As one of the latest efforts to stir the stagnated migraine market - Pozen Inc.'s combination therapy Trexima, which pairs sumatriptan with the non-steroidal anti-inflammatory drug naproxen - continues to have trouble, Endo Pharmaceuticals Inc.'s Frova (frovatriptan) might be able to make headway. But it's too early to put a lot of money on that bet.

Pozen's shares tumbled 43 percent on word of its second approval letter for Trexima. Cardiovascular worries that the FDA cited earlier apparently have been laid to rest by safety data submitted by Pozen and partner GlaxoSmithKline plc, along with the promise to conduct a post-market study that evaluates Trexima's effect on blood pressure.

Now the concern is toxicity. The FDA zeroed in on a single preclinical Chinese hamster ovary study that showed genotoxicity with high doses of sumatriptan and naproxen together, but no such effect with either of the drugs by itself. The first approvable letter had touched on the CHO study and asked for a second CHO study plus a mouse lymphoma TK assay, which Pozen completed.

The new CHO study confirmed the first. The mouse lymphoma test, though, came up with no genotoxicity, nor did previous Ames tests and in vivo mouse micronucleus assays. Still, the FDA wants a new clinical trial. Pozen planned to meet with the agency and discuss the design of the study. Pozen's partner GSK owns Imitrex, the market leader in migraine, in which sumatriptan by itself is the active ingredient. Imitrex likely will face generic competition in two years.

A Phase III trial of Trexima demonstrated superior sustained pain-free response compared to naproxen (p<0.001) or sumatriptan (p=0.009) alone, but Pozen hasn't had much luck with migraine drugs. Two earlier compounds - MT 300, a new formulation of dihydroergotamine mesylate, and MT 100, a naproxen/metoclopramide combo - got not-approvable letters from the FDA, though MT 100 later won approval outside the U.S.

The FDA last week asked for an extension to evaluate Endo's Frova in menstrual migraine. Already cleared for acute migraine in adults, Frova could gain somewhat bigger market share if its longer half life helps the drug catch on for the prophylactic treatment of menstrual migraine. The selective serotonin receptor agonist takes longer to kick in, but has the longest half-life in the triptan class: 26 hours.

Endo in-licensed Frova from Vernalis plc about three years ago, providing a $50 million loan facility that Vernalis used to pay Elan Corp. plc for the rights to the compound, which Vernalis agreed earlier in 2004 to buy back for that amount.

Frova sold $12.8 million in the second quarter, compared to $13 million for the same period last year. What could the menstrual indication mean? Possibly not much.

Most women who get migraines tend to suffer more, or worse, episodes around their periods, but any of the other drugs also work. For Endo, reimbursement could be an even bigger headache, since using a triptan for a week or two during a menstrual cycle could get very costly - more expensive than most HMOs or third-party payers would want to cover. The FDA said it would shortly provide Endo with guidance on when to expect a decision on Frova.

Megan Murphy of Lazard Capital Markets wrote in a research report last week that the drug is "not material to our long-term outlook for [Endo] shares," and a survey of physicians including neurologists, general practitioners and obstetricians/gynecologists suggested a market share gain of only 1.5 percent over the next two years, given the menstrual migraine indication.

The market itself is potentially much larger than currently served. The National Headache Foundation says almost 30 million Americans suffer from migraine, with women affected three times more often than men. The condition typically strikes between the ages of 15 and 55, and 70 percent to 80 percent of those who suffer migraines have a family history of the disease - though less than half of all migraine sufferers have been diagnosed. The headaches are often chalked up to sinus trouble or tension.

Separately, a group of Endo shareholders at the start of the month diagnosed the company's failure to perform to the standard set by the Dow Jones index, Nasdaq and the S&P 500 - each of which has appreciated 26.7 percent, 31.8 percent, and 22.8 percent respectively over the past 12 months, compared to 11.5 percent for Endo.

James Mackey, managing member of D.E. Shaw & Co. LLC, to Peter Lankau, Endo's CEO, blamed the shortfall on "an inefficient capital structure, [the] publicly stated intention to diversify away from pain management, and the perceived [but overstated] risk" of a generic threat to Lidoderm, Endo's lidocaine patch for post-herpetic neuralgia. Shaw owns about 5.6 percent of Endo's outstanding shares.

Endo has upwards of $700 million in cash, and has made known its plan for an acquisition - but the Shaw shareholders want the firm to add debt and do a share buyback, buying back shares with a majority of the cash, which would then boost earnings per share by more than 20 percent. "In this scenario, we believe the company would retain sufficient financial flexibility to execute appropriate strategic transactions as they arise," Mackey wrote.

Plenty of other migraine therapies haven't made the grade. Among the historical failures is NPS Pharmaceuticals Inc. and Canadian subsidiary NPS Allelix Corp.'s candidate ALX-0646, a triptan-class serotonin agonist like Frova, which was licensed to Forest Laboratories Inc. in 2000 for development and distribution. By July of 2003, the pair resolved a legal fight over termination of their pact, and NPS said it was pursuing the compound for indications other than migraine.

In 1999, just as Phase III trials were slated to begin, Eli Lilly and Co. broke off its deal with Synaptic Pharmaceutical Corp. for development of the serotonin agonist LY334370. Lilly balked at animal toxicity data. A handful of triptans have made it to market, though, the first being Imitex, cleared in 1993 and followed by a half-dozen others.

Along with such players as Pozen and Endo, others are trying to beat Imitrex for migraine, or at least grab market share. 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.

Among the companies to make news recently with earlier-stage progress in migraine is NeurAxon Inc., which reported positive safety and pharmacokinetics data from a Phase I trial of NXN-188, a small molecule that the company said uses 5-HT agonism while inhibiting neuronal nitric oxide synthase. NeuroAxon plans to move into a Phase IIa trial this quarter.

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