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.
-Gepants
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.
https://practicalneurology.com/articles/2019-may/migraine-preventive-therapies-in-development
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