Anti-CGRP monoclonal antibodies in cluster headache: what can we learn from recent clinical trials
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Anti-CGRP monoclonal antibodies in cluster headache: what can we learn from recent clinical trials Luca Giani 1 & Alberto Proietti Cecchini 1 & Massimo Leone 1
# Fondazione Società Italiana di Neurologia 2020
Calcitonin gene-related peptide (CGRP) is considered a key molecule in the pathophysiology of cluster headache (CH). Sensory neurons in the trigeminal ganglion are rich in CGRP and release it upon stimulation. The CGRP released by unmyelinated trigeminal sensory neurons leads to the activation of Aδ meningeal nociceptive trigeminal fibers and modulates pain transmission in the trigeminocervical complex (TCC). This process takes place both in periphery (either inside the trigeminal ganglion or along the nerve trunk through axon-axon synapses) and inside the TCC. CGRP probably participates also in a connection between the trigeminal ganglion and the sphenopalatine ganglion. In humans, a clear link between the CGRP pathway and CH was first demonstrated by the observation of an increase in CGRP concentrations in the ipsilateral-to-the-pain external jugular vein during CH attacks. The subsequent administration of sumatriptan terminates the attack and simultaneously normalizes the CGRP plasma levels. Further, the intravenous infusion of CGRP can induce CH attacks in patients with active CH (i.e., episodic in-bout and chronic CH). Accordingly, a novel therapeutic approach with monoclonal antibodies (MoAbs) against CGRP was trialed in recent years to prevent CH. Efficacy of galcanezumab and fremanezumab, both humanized anti-CGRP IgG monoclonal antibodies already approved for the treatment of migraine, was investigated in phase III clinical trials in episodic and chronic CH. Galcanezumab proved effective in reducing the frequency of attacks in episodic CH (ECH) [1]. Galcanezumab 300 mg was compared with placebo; both drugs were administered subcutaneously at baseline and after 4 weeks. No other preventive treatments were allowed. One hundred and six patients were finally enrolled and randomized. The baseline frequency of headaches was similar in the * Massimo Leone [email protected] 1
Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico “Carlo Besta”, Via Celoria, 11, 20133 Milan, Italy
two groups, at 17.8 ± 10.1 attacks/week (± SD) in the galcanezumab group and 17.3 ± 10.1 in the placebo group. The primary endpoint was the mean change in the weekly frequency of CH attacks from baseline across weeks 1 through 3 after the first dose. The galcanezumab group had a reduction of 8.7 ± 1.4 attacks/week, while in the placebo group, the attacks went down by 5.2 ± 1.3 (between-group difference in mean change, 3.5 attacks per week; 95% confidence interval, 0.2 to 6.7; p = 0.04). The first key secondary endpoint was the percentage of patients who had a reduction of at least 50% in headache frequency at week 3: this was 71% in the galcanezumab group and 53% in the placebo group (p = 0.046) [1]. Examining the single-week epochs, the efficacy of the active treatment over placebo was signif
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