Washington Editor

Pozen Inc.'s stock Monday took a major hit on news that the FDA rejected the firm's injectable migraine candidate because it failed to achieve statistical significance on secondary endpoints at the two-hour measuring point.

The company's stock (NASDAQ:POZEN) lost $5.83 Monday, or 32.8 percent, to close at $11.94.

Pozen and partner Xcel Pharmaceuticals Inc. were seeking approval of MT 300, a new formulation of dihydroergotamine mesylate (DHE) in a prefilled syringe, for migraines. The FDA issued a not-approvable letter based on the failure to achieve statistical significance for relief of the secondary symptoms including nausea, sensitivity to light and sensitivity to sound at two hours. No safety issues were cited, Chapel Hill, N.C.-based Pozen said.

As for Pozen's next move, John Plachetka, company chairman, president and CEO, told BioWorld Today he'll make that decision after discussions with the FDA. He's not sure whether additional studies will be needed.

"They acknowledged that we hit our primary endpoint, which was sustained pain relief," he said. "We did in fact hit the secondary endpoints for sustained benefit - with the exception of sustained nausea benefit - in one of the two Phase III trials, but they refused to accept sustained benefit for nausea, photophobia and phonophobia as the analysis plan for the secondary benefits."

The agency would like Pozen to demonstrate that it has a short-term benefit for nausea, in particular Plachetka said.

"We did not have a statistically significant benefit within four hours for the relief of nausea in either of our Phase III trials," he said. "The benefit came - it was just a little slower - and we had a lower incidence of nausea after the baseline reading throughout the observation period, but it never got statistically better than placebo."

In July 2002, the first pivotal Phase III study, which dosed 619 patients, showed a statistically significant sustained response rate when compared to placebo - 37 percent vs. 19 percent (p<0.001). In October 2002, the company released data from the second pivotal Phase III trial, involving 550 acute migraine sufferers, which also showed a statistically significant benefit for MT 300 patients of 34 percent vs. 21 percent. (See BioWorld Today, July 23, 2002, and Oct. 7, 2002.)

"People are surprised at the FDA's decision because MT 300 is just a more convenient version of an already marketed drug," Sapna Srivastava, an analyst with ThinkEquity Partners in New York, told BioWorld Today. "The safety and efficacy of this drug have been known for over 50 years - that's why it is such a huge surprise that it did not get approved." (Basel, Switzerland-based Novartis AG sells D.H.E-45, an injectable version of dihydroergotamine mesylate.)

Srivastava believes Pozen's stock took a nosedive because Wall Street has concerns about how MT 300 will impact MT 100, an oral first-line migraine therapy. MT 100, a new chemical entity that will have to pass rat and mouse carcinogenicity studies before it can make it to market, is made from metoclopramide (for nausea control) and naproxen sodium (a pain reliever).

While the FDA is considering approval of MT 100 (the NDA was accepted for filing Oct. 7), Srivastava said that candidate is more important to Pozen because its potential worldwide market value is about $300 million to $400 million. Indeed, MT 300 is potentially worth a mere $20 million to $50 million, she said.

"Honestly, I think MT 100 has a better chance than MT 300," Srivastava said, adding that there's not enough information available to make a good judgment on MT 300's future.

Plachetka said trials for MT 100 achieved acute endpoints for nausea and sensitivity to light and sound.

"I don't think we are in the same situation there [with MT 100]," he said. "The real issue is whether the FDA will continue to accept the sustained pain benefit as the primary measure by which we differentiate from naproxen by itself. Clearly, this is the advantage of our product."

In other business related to MT 100, Pozen received a letter of comments from an advisory group to the Medicines and Healthcare Products Regulatory Agency relating to the Marketing Authorization Application. Following standard procedure in the UK, Pozen intends to submit a response to the comments raised by the panel.

Meanwhile, in the U.S., Xcel, of San Diego, is in a SEC-imposed quite period due to filing for an initial public offering and therefore could not comment Monday, said Julie Bierle, Xcel's manager of investor relations. Xcel and Pozen joined forces for commercialization of MT 300 in early September in an agreement worth about $10 million to Pozen. Xcel sells D.H.E. 45 and the nasal spray version called Migranal. (See BioWorld Today, Sept. 5, 2003.)

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