Shares of Pozen Inc. fell 43 percent on Thursday after the company received a second approvable letter from the FDA for lead candidate Trexima, a migraine drug combining 85 mg of sumatriptan with 500 mg of naproxen sodium.

In a conference call, Pozen's chairman, president and CEO John Plachetka said the agency's concerns center on a single preclinical genotoxicity study which might be able to be addressed in a matter of months with a small, single-dose clinical trial. Even so, the Chapel Hill, N.C.-based company's stock (NASDAQ:POZN) fell $7.52 to close at $9.93 on Thursday.

Pozen's first approvable letter for Trexima, which sent the stock spiraling down 60 percent just over a year ago, focused on cardiovascular safety. In response, Pozen and partner GlaxoSmithKline plc submitted safety data from clinical trials and from GSK's database. The companies also agreed to conduct a post-market study to evaluate Trexima's effect on blood pressure. Their response appears to have been sufficient, as the agency did not request any additional cardiovascular safety data in the second letter. (See BioWorld Today, June 12, 2006.)

Instead, the second letter focused on a Chinese hamster ovary (CHO) study that showed genotoxicity with high doses of sumatriptan and naproxen sodium in combination but not with either drug alone. The first approvable letter also mentioned the CHO study and had requested a second CHO study and a mouse lymphoma TK assay, which Pozen completed even though Plachetka said he thought the issue was "not as important" as the cardiovascular safety questions at the time.

The second CHO study confirmed the genotoxicity finding, although the mouse lymphoma study and previous Ames tests and in vivo mouse micronucleus assays did not show any genotoxicity. Plachetka said the results "could be due to the [CHO] assay procedure," and Pozen intends to investigate any pH changes, temperature changes, precipitate formation or other factors that could have influenced the test.

The FDA, however, indicated it wants to see a clinical trial rather than more preclinical analysis. There is precedent for such a trial, since "30 to 40 percent of drugs have one positive gene-tox test in the battery," Plachetka said. Examples provided to Pozen by the FDA included just 12-30 patients, and Plachetka suggested Pozen's trial could require just one dose with blood assays conducted soon afterward.

Pozen intends to request a meeting with the FDA to discuss the trial design, and discussions regarding packaging, labeling and a final trade name for Trexima are ongoing. Yet Plachetka said the company will move forward with the trial and with the CHO testing while waiting for the agency's input. "We will do everything in a time critical fashion," he said, adding that once data are submitted, Pozen will "lobby strongly" for a two-month review cycle.

Pozen has every reason to move quickly. GSK's market-leading migraine drug Imitrex, in which sumatriptan is the active ingredient, may face generic competition in two years. Trexima was being groomed to serve as the next-generation brand-name option for the blockbuster franchise. Yet Lazard Capital Markets LLC analyst Megan Murphy estimated the latest approvable letter could set Pozen back another year, which would "put a tremendous amount of pressure to convert the Imitrex franchise, likely against generic competition."

And generics aren't the only threat on the horizon. The FDA is reviewing the supplemental new drug application for Frova (frovatriptan succinate, Endo Pharmaceuticals Inc. and Vernalis plc) for short-term prevention of menstrual migraine. Alexza Pharmaceuticals Inc.'s aerosol version of the oft-used intravenous drug prochlorperazine, AZ-001, recently yielded positive data in a Phase IIb migraine study.

A Phase III trial of Trexima demonstrated superior sustained pain-free response compared to naproxen (p<0.001) or sumatriptan (p=0.009) alone. Yet Murphy said in a report that she is "inclined to believe that the FDA just doesn't want to approve Trexima." She removed the drug from her valuations and downgraded Pozen to "hold" from "buy."

But perhaps the third time will prove to be the charm for Pozen, both in terms of review cycles for Trexima and in terms of the company's migraine efforts. Two earlier Pozen migraine drugs - MT 300, a new formulation of dihydroergotamine mesylate (DHE), and MT 100, a combination of naproxen sodium and metoclopramide - received not-approvable letters from the FDA. MT 100 later went on to gain approval outside the U.S. (See BioWorld Today, Oct. 21, 2003, and June 2, 2004.)