Migraine Drug Research Heats Up As Market Soars

The recent success of Imitrex-the antimigraine drug made by Glaxo Wellcome Inc. of Research Triangle Park, N.C.-has ignited a fury of pharmaceutical research. Imitrex (generic: sumatriptan) is the first serotonin (5-HT) agonist, or mimic, made to fight migraines. In 1996, Imitrex tablets reaped $840 million in worldwide sales. Now, a half-dozen companies are creating new brands of migraine relief-and opening the door to neuroscientists and molecular biologists in the process. A TRAILBLAZER: The usccess of Imitrex, the migraine drug from Glaxo Wellcome that reaped $840 million in sales last year, has promped other companies to develop similar drugs. According to the National Headache Foundation in Chicago, Americans spend more than $4 billion annually on drugs to stop migraine pain. For years, the standbys have been aspirin and a variety of drugs based on ergotamine, a compound that generally reduces blood vessel swelling. Drug companies had largely dismissed the headache market until Imitrex took off. "Whenever there's only one drug that works well, it provides a major incentive to pharmaceutical companies to fill the gap," says Alex Zisson, an investment analyst at Hambrecht & Quist in New York. "And that's definitely the case with migraine. Plus, there's a lot of new scientific understanding about the pain. So that also fuels the research." At least 16 million Americans suffer searing migraine pain. Blamed on dilating blood vessels in the brain, migraines differ biochemically from ordinary "tension" headaches, caused by muscle pain. Migraines also spark uniquely intense symptoms: between four and 72 hours of pain, nausea, and sensitivity to light or noise. The headaches can result from genetics and a host of environmental triggers, including caffeine, alcohol, and bright lights. And because 70 percent of those who suffer are women, monthly hormonal changes have been implicated as triggers. Like Imitrex, most new-generation migraine drugs will mimic 5-HT, a neurotransmitter that is altered when migraines strike. Nicknamed "the triptans," these 5-HT receptor agonists are in the pipeline at Zeneca Pharmaceuticals, a business unit of Zeneca Inc. in Wilmington, Del.; Eli Lilly & Co. in Indianapolis; SmithKline Beecham in Philadelphia; Pfizer Inc. in New York; Merck & Co. Inc. in Whitehouse Station, N.J.; and Bristol Myers Squibb Co. in New York. Glaxo Wellcome also is creating a follow-up compound to Imitrex. One smaller company, publicly owned CoCensys Inc. in Irvine, Calif., is working on a different compound that would ease inflammation of blood vessels. Completely new drug targets could emerge-particularly if companies aim for drugs that can prevent migraines altogether, rather than simply stop the pain after it starts. "All of this opens up a lot of research opportunity," says Theresa Branchek, vice president of pharmacology at Synaptic Pharmaceutical Corp., a Paramus, N.J.-based biotech company collaborating with Eli Lilly on an anti-migraine compound. "In the past, migraine research was for people interested primarily in blood vessels or blood flow." As the field evolves, she says, researchers are questioning the neurobiology behind these headaches. Why do people get migraines in the first place? Finding the answer, Branchek adds, will require scientists trained in molecular biology, neurology-and even genomics. The classical view of migraine physiology holds that dietary or environmental triggers often spark a sequence of chemical events causing blood vessels in the brain to alternately tighten and relax, which leads to throbbing pain. Changing levels of 5-HT in the brain appear to play a role. Imitrex is a 5-HT1 receptor agonist; it was designed to mimic 5-HT. In doing so, the drug constricts blood vessels and reduces blood flow in the brain. In recent years, however, migraine's biochemical picture has grown more complex. At Harvard University, Michael Moskowitz and colleagues have found that certain 5-HT receptors in a different part of the brain-the trigeminal nucleus-also contribute to migraine pain (V. Limmroth et al., British Journal of Pharmacology, 117:99-104, 1996). Nerve cell axons branch from the trigeminal nucleus to the cerebral blood vessels that dilate during a migraine attack. When stimulated, these nerve cells apparently release neuropeptides that inflame the blood vessels and perpetuate their dilation. CHOICE ATTACK: Drug companies can now create migraine drugs that target either dilating blood vessels or nerve cells in the trigeminal nucleus, says neurobiologist Edith Hamel So migraine pain may come from two basic locations: the dilating blood vessels themselves and nerve cells in the trigeminal nucleus. "The question becomes, what are the most important sites of action for a migraine drug?" says Edith Hamel, an associate professor of neurobiology at McGill University in Montreal. "Drug companies can now create compounds that are more selective for one or another type of 5-HT receptor found in these [locations]." In theory, the more selective a drug is, the more effective it is. Highly selective drugs may also cause fewer side effects. Imitrex, which acts on 5-HT receptors in both the trigeminal nucleus and cerebral blood vessels, does have some side-effect problems. In addition to working in the brain, the drug affects 5-HT sites along coronary arteries, occasionally leading to chest tightness or other heart problems. By acting specifically on a certain variety of 5-HT receptor, some of the new triptans might avoid this difficulty. For example, researchers at Synaptic Pharmaceutical and Eli Lilly are developing a 5-HT 1F receptor agonist. This drug works only at 5-HT receptors in the trigeminal nucleus. "Because 1F agonists don't contract blood vessels, we predict that you won't have the potential cardiovascular [side effects] with this compound," Branchek says. The team found their lead compound by cloning 14 5-HT receptor subtypes and then using those subtypes in assays to make selective drugs. 16 million to 18 million Americans suffer from migraines. 70 percent of migraine sufferers are women. Migraine sufferers spend more than $4 billion every year on over-the-counter pain relievers. In 1996, worldwide sales of Imitrex tablets, the only serotonin receptor agonist on the market, totaled $840 million. Sources: National Headache Foundation; Glaxo Wellcome Inc. Meanwhile, scientists at SmithKline Beecham and Vanguard Medica Group PLC in Surrey, United Kingdom, are developing a 5-HT 1D receptor agonist. Again, fewer side effects are the key. "Its strength is that it has a very pronounced selectivity for cerebral blood vessels, rather than cardiovascular blood vessels," explains Nicholas Heightman, commercial director for Vanguard Medica. "It also appears to have a long half-life, so its effect should last." Heightman says researchers will discuss the compound at next month's meeting of the American Society for the Study of Headache in New York. Aside from causing fewer side effects, new 5-HT receptor agonists might act more quickly or last longer than Imitrex. The next triptan to market will likely be Zomig (generic: zolmitriptan), made by Zeneca. The Food and Drug Administration (FDA) is expected to rule on Zomig later this year. Like Imitrex, Zomig acts as a 5-HT1 agonist at both cerebral blood vessels and the trigeminal nucleus. However, it is absorbed more quickly-and thus should act faster-than Imitrex, according to Don Stribling, Zeneca's international product development manager for central nervous system drugs. Not to be outdone, Glaxo Wellcome is developing its own drug to follow Imitrex. The new compound will last longer and be easier for the body to absorb, according to Stephen O'Quinn, clinical program head of migraine research at the company. FUELING THE FIRE: New scientific understanding of migraines and the market success of Imitrex mean the drug will soon have competition, says investment analyst Alex Zisson. To develop the triptans, companies are calling on researchers who can understand both faces of migraine: the classical vascular approach and the more recent neurological studies of the trigeminal nucleus. "To have a successful migraine discovery program, you need a team of people with a focused interest in neuroscience who also have a blood flow interest," says Heightman. "From a biology point of view, that's critical. Also, there's an increasing demand for cell biologists, rather than pharmacologists." He adds that job hunters would do well to learn about the latest pharmacological tools, such as ligand-binding systems and combinatorial chemistry. The same types of talents also work well outside the world of triptan research, explains David Lee, executive vice president of research and development at CoCensys. At Lee's company, researchers are creating synthetic varieties of neuroactive steroids called epalons that may decrease the painful inflammation associated with migraines. "Neurophysiologists who understand the [trigeminal] component and the perception of pain are very important to the field," Lee says. The new generation of migraine drugs are all "abortive"-they stop a migraine attack after it has started. That helps headache sufferers, of course. But only for a while. "Some patients [have] 10 or more migraines a month," says Stribling. "Even with an acute treatment, that can be quite disabling." What's more, Stribling adds, about a third of the time, the triptans wear off before the migraine attack has ended. FOR MORE INFORMATION: CoCensys Inc. http://www.cocensys.com Eli Lilly & Co. http://www.lilly.com Glaxo Wellcome Inc. http://www.glaxowellcome.co.uk National Headache Foundation http://www.headaches.org SmithKline Beecham http://www.sb.com Zeneca Pharmaceuticals http://www.zeneca.com A better therapeutic solution would be to prevent migraines from striking in the first place. Genomics may be one route to new prophylactic drugs (A. Joutel et al., Nature Genetics, 5:40-5, 1993). Academic researchers in Holland recently identified a gene for a calcium channel associated with a rare type of familial migraine. "The question is whether findings like these can be extended to more common migraine varieties," says Glaxo Wellcome's O'Quinn. If so, he says, genomics could be the coming frontier for migraine drugs. That would spark new demand for molecular biologists with genetics experience. Molecular epidemiologists-or scientists who find and clone genes behind disease-would also find a home in genomics-based research. For the moment, however, migraine genomics falls within basic academic research. Meanwhile, industry labs are busy trying to build on what they already know about biochemical pathways in migraine. "Clearly, there are [new] biochemical points at which to intervene," concludes Heightman. Kathryn S. Brown is a freelance science writer in Columbia, Mo.

Migraine Drug Research Heats Up As Market Soars

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