New acute and preventive migraine treatments target novel mechanisms and show promise for relieving symptoms.
PHILADELPHIA—Emerging migraine therapies, such as those that target receptors of 5-hydroxytriptamine (5-HT), calcitonin-gene related peptide (CGRP), and glutamate, may lead to more effective migraine drugs in the near future, according to Peter J. Goadsby, MD, PhD.
“The pipeline is great. It’s absolutely clear [that] things are going to get better,” Dr. Goadsby commented at the 14th Congress of the International Headache Society. “We don’t know what is going to be available in five years, but it’s going to be better than what’s available now.” Dr. Goadsby is Director of the University of California, San Francisco, Headache Center.
Serotonin Receptor Agonists
Neurally acting anti-migraine agents (NAAMA) that target 5-HT1F receptors represent a paradigm shift in migraine therapy. With their non-vasoconstrictor mechanism of action, these new drugs, such as COL-144, show promise as an alternative to triptans in the acute treatment of migraine.
Phase II trials of IV COL-144 showed significant pain relief and freedom from pain at two hours, as well as sustained response, with no significant adverse effects. An oral solution and a tablet formulation have shown similar efficacy.
Also on the horizon in the serotonin receptor agonist family is Levadex, a novel, orally inhaled formulation of dihydroergotamine (DHE). A phase II study showed that onset of pain relief was achieved within 10 minutes, along with positive two-hour pain-free and sustained pain-free rates, according to researchers. Common side effects were similar to those with IV DHE, including nausea, as well as cough and taste changes typical of inhaled medications.
“There will be further studies on this, but at least you can see where this may fit into your clinical arm in practice, particularly for people with prolonged attacks, for people who are looking for some sort of fast action, and especially for those in whom triptans have been some sort of a problem,” Dr. Goadsby commented.
CGRP-Receptor Antagonists
Another class of drugs being studied is the CGRP-receptor antagonists, such as telcagepant and olcegepant. These therapies block the potent vasodilator activity of the neuropeptide CGRP and mediate the physiologic effects of the receptor activity-modifying protein (RAMP).
Telcagepant, which recently completed Phase III trials, was shown to be as effective as triptans, but without the triptan-like adverse cardiovascular effects. Olcegepant, which acts in the spinal trigeminal nucleus, is another promising agent in the pipeline.
“The CGRP-receptor antagonists offer some optimism for all patients, even those with terrible hemiplegic migraines and prolonged aura syndrome,” Dr. Goadsby noted.
Glutamate Receptor Antagonists
Another therapeutic target is glutamate, an excitatory neurotransmitter that has been shown to play a key role in both migraine and epilepsy pathophysiology. Ionotropic glutamate receptor agonists NMDA, kainate, and AMPA are involved in trigeminovascular activation, central sensitization, and cortical spreading depression. Drugs aimed at blocking their action are showing promise in treating acute attacks and have potential for preventing future attacks, according to Dr. Goadsby.
Glutamate receptor antagonists in the pipeline include tezampanel (LY-293558), an AMPA and kainate receptor antagonist; LY-466195, a GLUK5 receptor antagonist; ADX10059, an mGluR5 modulator that shows promise as a prophylactic agent; and perampanel, an AMPA receptor antagonist that is also being investigated as a preventive treatment for migraines. All are currently in phase II trials.
Preventing Chronic Migraines
For patients with chronic migraines, prophylaxis therapies are also in the pipeline. A novel treatment under review targets neuronal-glial gap junctions, which play a prominent role in cortical spreading depression. The gap-junction modulator tonabersat shows promise in the prevention of migraine with aura, but not for migraines without aura, a study at the University of Copenhagen, Denmark, found.
“The researchers used the primary end point of reducing aura, regardless of whether the aura was associated with headache,” Dr. Goadsby reported. “Wouldn’t it be wonderful if we could start to develop models to dissect the paths of parts of the disorder, and you could actually predict what would happen?”
Botox for Chronic Migraine
A new direction in the prevention of chronic migraine is the use of onabotulinumtoxin (Botox) type A. Two phase III, double-blind, parallel-group, placebo-controlled, multi-center studies (PREEMPT 1 and 2) involving 1,384 chronic migraineurs found subjects who received a series of Botox injections at seven specific head and neck muscle areas experienced significantly reduced headache-related disability and improved functioning and overall quality of life.
Of the two studies, however, one failed to meet its primary end point of change in baseline frequency of headache episodes to headache frequency at week 24, compared with placebo. The other study was significantly more effective than placebo in achieving its primary end point of reduction in frequency of headache days.