Tuesday, May 14, 2019

Golden age of migraine therapy

The recent Food and Drug Administration (FDA) approval of 3 calcitonin gene-related peptide (CGRP) monoclonal antibody therapies has cast a spotlight on the field. Several millions and perhaps billions of dollars have been spent advertising these 3 medications—galcanezumab, fremanezumab, and erenumab—attracting more people with migraine to pursue medical care for the condition than ever before.

Other antibody and small-molecule CGRP antagonists are also in development, and new targets are being considered. Just as CGRP was targeted after it was shown that infusing CGRP in individuals with migraine induced attacks, similar studies are being conducted with pituitary adenylate cyclase-activating polypeptide (PACAP). This exciting target has been identified for the acute and preventive treatment of migraine and with a second migraine-specific therapeutic target, we are perhaps moving into a golden age of migraine therapy. We have more treatment options to offer individuals with migraine than ever before requiring thoughtful and informed care from neurologists, primary care physicians, pain physicians, and other specialists.

Calcitonin Gene-Related Peptide

Calcitonin gene-related peptide is among the most potent vasodilatory neuropeptides in humans and has been shown to induce trigeminovascular inflammation with subsequent peripheral and central pain sensitization that is pertinent to migraine pathogenesis. Receptors for CGRP are found on trigeminal Aδ fibers, endothelial cells, and others leading to neurogenic inflammation and activation of the trigeminovascular system.  Although CGRP cannot cross the blood-brain barrier, it modulates nociceptive pathways involving the brainstem, thalamus, and cingulate cortex. CGRP levels are elevated during migraine attacks, and CGRP infusions trigger delayed migraine attacks in susceptible individuals. For these reasons, CGRP antagonists have been explored as a novel therapeutic class in migraine.

Calcitonin Gene-Related Peptide Antagonists

Monoclonal Antibodies

Eptinezumab, which binds to CGRP, is the only MAb CGRP antagonist delivered intravenously. In clinical trials.Eptinezumab has demonstrated superiority over placebo for migraine prevention, and the drug is under review by the FDA at the time this article is being written. The Table lists a summary of 2 trials of eptinezumab for individuals with episodic or chronic migraine. Participants with episodic migraine (≤ 14 headache days/month, ≥ 4 migraine days) who had single-dose infusions of 100 mg or 300 mg of eptinezumab had significantly reduced mean monthly migraine days (MMD) in 12 weeks (baseline 8.5 MMD, 100 mg −0.7 placebo-adjusted days, 300 mg -1.1 placebo adjusted days). A year after the fourth infusion, those treated with 300 mg of eptinezumab had a reduction of 5.2 MMD compared with 4.0 MMD reduction for those given placebo (nonsignificant); 31% of participants in the treatment group achieved headache freedom vs 21% of participants who received placebo. For individuals with chronic migraine (15-26 headache days/month, ≥ 8 migraine days), treatment with 100 mg or 300 mg of eptinezumab reduced MMD in 12 weeks (baseline 16.1 MMD, 100 mg −2.1 placebo-adjusted days, 300 mg −2.6 placebo-adjusted days).

In both studies, the percentage of participants treated with eptinezumab who achieved at least 50% and 75% reductions in MMD was significantly higher than in those who received placebo. For participants with chronic migraine treated with eptinezumab, the number of participants achieving 100% freedom from headache was statistically significant compared with those who received placebo (Table). In both studies, those receiving eptinezumab were also headache-free 1 day after treatment about twice as often. The most commonly reported adverse events (> 2%) were upper respiratory tract infection, nasopharyngitis (common cold), fatigue, urinary tract infection, diarrhea, and oropharyngeal (mouth) pain. The former 2 events are reported 1% to 2% more in the treatment groups than in the placebo group.


The -gepants are small molecule CGRP receptor antagonists. They have been studied for more than a decade for acute and preventive migraine treatment. Early trials demonstrated superior clinical efficacy to placebo with no cardiovascular side effects, making -gepants potentially a favorable option for people with contraindications to triptans and ergots. Although initial clinical development was hampered by potential hepatotoxicity, the next generation -gepants seem to have similar clinical properties without significant hepatic side effects.

Both rimegepant and atogepant are under investigation for migraine prevention.10-12 In a phase 2b/3 trial,a after 12 weeks of daily atogepant use (10 mg to 120 mg), there was a significant reduction in MMDs/probable migraine days (3.55-4.23 absolute days and 0.7-1.38 placebo-adjusted days). The most common adverse events were nausea, fatigue, constipation, nasopharyngitis, and urinary tract infection. The liver safety profile was similar to placebo. Data from a clinical trialb of rimegepant for migraine prevention are expected in 2020.

Pituitary Adenylate Cyclase Activating Peptide Antagonists

Pituitary adenylate cyclase-activating peptide (PACAP) is a 38 amino acid peptide that shares 68% homology with vasoactive intestinal peptide (VIP) and is a widely distributed neuropeptide. Involved in inflammatory regulation, hypothalamo-pituitary-gonadal axis modulation, energy homeostasis, and pain transmission, PACAP and VIP bind to VPAC1 and VPAC2 receptors with equal affinity. However, PACAP is 100 times more selective than VIP for the PAC1 receptor, which has multiple isoforms with similar responses to adenylate cyclase stimulation but variable responses to phospholipase C. Pertinent to migraine, PACAP-containing fibers and PAC1 receptors are found in the periventricular nucleus of hypothalamus, periaqueductal gray, locus coeruleus, solitary nucleus, trigeminal nucleus caudalis, and trigeminal ganglion, which are all involved in migraine. Levels of PACAP increase during migraine attacks and decrease after successful treatment with sumatriptan. Infusion of PACAP also induces immediate headache followed by a migraine-like attack after a mean of 6 hours, along with dilation of middle cerebral artery and superficial temporal artery. These phenomena were observed less than 20% of the time after VIP infusion. PACAP levels were increased after infusion of PACAP38 only in those participants who later reported migraine-like attacks. Such a correlation presents an interesting opportunity for PACAP blockade in migraine prevention. At this moment, biologics seem a better option than small molecules in blocking the PACAP/PAC1 pathway. A PAC1 receptor blocking antibody, AMG301, has been studied in a recently-completed phase 2a trialc for migraine prevention, but results are not yet available. Clinical trials are planned but not yet underway for a potent PACAP neutralizing antibody with picomolar affinity, ALD1910.17 The effect of long-term blockade of PACAP/PAC1 pathway on endocrine systems, energy metabolism, and inflammatory regulation remains to be investigated.


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