Calcitonin gene-related peptide (receptor) antibodies: an exciting avenue for migraine treatment

DOI: https://doi.org/10.1186/s13073-018-0524-7

Abstract-Summary Specific prophylactic migraine treatments are urgently needed because of the unmet needs of many migraine patients.

Why Do We Need New Drugs for Migraine? Migraine attacks typically consist of severe, unilateral headaches that are accompa- nied by nausea, vomiting and photo- and phonophobia, lasting 4–72 h [67].

Migraine is a multifactorial genetic disorder for which several dozen gene vari- ants, all with small effect size, have been identified that suggest the involvement of neuronal and vascular mechanisms in disease pathology [182].

Similar disease mechanisms, albeit involving different genes, have surfaced in rare monogenic familial hemiplegic migraine (FHM) and in various monogenic syn- dromes in which migraine is very prevalent among mutation carriers, for example, familial advanced sleep-phase syndrome (FASPS) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) [182]. Attack frequency may increase with overuse of acute headache medication, resulting in a transition from episodic to chronic migraine (defined as 15 or more headache days per month with at least 8 migraine days).

Calcitonin Gene-Related Peptide and Its Receptor: Drug Targets for the Treatment of Migraine Goadsby and colleagues [183] described a trial on the CGRP receptor antibody erenumab in a population of 955 migraine patients with episodic migraine.

4.2 Preventive Treatment

695

Both doses of erenumab significantly differed from placebo in the primary end point; the mean decrease in migraine days per month was 3.2 (70  mg) and 3.7 (140 mg) days in the erenumab group and 1.8 days in the placebo group.

A ≥50% reduction in the mean number of migraine days per month was achieved for 43% (70 mg) and 50% (140 mg) of patients when compared to pla- cebo (27%).

Silberstein and colleagues [184] performed a trial with the CGRP antibody

fremanezumab in 1130 patients with chronic migraine.

A ≥50% reduction in the mean number of headache days per month was achieved for 38% (quarterly) and 41% (monthly) of patients when compared to pla- cebo (18%).

CGRP Mechanisms and Challenges It is interesting to speculate whether there is a clinically relevant difference between blockade of the receptor (erenumab) or blockade of CGRP itself (eptinezumab, fremanezumab, galcanezumab).

The amylin1 receptor (calcitonin receptor (CTR) instead of CLR coupled to RAMP1 and RCP) was recently described to act as a functional CGRP receptor in the trigeminal system, and probably also in the vasculature [185].

Another relevant question is where the site of action of the antibodies is

located.

Their point of action will most probably be located outside the BBB and could include a vascular site, or neuronal structures that are not protected by the BBB, such as the trigeminal ganglion and the paraventricular structures.

A vascular action for CGRP seems to be present in, for example, the protec- tive mechanism against ischemia (which is relevant in view of cardiovascular safety [185]) or hypertension, as has been demonstrated in CGRP- knockout mice that showed enhanced hypertension in response to angiotensin II infu- sion [186].

Conclusions The advent of CGRP (receptor)-binding antibodies represents a valuable novel treatment option for migraine.

To current prophylactic antimigraine drugs, this is the first class specifically

developed for the treatment of migraine.

The emergence of this novel class of drugs is good news, but it is fair to state that blockade of the CGRP pathway does not seem to be a panacea for all migraine patients, as response rates are not perfect.

Future research should focus on identifying characteristics of patients who do not respond to CGRP (receptor) blockade, for example, genetic factors that deter- mine response.

Acknowledgement A machine generated summary based on the work of MaassenVanDenBrink, Antoinette; Terwindt, Gisela M.; van den Maagdenberg, Arn M.  J. M. 2018  in Genome Medicine.

696

4 Treatment

Shaping the future of migraine targeting Calcitonin-Gene- Related-Peptide with the Disease-Modifying Migraine Drugs (DMMDs)