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Monoclonal antibodies blocking CGRP transmission: An update on their added value in migraine prevention - 24/11/20

Doi : 10.1016/j.neurol.2020.04.027 
J. Schoenen , M. Manise, R. Nonis, P. Gérard, G. Timmermans
 Headache Research Unit, Department of Neurology, University of Liège, Citadelle Hospital, 4000 Liège, Belgium 

Corresponding author.

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Highlights

By blocking CGRP transmission for a long duration in the peripheral portion of the trigeminovascular system, responsible for migraine headache, monoclonal antibodies blocking CGRP or its receptor (CGRP/rec mAbs) are in fact durable attack treatments that leave in theory untouched the central nervous system facets of migraine pathophysiology.
Pivotal randomized placebo-controlled trials have proven their efficacy in migraine prevention, rapid onset of action, sustainability and long duration of effect, quality of life improvement, safety and excellent tolerance. They are also effective, though at a slightly lower degree, in the most disabled subgroups of patients, like those with chronic migraine, prior preventive treatment failures or medication overuse headache.
There are subtle differences between eptinezumab, erenumab, fremanezumab and galcanezumab, but comparisons between respective trials are not reliable because of methodological differences and the lack of direct comparative trials.
Compared with the most effective classical preventive migraine therapies, CGRP/rec mAbs stand out by an unprecedented favorable efficacy over adverse effect profile, rather than by a superior effect size.
Preliminary pharmaco-economic studies suggest that erenumab is cost-effective in chronic migraine, but not in episodic migraine unless its price is reduced and indirect costs are considered.

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Abstract

The avenue of effective migraine therapies blocking calcitonin gene-related peptide (CGRP) transmission is the successful outcome of 35 years of translational research. Developed after short-acting, the small antagonists of the CGRP receptor (the “gepants”), the monoclonal antibodies blocking CGRP or its receptor (CGRP/rec mAbs) have changed the paradigm in migraine treatment. Contrary to the classical acute medications like triptans or nonsteroidal anti-inflammatory drugs (NSAIDs) with a transient effect, they act for long durations exclusively in the peripheral portion of the trigeminovascular system and can thus be assimilated to a durable attack treatment, unlike the classical preventives that chiefly act upstream on the central facets of migraine pathophysiology. Randomized controlled trials (RCT) of eptinezumab, erenumab, fremanezumab and galcanezumab have included collectively several thousands of patients, making them the most extensively studied class of preventive migraine treatments. Their results clearly indicate that CGRP/rec mAbs are significantly superior to placebo and have been comprehensively reviewed by Dodick [Cephalalgia 2019;39(3):445-458]. In this review we will briefly summarize the placebo-subtracted outcomes and number-needed-to-treat (NNT) of these pivotal RCTs and analyze new and post-hoc studies published afterwards focusing on effect size, effect onset and sustainability, response in subgroups of patients, safety and tolerability, and cost-effectiveness. We will also summarize our limited real-world experience with one of the CGRP/rec mAbs. Although methodological differences and lack of direct comparative trials preclude any reliable comparison, the overall impression is that there are only minor differences in efficacy and tolerability profiles between the four monoclonals: the average placebo-subtracted 50% responder rates for reduction in migraine headaches are 21.4% in episodic migraine (NNTs: 4–5), 17.4% in chronic migraine (NNTs: 4–8). Patients with an improvement exceeding 50% are rare, chronic migraineurs with continuous headache are unlikely to be responders and migraine auras are not improved. The effect starts within the first week after administration and is quasi maximal at one month. It is sustained for long time periods and may last for several months after treatment termination. CGRP/rec mAbs are effective even after prior preventive treatment failures and in patients with medication overuse, but the effect size might be smaller. They significantly reduce disability and health care resource utilization. The adverse effect profile of CGRP/rec mAbs is close to that of placebo with few minor exceptions and despite concerns related to the safeguarding role of CGRP in ischemia, no treatment-related vascular adverse events have been reported to date. Putting the CGRP/rec mAbs in perspective with available preventive migraine drug treatments, their major advantage seems not to be chiefly their superior efficacy but their unprecedented efficacy over adverse event ratio. Regarding cost-effectiveness, preliminary pharmaco-economic analyses of erenumab suggest that it is cost-effective for chronic migraine compared to no treatment or to onabotulinumtoxinA, but likely not for episodic migraine unless attack frequency is high, indirect costs are considered and its price is lowered.

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Keywords : CGRP/CGRPrec monoclonal antibodies, Efficacy, Tolerability, Added-value, Migraine prevention


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Vol 176 - N° 10

P. 788-803 - décembre 2020 Retour au numéro
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