Pozen Inc.'s stock plummeted Tuesday on news that it received a not-approvable letter from the FDA for its migraine drug MT 100.

The oral drug, a combination of naproxen sodium and metoclopramide, fell short of FDA expectations by not clearly meeting criteria and by not showing superiority over naproxen for sustained pain relief. The FDA also raised safety issues, including concerns about the risk of tardive dyskinesia (TD), a side effect that causes involuntary movement, usually of the face and tongue.

Pozen officials received the letter on Friday. They dug through data over the Memorial Day weekend, but in a conference call Tuesday couldn't answer analysts' questions as to why there was such a disconnect between the company and the FDA.

"Based on our understanding of our many previous communications with the FDA and the data contained in the NDA, we are extremely surprised and very disappointed by the agency's action," said John Plachetka, chairman, president and CEO of Chapel Hill, N.C.-based Pozen. "Maybe they changed their criteria after looking at the drug in the landscape of antimigraine agents that are currently available, but that wasn't communicated to us until this letter."

The news Tuesday drove down Pozen's stock (NASDAQ:POZN) $3.69, or 37.2 percent, to close at $6.23.

Pozen filed its new drug application for MT 100 last summer, adding rat carcinogenicity data to the package early this year. (See BioWorld Today, Aug. 1, 2003.)

Despite the shock felt among Pozen's management, the not-approvable letter came as no surprise to Jason Zhang, a senior biotech analyst at Independent Research Group in New York. He said the company's sustained pain response endpoint (the lack of pain during a 24-hour period) might not have been good enough for the FDA - all migraine drugs to date have been approved based on pain response at two hours following treatment.

"We certainly raised all the questions beforehand," Zhang told BioWorld Today. "We even took out MT 100 completely from our model because we didn't think this had more than a 50 percent chance of getting approved."

In the letter, the FDA said MT 100 showed an unambiguous statistically significant superiority over a control in measuring pain and the symptoms of nausea, photophobia and phonophobia. However, the product did not clearly meet those criteria in a second study, and the agency also cited the lack of superiority of MT 100 over naproxen for sustained pain relief, the primary endpoint for the two component studies.

Company officials believe the agency has a different understanding as to the appropriate statistical analysis of the sustained pain relief endpoint, Plachetka said.

The FDA's letter also noted that there were no detected cases of TD in the 300 patients given MT 100 for at least one year. The letter said that the absence "is consistent with a true rate of TD of about 1 percent, an unacceptably high risk," considering the product showed no advantage over its potential competitors. In order to disprove that, Pozen would need to do a study with several hundred more patients showing the rate was well below 1 percent.

"If that side effect did show up to be 1 percent in a larger patient population, I would think the drug has no chance at all," Zhang said.

During the seven years that Pozen has worked on the development of MT 100, the FDA never raised the issue of TD as a potential safety concern, Plachetka said. Zhang said he, too, was surprised that the issue surfaced.

Finally, the FDA expressed concern in the letter over a potential risk of carcinogenicity, presumably due to metoclopramide, based on animal studies. Pozen filed data from a two-year rat carcinogenicity study in January as part of the NDA filing. The study 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, Jan. 29, 2004.)

Before the FDA required rat carcinogenicity studies of MT 100, Zhang expected the product had a $200 million potential in annual worldwide sales. But he saw the carcinogenicity concerns, which arose in 2001, as a roadblock for approval, not to mention that MT 100 did not always show a response or symptom relief at two hours following treatment.

"For migraine drugs, you really have to measure pain in scores of two hours post-dosing," Zhang said. "That's the traditional gold standard of a primary endpoint. If you look at all other acute migraine drugs, they are approved at that. And they show symptom relief at two hours, as well."

Plachetka said that based on discussions with the FDA, the company believed it had some "latitude" in that two-hour time frame. Depending on the study, MT 100 showed a response at 2.5 hours in some cases and 1.75 hours in other cases.

"We are shocked that this latitude appears not to have been given," he said. "But until we can actually have this discussion [with the FDA], there may be another issue that we're just not aware of."

It is the second not-approvable letter the company has received for a migraine drug. MT 300, a new formulation of dihydroergotamine mesylate in a pre-filled syringe, also received in October the thumbs-down for failing to achieve statistical significance in relief of secondary symptoms, including nausea, sensitivity to light and sensitivity to sound at two hours. (See BioWorld Today, Oct. 21, 2003.)

Although Pozen officials are meeting with the FDA to talk about the future of MT 300, and now the future of MT 100, two not-approvable letters in less than a year speaks poorly of the company, Zhang said.

"You have two drugs in a row now rejected by the FDA," he said. "You are dealing with the same disease. So this is not a very good track record, to say the least."

As for Pozen's financial guidance for this year, Plachetka said it is unchanged and unaffected by the letter. Nycomed Danmark ApS, of Roskilde, Denmark, holds exclusive Nordic sales rights to MT 100. Any payments expected by Pozen from Nycomed are contingent on approval of MT 100 in the UK, which is expected later this year. MT 100 is not partnered in the U.S.

Pozen's third pipeline drug, Trexima (formerly MT 400), entered a Phase III migraine program last month, a milestone that brought $15 million to the company from London-based partner GlaxoSmithKline plc. (See BioWorld Today, May 19, 2004.)

Plachetka expects to re-examine the design of the Phase III for Trexima based on the problems it has run into with the FDA concerning MT 100. Zhang believes Trexima has more potential than Pozen's earlier products. It has shown some superiority over the marketed triptan Imitrex, he said, as opposed to simply showing non-inferiority. The two Phase III trials are designed to compare Trexima to placebo with regard to pain response and symptom relief two hours following treatment. It also should show that the drug's combination is superior to its individual components. Pozen plans to file an NDA for Trexima, a combination of sumatriptan and naproxen sodium, sometime in the second half of 2005.

As of March 31, Pozen had more than $56 million in cash, not including the $15 million milestone payment from GSK last month. Plachetka said the company plans to expand into new therapeutic areas beyond migraine.

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