Safety and Tolerability of 3 CGRP Monoclonal Antibodies in Practice: A Retrospective Cohort Study

Abstract

Objective We sought to assess the safety and tolerability of 3 calcitonin gene‐related peptide (CGRP) monoclonal antibodies in patients with chronic migraine who have failed multiple classes of migraine preventive therapies. Background CGRP is an important neuromodulator implicated in the pathogenesis of migraine. They are approved for the treatment of episodic and chronic migraine. In current clinical practice, CGRP monoclonal antibodies are used in patients who have failed multiple preventive agents, but safety, tolerability, and efficacy have not been well described in real‐world populations outside of clinical trials. Methods This was a single‐center, observational, retrospective study in adults with chronic migraine treated with a CGRP monoclonal antibody between May 1, 2018 and September 30, 2019. Charts were reviewed at 0, 3, and 6 months after treatment. Results From May 1, 2018 to September 30, 2019, 77 patients with chronic migraine were prescribed 90 treatment trials of a CGRP monoclonal antibody. Patients reported adverse outcomes in 2/5 (40.0%) with erenumab 70 mg, 32/46 (69.6%) with erenumab 140 mg, 8/16 (50.0%) with fremanezumab, and 15/23 (65.2%) with galcanezumab. The most frequent adverse effects were constipation and injection site reactions. Adverse effects leading to discontinuation were reported as follows: erenumab 70 mg 1/5 (20.0%), erenumab 140 mg 10/46 (22.7%), fremanezumab 1/16 (6.3%), and galcanezumab 1/23 (4.3%), with 13/90 (14.4%) discontinuation rate overall. The most frequent reasons for discontinuation were lack of improvement in 17/90 (18.9%) and constipation in 4/90 (4.4%). A 50% or greater reduction in the number of severe headache days per month was achieved for 32/66 (48.5%) at 3 months and 17/48 (35.4%) at 6 months. Conclusions In patients with chronic migraine, the 3 CGRP monoclonal antibodies were well tolerated, and reduced the number of severe headache days.

Erenumab for Migraine Prevention in a 1-Year Compassionate Use Program: Efficacy, Tolerability, and Differences Between Clinical Phenotypes

“…Surprisingly, constipation was reported in maximally 3.2% of patients in the erenumab RCTs. By contrast, it is the most prevalent side effect mentioned in most real-world studies where its incidence ranges from around 8 (31,32) to more than 20% (18,19,27,29,33). The reason for the discrepancy between RCT and subsequent studies is not clear.…”

“…A number of "real-world" studies and registries of migraine treatment with erenumab in North American (18)(19)(20)(21)(22)(23)(24)(25), European (26)(27)(28)(29)(30)(31)(32)(33), or Australian patients (34) have been published recently and included mainly patients with CM (Supplementary Table 1). With one exception (21), all the studies from North America were retrospective (18-20, 22, 23, 26), while all studies but two (26,30) studies from other geographic areas had a prospective design.…”

“…Constipation may have been underreported in RCT. Constipation seems to occur less frequently with the CGRP-ligand mAbs (18). Erenumab-induced constipation could be related to the finding that the calcitonin gene Calcrl, which encodes the CGRP receptor component to which erenumab binds, is highly expressed in enteric neurons in mice (43).…”

Constipation Caused by Anti-calcitonin Gene-Related Peptide Migraine Therapeutics Explained by Antagonism of Calcitonin Gene-Related Peptide’s Motor-Stimulating and Prosecretory Function in the Intestine

“…It is worth noting that the lowest rate of erenumab-associated constipation (7.6%) was found in Spanish patients ( Belvís et al, 2021 ), while the highest rates (32.6–65%) were found in Dutch ( de Vries Lentsch et al, 2021 ) and US ( Alex et al, 2020 ; Kanaan et al, 2020 ) patients as well as in a Danish cohort of patients with headache attributed to mild traumatic brain injury ( Ashina H. et al, 2020 ). A more detailed analysis indicates that constipation due to erenumab depends on dose ( Alex et al, 2020 ) and is most prominent at the start of treatment ( Lambru et al, 2020 ). Antibodies targeting CGRP itself appear to be equally liable to cause constipation as erenumab ( Table 1 ).…”

CGRP Monoclonal Antibodies for Prevention of Migraine: There are Many Adverse Effects

“…One of the observational studies concluded that adverse effects resulted in 33% of erenumab discontinuations [2]. Another study described 63.3% of patients as having reported an adverse effect, but they concluded that the CGRP monoclonal antibodies were well tolerated [3]. We published a study of 119 chronic migraine patients who had utilized one of the CGRP monoclonals [4].…”