LONDON – The drug development pipeline for migraine holds numerous promising new classes of medications addressing novel therapeutic targets – and that’s welcome news because recent surveys indicate a substantial proportion of migraineurs aren’t satisfied with their current options for acute treatment and prophylaxis.
However, most of the novel agents are in only phase II studies. And snares abound on the path ahead to the marketplace, as recent history demonstrates.
Dr. Rigmor Hojland Jensen
The pharmaceutical industry seems less enthusiastic overall about developing new drugs for headache now than it was 15 years ago. It’s a shame because an enormous underserved market exists for new agents that can offer the triad of efficacy, convenience, and tolerability, Dr. Rigmor Højland Jensen said at the European Headache and Migraine Trust International Congress.
A chill was cast over the field of headache treatment development last year when Merck abruptly announced a halt to further development of telcagepant, a previously highly promising, first-in-class calcitonin gene-related peptide (CGRP) antagonist, after elevated liver enzymes emerged as a concern in analysis of a completed phase III randomized clinical trial, she said.
CGRP plays a key role in neurovasoconstriction. The promise of the CGRP antagonists for short-term treatment of migraine is that they will provide the cerebral vasodilatory efficacy of the triptans without the cardiovascular side effects. However, the future post-telcagepant remains uncertain for other agents in this class, including Boehringer Ingelheim’s olcegepant as well as other CGRP antagonists in phase II studies being developed by Bristol-Myers Squibb, Eli Lilly, and Merck, noted Dr. Jensen, president of the European Headache Federation and professor of neurology at the University of Copenhagen.
Meanwhile, the development of highly selective antibodies to CGRP looks very promising, although these agents are still in the preclinical stage.
Dr. Jensen said surveys indicate roughly 40% of patients with migraine are unhappy with the triptans and simple analgesics used as first-line short-term therapy, either because of lack of efficacy or side effects. Moreover, the current options for migraine prophylaxis leave much to be desired.
"We don’t know how prophylaxis works. It’s nonspecific, often ineffective, and has side effects. We really need good prophylactics without side effects," Dr. Jensen said.
The drug furthest along in development for acute migraine is oral lasmiditan, a selective serotonin 5-hydroxytryptamine 1F receptor antagonist with no vascular effects. Lasmiditan, being developed by CoLucid Pharmaceuticals, is currently in phase III trials.
"This one is just around the corner," according to the neurologist.
In a recent phase II study, lasmiditan showed an excellent response rate 2 hours after administration, with no vasoconstriction (Lancet Neurol. 2012;11:405-13).
Nitric oxide synthase (NOS) has emerged as a promising new nonvascular target for acute migraine therapy. NeurAxon, a Canadian company, has developed a first-in-class selective inhibitor of the neuronal form of NOS, which modulates the central and peripheral response to pain and neuronal sensitization.
In a recent randomized, placebo-controlled phase II study of 179 patients with migraine without aura, this agent, known for now as NXN-188, produced prolonged pain relief that became significant beginning 3 hours after administration and remained so for 24 hours even though rescue medication wasn’t permitted. The side effect profile was reassuringly benign.
Other companies have developed selective inhibitors of the inducible form of NOS, which is released by macrophages. Inducible NOS participates in the immune response to stress and inflammation, making it another attractive target for acute migraine therapy, Dr. Jensen continued.
Turning to emerging agents for migraine prophylaxis, she highlighted several novel drugs now in phase II studies: DP-VPA, a valproic acid prodrug being developed by the Israeli company D-Pharm; a botanically sourced compound, MGX-008, that comes from the bark of the Monterey pine and is under development by Migco; an oral leukotriene D4 receptor antagonist backed by Lilly; and lacosamide, also known as BGG492, an AMPA/kainate glutamate receptor antagonist under development by Novartis.
In addition, a couple of very familiar drugs – the angiotensin receptor blocker candesartan and the muscle relaxant cyclobenzaprine – are now in phase III trials for migraine prevention.
Dr. Jensen reported serving on the advisory boards for ATI, Medotech, Neurocore, and Linde Gas and on the speakers bureaus for Pfizer, Merck, and NorPharma.