Washington Editor

ROCKVILLE, Md. - Prospects are growing dim for MT 100, a migraine drug developed by Pozen Inc.

"If you're handicapping things, the odds are not great that we're going to get this not-approvable letter turned over," Chairman, President and CEO John Plachetka said following a meeting of the FDA's Peripheral and Central Nervous System Drugs Advisory Committee. But he added that he didn't want to "put words in the FDA's mouth."

The panel, which was not convened to vote on approvability, called for more data on the oral combination product because of the link of one of its components, metoclopramide, to tardive dyskinesia, a side effect that causes involuntary movement of the face and tongue. That call for additional data will be relayed to the FDA, with which the company hopes to meet in the coming weeks to better determine the drug's fate. But Plachetka declined to speculate as to whether Pozen would undertake another study to elucidate MT 100's efficacy and safety relative to tardive dyskinesia.

"We'll talk to the division, I'm sure, very soon," he said. "And we'll go from there."

But the message from many on the panel was clear.

"It behooves us to ask for the most rigorous endpoints in any trial," said committee member Michael Welch, the president and CEO of the Rosalind Franklin Institute of Medicine and Science in Chicago. "What patients really want is to be pain-free as soon as possible."

Standard approval criteria for migraine drugs stipulate that a product must relieve pain, nausea, photophobia and phonophobia at two hours. But most of the meeting focused on the FDA's concerns about MT 100's potential tardive dyskinesia connection. In light of that, Welch and others on the panel recommended further study to demonstrate the drug's ability to free patients of pain at two hours, rather than simply relieve it. That was echoed by the FDA's Russell Katz, the director of its division of neurology products, who said "they have to show something in two hours."

Chapel Hill, N.C.-based Pozen, which said there were no reports of that side effect in any of the more than 3,700 patients in the product's Phase III program, had posited an annual tardive dyskinesia risk of up to 0.038 percent for metoclopramide at a daily dose of 30 mg to 40 mg for 72 days per year, but panelists agreed 11-1 that such an estimate was unreasonable.

"In today's environment," Plachetka said, "I think people err on the side of safety."

Marshall Reese, Pozen's executive vice president for product development, had previously pointed out that the FDA never indicated its tardive dyskinesia concerns during MT 100's development prior to its regulatory filing. Still, the agency cited that risk, among others, in issuing a not-approvable letter last year, an event that caused the company's stock to fall 37.2 percent. The FDA said the risk was 1 percent, with which one panelist agreed, though most others admitted uncertainty as to an exact figure. (See BioWorld Today, June 2, 2004.)

"It's apparent that no one was able to nail down precisely the risk associated with metoclopramide," Plachetka said. "Despite presenting all of the known information, from Pozen's review and from the FDA's database, it's remarkable that all of the committee members were still unable to come up with a risk estimate for tardive dyskinesia."

On its own, metoclopramide is used to relieve nausea and enhance gastric emptying. The proposed daily dosage of MT 100 includes 13.5 mg of metoclopramide, and the 12 panelists voted unanimously that there is sufficient evidence that its chronic-intermittent administration poses a tardive dyskinesia risk. They also voted unanimously that patients likely would use the drug beyond its indicated limits, should it ever receive approval, and that it's impossible to define a maximum number of monthly doses to avoid tardive dyskinesia.

The product also is comprised of naproxen sodium, a non-steroidal anti-inflammatory drug for pain. The agency has contended that MT 100 is not superior to naproxen alone, and therefore the inclusion of metoclopramide is unnecessary in light of its side-effect profile. Reese, who described MT 100 as a "pill within a pill," countered that the doses of both components "are well below" those approved for other indications. "We feel that the risk of tardive dyskinesia is very low," he added, "and certainly much less than 1 percent."

In support of Pozen, Tony Schapira, a neurology professor at the Royal Free Hospital School of Medicine in London, pointed to data gathered in the UK on the use of metoclopramide combinations with analgesics. Three such products are approved there at a total daily metoclopramide dose of 30 mg per day, and in 25 years of use for the acute treatment of migraine, no tardive dyskinesia cases have arisen. A parallel was drawn by Reese, who reported only rare cases of tardive dyskinesia in the U.S. discovered through post-approval surveillance.

"The potential risk of tardive dyskinesia should not preclude the ultimate approval of MT 100," he said.

Plachetka concluded that the panelists were "uncomfortable with making a decision" without more information. "But the reality is that tardive dyskinesia is such a rare event," he said, "nobody has it."

MT 100's new drug application was filed two years ago, after which the company added rat carcinogenicity data to the submission. Clinical studies enrolled more than 7,700 patients; the rodent findings provided no evidence that maximum tolerated doses of metoclopramide and naproxen produced any statistically significant differences in findings from those seen with metoclopramide alone. (See BioWorld Today, Aug. 1, 2003, and Jan. 29, 2004.)

Recently, Pozen's migraine drug developments have been more positive. Earlier this year, Pozen reported data showing that Trexima (formerly MT 400), a product partnered with London-based GlaxoSmithKline plc, met all regulatory endpoints in the second of two pivotal trials. (See BioWorld Today, April 22, 2005.)

Plachetka walked away from Thursday's panel meeting confident in the future of Trexima, for which the company plans to file a new drug application this quarter. Its primary benefit, he pointed out, is its ability to keep patients free of pain for a sustained period "which the committee acknowledged is the ultimate goal. And Trexima clearly is going to be far superior to all the other treatments out there because it's the first product" to meet such a sustained pain-free endpoint.

On Thursday, Pozen's shares (NASDAQ:POZN) fell 43 cents to $7.97.