Encysive Pharmaceuticals will file an appeal under FDA's Formal Dispute Resolution proceedings over what it argues is the agency's inaccurate data analysis of the STRIDE-2 pivotal trial for its investigational endothelin receptor antagonist Thelin (sitaxsentan).

The company announced its decision to challenge the agency's position June 18 after receiving a third "approvable" letter for the pulmonary arterial hypertension candidate June 15 recommending an additional clinical trial to demonstrate efficacy (¹ Also see "Thelin's Third "Approvable" Letter Recommends Additional Clinical Trial" - Pink Sheet, 15 June, 2007.).

"We see our disagreement with the FDA as a regulatory procedural issue and not scientific," Chief Executive Officer Bruce Given stated during a June 18 conference call.

"In a nutshell, our disagreement with the FDA on the one substantive item in the July 2006 approvable letter which was repeated in the June 15 letter is that they analyzed the STRIDE-2 data differently," he said. "In our strong opinion, their analyses did not use the properly designed and executed STRIDE-2 [Special Protocol Assessment] analysis plan and are thus post hoc."

"We believe that the SPA process protects us from such post hoc analysis, and this forms the basis of our disagreement with the agency," he added.

Encysive's May 2005 NDA submission for Thelin was based on the STRIDE-2 trial, conducted under an SPA, which compared Thelin to Actelion's endothelin receptor antagonist Tracleer (bosentan), using a six-minute walk test as the primary endpoint.

Results of the 226-patient trial showed that Thelin increased a six-minute walk test by 31.4 meters over placebo, in comparison to an improvement of 29.5 meters with Tracleer. Despite the limited efficacy benefit, Encysive had been seeking to distinguish Thelin by its safety profile with a lower rate of liver abnormalities (² Also see "Encysive Avoids Additional Trials For Thelin NDA" - Pink Sheet, 25 May, 2006.).

Despite achieving a statistically significant efficacy benefit in the trial, as determined prior to its initiation, Given argued that FDA has moved the "goalpost."

"Historically, FDA has had a tendency to take sponsors' data and play with it and decide after the fact that maybe they'd like to see data analyzed some other different ways," he said.

Encysive pointed out that STRIDE-2 has served as the basis for approval of Thelin in Europe, Canada and Australia.

"The approach that seems to have been taken by the European, Canadian, Australian authorities is that they looked at the protocol, they looked at the analysis plan and then they looked at whether the trial had been properly conducted according to the analysis plan and was statistically significant," Given said.

The exec also acknowledged that after receiving a second approvable letter for Thelin in July 2006, Encysive moved to initiate dispute resolution proceedings, but was dissuaded by FDA, which urged the firm to work collaboratively with the agency instead.

"We genuinely believed that they had come to agree with our position," Givens said. For example, he said FDA had commented on their risk management plan for Thelin and finalized drug packaging, and that FDA had also asked to see the firm's launch marketing materials.

Under FDA's May 2002 guidance for industry on SPAs, the agency says, "having agreed to the design, execution and analyses proposed in protocols ... the agency will not later alter its perspective on issues of design, execution or analyses unless public health concerns unrecognized at the time of protocol assessment under this process are evident." The guidance goes on to call SPAs "binding," yet nonetheless lays out several occasions when the nature of the SPA could change.

Among those caveats is a statement that "a clinical protocol assessment will no longer be considered binding if the director of the review division determines that a substantial scientific issue essential to determining the safety or efficacy of the drug has been identified after testing has begun."

As a result of the latest regulatory action, Encysive said it plans to initiate a restructuring and head count reduction program in the U.S. The company had a cash balance of roughly $54 million as of June 15, with an additional $10 million in restricted cash from royalties set to become available by July 1.

The approvable letter is particularly bleak for Encysive because it came the same day Gilead received approval for a competitive product, Letairis (ambrisentan), for PAH that is launching immediately (³ Also see "Gilead Letairis Will Be Available Through LEAP Restricted Distribution Program" - Pink Sheet, 15 June, 2007.).

- Jessica Merrill (j.merrill@elsevier.com)

Encysive To Enter Dispute Resolution With FDA Over Third Thelin “Approvable” Letter

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