Washington Editor

Pozen Inc. believes favorable results from a rat carcinogenicity study will help convince the FDA to approve MT 100, an oral first-line therapy for the treatment of migraine.

Wall Street also agreed, boosting the company's stock (NASDAQ:POZN) 26.4 percent Wednesday, or $3.04, to close at $14.54.

The rat study provided no evidence that maximum tolerated doses of metoclopramide and naproxen, the two active components in MT 100, produced any statistically significant differences in findings from those seen with metoclopramide alone, Chapel Hill, N.C.-based Pozen said.

None of the tumors noted in the study were believed to be directly related to metoclopramide or naproxen. Instead, investigators considered tumors to be secondary to metoclopramide-induced increases in the levels of hormone prolactin in the affected rats, the company said.

"The overall conclusion of the rat study is that MT 100 poses very little risk to patients," John Plachetka, Pozen's chairman, president and CEO, told BioWorld Today. "This study was designed to detect any interaction between metoclopramide and naproxen and to determine if the drugs had any tumor-promoting effects on their own.

"MT 100 is a very promising product, and I think many of the investors in Pozen see the value of it and believe it has the opportunity to become a first-line therapy and will be a major product in the field of migraine," Plachetka said.

MT 100, a pill that can be taken early in a migraine attack, should provide a patient with relief similar to what one would expect from 50 mg of Imitrex (a triptan, marketed by London-based GlaxoSmithKline plc), the market leader in the U.S. Plachetka said there's a reduced risk of cardiovascular side effects in MT 100 compared to triptans.

Pozen submitted the new drug application for MT 100 in August, based on a commitment to complete the rat carcinogenicity study in early 2004. Initially, the company did not believe rat or mouse studies would be necessary because metoclopramide (for nausea control) and naproxen sodium (a pain reliever) have been on the U.S. market since the 1970s. Nevertheless, the FDA classified MT 100 as a new chemical entity, which must pass such tests. (See BioWorld Today, Jan. 29, 2001, and Aug. 1, 2003.)

Previously, Pozen completed a successful six-month oral carcinogenicity study in p53 transgenic mice.

"Taking into consideration all the data we've generated, which includes the p53 mouse studies submitted last year, which showed no evidence of any tumors and no evidence of increase in prolactin, we believe these are very favorable results for MT 100," Plachetka said. "We believe the FDA will review this, and we should have a very nice communication from them on or around the last day of May."

The agency accepted the NDA for review in October, pushing the Prescription Drug User Fee Act action date to May 31, 2004.

The rat study evaluated the incidence of tumors among six groups of male and female Wistar han rats that received daily oral doses of metoclopramide and/or naproxen. One group received metoclopramide alone at its maximum tolerated dose (MTD), while another group received naproxen alone at its MTD. Three groups received naproxen at its MTD combined with metoclopramide at either a low or medium dose or at its MTD. A control group received placebo.

More than 8,000 patients with migraines have participated in Phase III trials in which MT 100 has been shown to provide significant benefits compared to placebo for the relief of pain and the associated symptoms of migraine, including nausea, sensitivity to light and sensitivity to sound.

And in two Phase III trials in which MT 100 was compared to Imitrex at 50mg, MT 100 demonstrated comparable efficacy and a lower percentage of patients reporting adverse events, Pozen said.

The company will seek a U.S. partner for MT 100. The product has been licensed to Nycomed Danmark ApS, of Roskilde, Denmark, for exclusive Nordic sales rights. Pozen has filed for approval in the UK.

Aside from the MT 100 NDA, Pozen and partner Xcel Pharmaceuticals Inc., of San Diego, have been working with the FDA to resolve issues surrounding approval of MT 300, a new formulation of dihydroergotamine mesylate (DHE) in a prefilled syringe, for migraines. (See BioWorld Today, Oct. 21, 2003.)

In October, 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, and the trial hit the primary endpoint of sustained pain relief.

Pozen's stock fell 32.8 percent ($5.83) to close at $11.94 the day the failure was made public.

Plachetka on Wednesday described MT 300 as a niche-type product that would be marketed only in the U.S. "I believe the negative influence on our share price was really far in excess of the contribution MT 300 had to our profitability. We thought MT 300 would be a nice $30 million to $40 million opportunity," he said.

Since the rejection, Plachetka said Pozen has met with the FDA and is preparing a response to the agency's concerns.