Monoclonal antibodies blocking CGRP transmission: An update on their added value in migraine prevention

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.