Wyeth will conduct a one-year study to resolve cardiovascular and hepatic safety concerns raised in an FDA "approvable" letter for its serotonin-norepinephrine reuptake inhibitor Pristiq (desvenlafaxine) as a treatment for menopausal hot flashes and night sweats.

"We understand and fully believe that in this environment where safety is so important ... that the agency simply wants to be reassured that as we go forward we understand this completely, which is obviously why they've asked for additional data," Wyeth Chief Medical Officer Gary L. Stiles said during a July 24 press conference.

The company, which had projected a third-quarter launch of Pristiq for the vasomotor symptoms claim, said it received the action letter July 23.

Wyeth is confident that the agency's ongoing review of a separate NDA for Pristiq in the treatment of major depressive disorder will not be affected by the safety issues. The firm plans to submit its complete response at the end of August to a January approvable letter it received for the MDD indication (¹ Also see "Wyeth’s Pristiq Deemed “Approvable” By FDA" - Pink Sheet, 23 January, 2007.). That letter did not require additional clinical studies, and the two applications contain the same safety data, Stiles pointed out.

"It's a different population, a different indication, and therefore, it's a different risk/benefit ratio, and so we have no indication from them whatsoever that they have further concerns," Stiles said.

The safety issue is neither surprising nor new, the exec said. Three patients out of approximately 2,000 women in Pristiq clinical studies had elevations in liver enzymes and were discontinued from the medication, after which their enzymes returned to normal, he explained.

Stiles said the cardiovascular events all occurred among women with "high cardiovascular factors" who received Pristiq during study '315, one of the four studies submitted to the agency. "We have looked at these multiple times in great depth and have looked at the events themselves and the events associated around them, and we have come to the conclusion that we do not believe that they are in any way caused by [Pristiq]."

FDA is asking for data from a randomized, placebo-controlled clinical trial in women with moderate-to-severe vasomotor symptoms associated with menopause that is at least a year in duration.

Wyeth remains firm in its determination to develop Pristiq both for VMS and as a follow-on for its blockbuster antidepressant Effexor XR (venlafaxine), which loses patent exclusivity in July 2010. Wyeth has suggested that Pristiq could surpass Effexor in the depression market (² Also see "Wyeth Suggests Pristiq Could Surpass Effexor XR In Depression Market" - Pink Sheet, 13 June, 2007.).

If approved, Pristiq would also find a substantial market for non-hormone VMS therapies, where there is as yet no FDA approved product (³ Also see "Wyeth’s Pristiq Shows Reduction In Hot Flashes In Menopausal Women" - Pink Sheet, 9 May, 2007.). The market is estimated at over $3 billion.

The VMS application has already been delayed once, for FDA to review data on a lower dose titration. The company's studies of 100 mg and 150 mg doses of Pristiq in VMS included a three-day 50 mg starting dose that was shown to be effective, with an improved side effect profile that included less nausea. The company is now studying the antidepressant in a 25 mg dose for titration purposes.

For moderate-to-severe VMS, 100 mg "appears to be optimal in terms of efficacy," Stiles said, adding that "obviously FDA will need to weigh in" on the recommendation. For depression, 50 mg is the lowest effective dose, but each of the doses studied, from 50 mg up to 400 mg, has produced efficacy, Stiles said. "We will likely be recommending that the dose would be 50 mg" for MDD.

FDA also asked for additional clinical and chemistry data that Wyeth said are "not approvability issues" and asked the company to address manufacturing and control issues Stiles said were not related to the drug or its components but to manufacturing processes.

"This does not relate whatsoever to" problems at Wyeth's Guayama, Puerto Rico, manufacturing facility, Stiles noted. That plant received a positive review from FDA in May after being cited for deficiencies in Good Manufacturing Practices (⁴ Also see "FDA Clears Guayama Manufacturing Facility" - Pink Sheet, 9 May, 2007.).

The Pristiq setback could open the door for some smaller companies to be first in the non-hormone VMS therapy space. Earlier in July Noven Pharmaceuticals announced it had acquired an SSRI in development for VMS. The low-dose form of Pexeva (paroxetine mesylate) should enter Phase III studies in the first half of 2008, with an NDA filing possible in 2009, the company said (⁵ Also see "Noven Gains Phase III Vasomotor Symptoms Candidate With JDS Acquisition" - Pink Sheet, 11 July, 2007.).

Another potential competitor is Depomed, which is studying its extended-release, gastric-retained gabapentin formulation in a Phase II trial for VMS (⁶ Also see "Depomed’s Gabapentin GR Fails Phase III Postherpetic Neuralgia Study" - Pink Sheet, 10 July, 2007.).

- Shirley Haley (s.haley@elsevier.com)

FDA Asks Wyeth For Additional Safety Study To Support Pristiq Vasomotor Claim

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