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Why Newer Migraine Blockers Fail Some Patients

Article In Brief

Research in an animal model of headache suggests that different underlying mechanisms at work in migraine may explain why some calcitonin gene-related peptide inhibitors, such as fremanezumab, may not work for everyone.

Not all migraines result from the same neurovascular changes targeted by newer antibody drugs. And this could potentially help to explain why many migraine sufferers do not respond to such targeted migraine blockers, researchers at Beth Israel Deaconess Medical Center reported in a study published May 24 in the online edition of the Journal of Neuroscience.

The investigators discovered fundamental differences in how laboratory rats responded to fremanezumab (Ajovy), a monoclonal antibody (mAB) that blocks calcitonin gene-related peptide (CGRP).

Prior research has suggested that there might be some functional connectivity between CGRP and cortical spreading depression (CSD), and that blocking CGRP might also prevent CSD and plasma protein extravasation (PPE) from affected vasculature.

CSD is a wave of neuronal depolarization thought to result in the activation of nerves that give rise to the headache phase of migraine with aura. CGRP is a potent vasodilator neuropeptide that triggers a migraine attack three to four hours after its infusion. PPE involves leakage of proteins from blood vessels into the surrounding environment in the dura.

Study Design

In the new study, the scientists used sophisticated high-resolution, real-time imaging to investigate how CSD and CGRP contribute to arterial dilatation and PPE in rats treated with fremanezumab. They were able to generate continuous views of spatial and temporal changes in dural and pial arteries and veins, as well as map how fluorescently-labeled fremanezumab diffused from blood vessels through PPE after CSD induction or systemic infusion of CGRP.

The study was designed to test the effect of the CGRP mAB on a single wave of CSD because, in migraine with aura, usually only one wave of CSD occurs, said lead author Rami Burstein, PhD, vice chairman of neuroscience, critical care, and pain medicine research at Beth Israel Deaconess Medical Center in Boston.

“The animal studies that opted to use multiple waves of CSD did so because they could not find any effect when studying only one wave of CSD,” he noted.

While fremanezumab blocked dural artery dilation after CGRP infusion, it did not block the CSD-induced dilatation of dural or pial arteries or dural PPE, the research team discovered.

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“The current study is more of a snapshot of what occurs with just one wave of CSD,” Dr. Riggins said, “and although the results support the authors conclusions, longer studies may give different results more relevant to the clinical situation in migraine patients.”—DR. NINA RIGGINS

“There is more than one truth to migraine pathophysiology, [and] it is unlikely that one theory will explain all types of migraine or the mechanisms of action of antimigraine drugs,” Dr. Burstein said.

“We believe that not all vascular responses in the meninges are born alike and, consequently, drugs that prevent vascular dilatation through different molecular pathways may have different therapeutic outcomes in different types of migraine.”

Fremanezumab is one in a class of new migraine and headache drugs that neutralize CGRP. Also included in this group are erenumab (Aimovig), the first CGRP receptor blocker approved, in May 2018, and galcanezumab (Emgality), which was approved in June 2018.

The research was funded by Teva Pharmaceutical Industries Ltd., and by the National Institutes of Health grants.

“With CSD's depolarization there is immediate and brief vasodilatation followed by prolonged vasoconstriction of cerebral pia and cortical arteries resulting in PPE. However, to date there has been no direct evidence of CGRP's role in post-CSD vascular events, or the ability of anti-CGRP monoclonal antibodies to alter the vascular response to CSD and the ensuing PPE in the dura or pia,” said Dr. Burnstein.

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“There is more than one truth to migraine pathophysiology, [and] it is unlikely that no one theory will explain all types of migraine or the mechanisms of action of antimigraine drugs.”—DR. RAMI BURSTEIN

Clinical Implications

The presumed connectivity between CSD and CGRP has been based on studies that have shown that both CSD induction and CGRP infusion dilate cortical surface arterioles, and that CSD-induced dilatation of pial arteries is mediated by CGRP and peripheral meningeal pain receptors, or nociceptors.

“Our study provides direct anatomical evidence that these antibodies reach the dura but not pia or the cerebral cortex, at least not at a high enough concentration to make a difference,” Dr. Burstein told Neurology Today.

Dr. Burstein told Neurology Today that the findings might help explain why many migraine patients benefit tremendously from this new treatment option (CGRP mAB) whereas others (initially estimated at about 50 percent) do not.

The researchers concluded that similar vascular responses in the meninges might be mediated by different mechanisms, and it is possible that a combination of drugs that prevent dilatation will have to be used, or different therapeutics for different types of migraine headache, he said.

“There is a lot of justified hype surrounding anti-CGRP antibodies as a new class of migraine agents. While highly promising, we think that migraine is more than just a CGRP disorder.”

Expert Commentary

“This is a well written and thought-provoking article,” said Nina Riggins, MD, PhD, FAAN, an assistant clinical professor in the division of headache and facial pain at the University of California, San Francisco.

“The findings are surprising as they appear to indicate that inhibition of CGRP activity with the use of a CGRP mAB has no effect on PPE or dilation of dural arteries, but does have effects on dilation of veins in the pia caused by CSD. Surprisingly, only pial vein dilation was blocked by the CGRP antibody.”

“The current study is more of a snapshot of what occurs with just one wave of CSD,” Dr. Riggins said, “and although the results support the authors' conclusions, longer studies may give different results more relevant to the clinical situation in migraine patients.”

Dr. Riggins added that there is no evidence to date that CGRP can trigger CSD, but there is evidence that by blocking CGRP it is possible to modulate CSD.

Robert Cowan, MD, FAAN, professor of neurology and chief of the division of headache medicine at Stanford University, told Neurology Today that the findings should be useful for neurologists and their migraine patients.

“I think most neurologists are reassured when they understand the mechanism of action of drugs they are using,” he told Neurology Today. “Studies such as this send the message that we don't yet know enough about the method(s) of action of CGRP, and perhaps CSD, in migraine.”

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Effects of fremanezumab on CSD-induced plasma protein extravasation events. (A) Example images of a plasma protein extravasation event (PPEE) occurring on the border of a dural blood vessel (red arrow). (B) Representative image showing location of PPEEs (red circles) during CSD in one rat. (C) Quantification of average frequency of PPEEs per 250 s bins (red) overlaid with a plot of average dural artery diameter (green) post CSD. (D) Quantification of the average number of PPEEs during CSD in drug (red) and vehicle (blue) injected rats.

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“I think most neurologists are reassured when they understand the mechanism of action of drugs they are using. Studies such as this send the message that we dont yet know enough about the method(s) of action of CGRP, and perhaps CSD, in migraine.”—DR. ROBERT COWAN

The findings underscore the importance of understanding what actually happens when a patient is given a medication, he noted. “For example, if one believes that CSD is the instigating event in migraine generation, and CGRP mAbs purportedly mitigate migraine, it might logically be assumed that the method of action of the medication is on CSD.”

If a migraine patient asks about the research, he said, they should be told that migraine is a complex interaction between the brain and its environment that is played out between the nerves, the glia, and the blood vessels. The new study emphasizes the complexity of those relationships, and the variety of paths available to better manage the disease, he explained.

“I would say the study's findings justify the authors' conclusions, at least with respect to rat brains. Drawing broader conclusions in humans is more speculative.”

Disclosures

Drs. Burstein and Riggins reported no disclosures. Dr. Cowan has consulting arrangements with all four manufacturers of CGRP mAbs and both manufacturers of CGRP antagonists.

Link Up for More Information

• Schain AJ, Melo A, Stratton J, et al. CSD-induced arterial dilatation and plasma protein extravasation are unaffected by fremanezumab: implications for CGRP's role in migraine with aura http://www.jneurosci.org/content/early/2019/05/23/JNEUROSCI.0232-19.2019. J Neurosci 2019; Epub 2019 May 24.