There may be some doubt about what's just "a bad headache" and what's a migraine, but those who suffer the latter are absolutely sure what they're feeling. Often, their initial clue is the dreaded "prodrome," a sense that the migraine is about to occur. Then begin the throbbing, pulsing pain and extreme sensitivity to light and sound, maybe with nausea and changes in vision, such as the appearance of auras.
The symptoms are distinct. But sufferers don't want to debate whether all these mean a genuine migraine. They just want the dizzying pain to go away.
Migraine headaches are less common than tension-type headaches, says the American Council for Headache Education, but they still afflict 25 million to 30 million people in the U.S., about 6 percent of all men and 18 percent of all women, or about 12 percent of the whole population.
Two-thirds or more of migraine victims are women (there's believed to be a hormonal link), and about half of the unlucky will first experience their migraines in childhood or adolescence.
The cause is unknown. Most likely, the migraine pain comes from blood vessels and nerves around the brain that swell as a result of activity in the brain stem, apparently involving serotonin, but not much is clear beyond that. About 60 percent of migraines are felt on one side of the head.
Likely triggers? You name it. Caffeine - either too much, or not as much as usual. Tyramine (found in aged cheese and fermented beverages). Sulfites. Stress, or relief from stress. Lack of sleep, or an altered sleep pattern. Moving from one altitude to another. A change in the weather.
There seems to be no single distinct identified internal cause or external trigger. What is fairly clear by now, though, is the lucrative migraine market, largely under the control of GlaxoSmithKline plc's Imitrex (sumatriptan succinate, also known as Imigran), which sold about $1.17 billion in 2001.
"Imitrex was the first tryptan developed and launched," said John Plachetka, president, CEO and chairman of Pozen Inc. The injected version was launched first, and a tablet version later.
"The market share is exactly in order of entry, and that's because there's no difference between the products," Plachetka said. "That's pretty typical. The first guy out always commands the biggest presence."
Also competing in the space is Novartis AG's injectable DHE-45 (dihydroergotamine mesylate). It's made in an inhaled version, too, called Migranal.
During the past two weeks, Pozen had two pieces of migraine news. What seemed to be the biggest item came first, when the company disclosed that its injectable drug, MT300, achieved its primary endpoint - sustained relief of pain - in its second pivotal trial. Although the drug, a new formulation of dihydroergotamine targeting various serotonin receptors, missed the secondary endpoints during the two hours after dosing, it showed statistical significance in providing relief of those symptoms on a sustained basis as well.
In July, Pozen's first pivotal Phase III study of MT300, dosing 619 patients, showed the sustained response was statistically significant compared to the rate for placebo - and gave relief at two and four hours after dosing, providing statistically significant benefit vs. placebo in the secondary endpoint measurements.
Pozen boasted its advantage over market leader Imitrex is a cardiovascular profile with less risk. Compared to DHE-45, MT300 causes less nausea, and comes in a pre-filled syringe rather than a glass ampule that the suffering patient must break open to use.
"MT300 is a different form of DHE-45," Plachetka noted. "Even if it operates as a niche product, it will be great for people who can't take oral medications."
As an injectable, DHE-45 "really only competes against Imitrex injection," he said. "Nobody else developed one because of the more pronounced side effect profile. DHE-45 is about an $8 million per year product. It's got a lot of problems in terms of convenience."
The fact is, though, nobody wants to fumble with syringes, ampules, needles or inhalers.
"Everybody wants to take one pill and have your headache go away for good," Plachetka said.
Which is where Pozen's second news bulletin, at least as important and dispatched several days after the MT300 update, comes in. In the United Kingdom, the company submitted for authorization to market another migraine drug, MT 100. It's an oral, first-line treatment, Pozen's own formulation of metoclopramide hydrochloride (metoclopramide) and naproxen sodium (naproxen).
The tablet is made so the metoclopramide is released first, attacking the nausea and improving the body's ability to absorb the naproxen, an anti-inflammatory pain drug.
"The second ingredient improves the absorption of the first by correcting the gastric emptying defect that occurs in migraine," Plachetka explained. Pain is often accompanied by slowed digestion.
Compared to naproxen alone, MT 100 has been shown to boost blood levels of the important compound by 15 percent, and to make it work 30 minutes faster after it's given to patients.
Pozen has conducted eight Phase III trials of MT 100, including - to use an excruciating pun - one "head to head" study with 546 patients that compared Pozen's treatment to Imitrex.
The two performed equally better than placebo, but the most common adverse event for the MT 100 group was drowsiness, whereas 7 percent of the Imitrex group had tightness in the chest and throat. Of the MT 100 patients, none in the group given one tablet developed the tightness, and less than 1 percent in the group given two tablets reported the side effect.
Plachetka said the upshot is simple: MT 100 enhances speed, efficacy and duration of relief without the unpleasant or potentially dangerous drawbacks of the currently used migraine treatments (such as Imitrex) - the triptans, of which a handful are marketed.
Once MT 100 is licensed in the UK, which is expected in the fourth quarter of next year, Pozen will be seeking approvals in other European countries through the mutual recognition process, and most of those could have the drug available in 2004.
In the U.S., Pozen is preparing for the FDA rat carcinogenicity data (which European regulators didn't ask for) from a two-year study.
"If this was a true new chemical entity [European officials would be interested in the rat data]," Plachetka said. "But this consists of two approved drugs, and we showed them data there's no interaction between them from a toxicity perspective, and they were convinced."
For the FDA, Pozen plans a rolling submission, submitting the new drug application next summer, with approval estimated in the first half of 2004. The company also has MT400, which it describes as "next-generation triptan therapy," gearing up for Phase III trials next year. Meanwhile, a search is on for a marketing partner to help with MT100.
Plachetka said he agrees with estimates by Peter Ginsberg, senior biotechnology analyst at U.S. Bancorp Piper Jaffray in Minneapolis, who put the European sales forecast for MT100 at $10 million in 2004, and estimated $34 million in 2005. In the U.S., Ginsberg predicted MT100 would sell $50 million in 2004 and $164 million in 2005.
More people are afflicted with migraine, Plachetka said, than those with more attention-grabbing diseases such as diabetes.
"Fifty percent of people don't take any drugs for it other than over-the-counter medicine, which probably doesn't work that well," he said. "Others take it half the time, and the rest of the time they just tough it out," often because insurance reimburses them only for a limited quantity of medicine.
When the non-tryptan MT100 is launched, Plachetka noted, it will occupy a place similar to Imitrex's, when that drug first hit the market and physicians latched onto the new treatment for a painful disorder.
"That's a good space to be in," he said.