SC IENCE & TECHNOLOGY
NEW SHOT AT MIGRAINES INJECTABLE ANTIBODIES
could realize a drug target’s promise
CARMEN DRAHL, C&EN WASHINGTON
FOLLOWING MIGRAINE drug discovery
receptors to constrict blood vessels in the brain and alleviate symptoms. However, about half of migraineurs, as sufferers are called, don’t respond to the drugs or cannot take them because of their cardiovascular risks. Even when triptans are effective, they don’t prevent migraine attacks. “The development of CGRP antibodies is all about migraine prevention,” says Peter J. Goadsby at the University of California, San Francisco, who in the 1980s co-led a team that learned that neurons release CGRP during migraines. A handful of drugs are approved for migraine prevention, but they aren’t widely used.
ed for the purpose of developing LY2951742, efforts can be an emotional roller coaster an antibody licensed from Eli Lilly & Co. for chemists and migraine patients. Both That antibody is now in a Phase II clinical groups have been buffeted by the promise trial in patients with migraines. of calcitonin gene-related peptide (CGRP), Migraines are debilitating headaches a neuropeptide implicated in migraine characterized by pain accompanied by “IN MIGRAINE management, you want to development, as a new drug target. And nausea, sensitivity to light, and visual dishit hard, and you want to hit early,” says both have been disappointed because that turbances called auras. The gold-standard Alder’s chief scientific officer, John A. promise has yet to translate to new mimigraine therapies are the triptans, small Latham. graine drugs. molecules that stimulate specific serotonin Drugs targeting CGRP would work difTwo firms are now evaluatferently from triptan medicaing drug candidates they say tions. Neurons release CGRP SOLDIERING ON could fulfill CGRP’s potential. during migraines; the peptide The CGRP drug development field These new candidates are anhas a role in transmitting pain is littered with casualties tibodies rather than the small and factors into the propagation molecules that are the typical of other symptoms as well. ClinCANDIDATE TYPE COMPANY STATUS ALD403 Antibody Alder Phase I denizens of the migraine drug ical trials from other companies BI 44370 TA Small molecule Boehringer-Ingelheim Unknown pipeline. have shown that blocking CGRP BMS-927711 Small molecule Bristol-Myers Squibb Phase II For example, Alder Biophartreats existing migraines withLY2951742 Antibody Arteaus/Eli Lilly & Co. Phase II maceuticals, a Bothell, Wash.out the triptans’ cardiovascular MK-3207 Small molecule Merck & Co. Discontinued based company, is studying side effects. Olcegepant Small molecule Boehringer-Ingelheim Discontinued ALD403, a monoclonal antibody, Both firms’ CGRP antibodPF-04427429 Antibody Pfizer Discontinued in a Phase I clinical trial in ies are designed to latch onto Telcagepant Small molecule Merck & Co. Discontinued healthy volunteers. And Arteaus the CGRP peptide so it cannot NOTE: Selected products in development. CGRP = calcitonin gene-related peptide. SOURCES: Company websites, clinicaltrials.gov Therapeutics, a two-person firm interact with its receptor. This in Cambridge, Mass., was foundis in contrast to small-molecule
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DOWN FOR THE COUNT Most migraine sufferers report between one and four attacks each month on average.
NOTE: Figures are self-reported. SOURCE: Neurology, 2007
CGRP drug candidates, which bind to the receptor to prevent CGRP action. Ideally, says Latham, antibodies could be administered at the start of each month. They would not be metabolized as rapidly as small-molecule drugs, remaining in the bloodstream to nip nascent migraines in the bud. One drawback to these antibody drugs is that even at once-per-month dosing, they would be more expensive than most smallmolecule drugs would be. However, Alder’s chief business officer, Mark J. Litton, says his firm’s yeast-based antibody-making platform is more cost-efficient than bacterial or mammalian-cell antibody-making methods. The goal, Litton says, would be to set the antibody’s price at about $5,000 to $8,000 a year. That range, he says, is comparable to the cost of Botox injections. Botox can also be used for migraine prevention, although its mechanism for that use is unclear. Alder and Arteaus are banking on the idea that the side effect profile of CGRP antibodies will prove better than those of some small-molecule migraine drugs. In its 2009 annual report, Merck & Co. disclosed that a small number of patients taking its investigational small-molecule CGRP receptor inhibitor telcagepant twice daily for migraine prevention had elevated liver transaminase enzymes, an indicator of liver damage. The company halted development of telcagepant in 2011 in light of “an assessment of data across the clinical program,” according to a financial statement. Another inhibitor, MK-3207, was pulled because of liver test abnormalities. Both Alder and Arteaus officials say they believe the liver effects are specific to the withdrawn compounds and
are not likely to be side effects of CGRP antibodies. Not all specialists consider prevention to be a critical property of migraine medications. To Lars Edvinsson of Sweden’s Lund University Hospital, the other leader of the 1980s team that made fundamental CGRP discoveries, prevention is necessary only in cases of long-lasting migraine attacks or in patients with more than three attacks per month. He thinks most migraineurs don’t fall into those categories. “As a doctor, I prefer to treat the attack, and when the attack is over there is no need for further medication.” Others believe prevention is a major advantage. In a large survey by migraine experts of headache sufferers published in 2007, 31.3% of migraineurs reported having three or more migraines a month. Symptoms varied in intensity, with 53.7% of migraineurs reporting severe impairment and the need for bed rest during an attack (Neurology, DOI: 10.1212/01. wnl.0000252808.97649.21). The study was funded in part by Ortho-McNeil Neurologics, a company that makes the antiseizure drug topiramate, which is also used for migraine prevention. The study team concluded that 38.8% of migraineurs should be considered for preventive therapy, but only 13.1% receive it. That “seems more than a passing few” who need prevention, if one takes the study at face value, Goadsby says. MORE FASCINATING than the ques-
tion of prevention, Edvinsson thinks, is the question of where CGRP antibodies act. The CGRP peptide and its receptor reside in both the brain and the peripheral nervous system. His team found that CGRP antibodies cannot traverse the blood-brain barrier (Br. J. Pharmacol., DOI: 10.1038/bjp.2008.346). So if the antibodies work to treat migraine, it could mean they’re acting outside the brain. That seems crazy for a headache disorder, he says, but if true it could prove to be a big leap in scientists’ understanding of migraine. That site-of-action knowledge will be useful to ongoing drug development efforts. Both antibodies and small molecules are making their way through clinical trials. Though time will tell whether any drugs will be approved, says Arteaus Chief Executive Officer David S. Grayzel, “I wouldn’t be running this company if I didn’t believe in CGRP.” ◾
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