting the NDA in May 2005, FDA issued an initial "approvable" letter for Thelin in March 2006, requesting an additional clinical trial. Encysive, however, did not conduct the additional trial and responded instead using data from the original STRIDE-2 study (² (Also see "Encysive Avoids Additional Trials For Thelin NDA" - Pink Sheet, 25 May, 2006.)). The company later received a second "approvable" letter due to formatting issues before finally receiving the third one in June.

After receiving the third letter, Encysive said it would formally initiate dispute resolution proceedings. The company maintains that STRIDE-2, which compared Thelin to Actelion's endothelin receptor antagonist Tracleer (bosentan) in a six-minute walk test and showed limited efficacy benefit, is sufficient to support approval (³ (Also see "Encysive To Enter Dispute Resolution With FDA Over Third Thelin “Approvable” Letter" - Pink Sheet, 18 Jun, 2007.)

The company's failure to receive FDA approval for Thelin has been particularly disheartening since Gilead gained FDA approval for its endothelin receptor antagonist Letairis (ambrisentan) the same day Thelin was deemed "approvable" (⁴ (Also see "Gilead Letairis Will Be Available Through LEAP Restricted Distribution Program" - Pink Sheet, 15 Jun, 2007.)).

As a result of the setback, Encysive announced plans to cut its U.S. workforce by 70 percent and appointed Cole, who was formerly chief operating officer, to the CEO post. In July, the company retained Morgan Stanley to assist in evaluating strategic options for the firm.

"To get to where we'd need to be to get approval and commercialize this in the U.S., we will have to do some sort of deal," Cole said. "We just don't know exactly what that is. We're in the early stages of discussing with Morgan Stanley and potential partners what it might look like."

-Jessica Merrill ([email protected])