Increased infection risk in patients on preventive CGRP-targeting therapies- a meta-analysis and clinical effect assessment.

Abstract

Background: Calcitonin gene related peptide (CGRP) pathway targeting therapies have proven efficacy, safety and tolerability. However, CGRP is also involved in immune responses, and reports of an increased risk of infection have emerged. This meta-analysis aims to verify whether CGRP-targeting therapies show evidence of increasing infection risk.

Methods: A systematic review was conducted according to PRISMA-Harms guidelines. A PubMed and Embase search result selection and extraction was performed. Risk of bias, sensitivity analysis, and fixed/random effects network meta-analyses were conducted for incidence of infectious adverse events in the studied populations with subsequent effect size assessment. An additional infectious serious adverse event search was performed in double-blind and open-label studies.

Results: The search and selection process yielded 37 randomized placebo-controlled trials. 22,518 patients (77.3% women) treated with erenumab, fremanezumab, galcanezumab, eptinezumab, atogepant and rimegepant participated in these studies. Preventive CGRP-targeting therapies appear to increase the infection relative risk (RR = 1.08 [1.01; 1.14], p = 0.016, Number Needed to Harm [NNH] = 287). However, in individual analyses only galcanezumab and eptinezumab showed an increase in risk of infections: galcanezumab at clinically used doses (RR 1.13 [1.02; 1.25], p = 0.024, NNH = 77); eptinezumab at higher doses (RR 1.23 [1.04; 1.45], p = 0.015, NNH = 24). Fremanezumab was associated with fewest infectious SAEs (n = 3 in 3 studies), while erenumab showed the highest incidence of these events (n = 36 in 11 studies).

Conclusions: CGRP has multiple and often potentially opposing effects on the immune system. In effect, preventive CGRP pathway antagonists (especially eptinezumab and galcanezumab) possibly only mildly increase the risk of infections. However, it is unlikely to affect most migraine patients considering relatively high NNH, low effect size and few infectious SAEs reported so far. The result of CGRP-targeting therapies potentially depends on the type of pathogen and patient's immune status. Consequently, in immunocompromised patients or at public health levels the increased infection risk may have more pronounced effect.