Combination of CGRP Monoclonal Antibodies and Gepants Safe as Migraine Preventive Strategy


In a cohort of nearly 250 patients with chronic or episodic migraine, less than 2% of patients experienced adverse events while on combination treatment.

Taoufik Alsaadi, chief medical officer and chair of the neurology department at the ACPN

Taoufik Alsaadi, MD, FAAN

A recently published retrospective study found that a combination of calcitonin gene-related peptide (CGRP) monoclonal antibodies (mABs) with gepants was a safe and well-tolerated treatment approach for patients with migraine. To the authors knowledge, this was the largest, real-world descriptive study that reported on the adverse events (AEs) experienced by patients who were prescribed CGRP antagonists and gepants concurrently.

In this single-center study performed at the American Center for Psychiatry and Neurology (ACPN) at Abu Dhabi, UAE, 516 patients with episodic or chronic migraine were identified, 234 of which were administered gepants in addition to their CGRP mAb (rimegepant: n = 215; ubrogepant: n = 19). With the two gepants and three CGRP mAbs currently available in UAE, there were various combinations that could take place with the treatment plans of patients: any subject independently taking only one of the two drug classes, or neither drug class, was excluded from the study analysis.

Led by Taoufik Alsaadi, chief medical officer and chair of the neurology department at the ACPN, more than half of the cohort (59.4%) had no previous preventative migraine treatment and most patients (68.7%) had no family history of migraine. In total, 42 of patients switched from 1 CGRP mAb to another, and 5 of these also switched from 1 gepant to another. Out of the 215 patients who initially took rimegepant, 11 patients were later switched to ubrogepant because of lack of efficacy, while 1 out of the 19 patients switched from ubrogepant to zolmitriptan as a result of ubrogepant no longer being covered by their insurance.

The study was limited by the retrospective nature and single-center design. In addition, the effectiveness of these combination treatment were not assessed. “We strongly believe that a larger sample, more real-world data, and randomized clinical trials are needed to fully characterize the effectiveness, safety, and tolerability of this combination treatment,” the study authors wrote.

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Out of the 234 patients on combined therapy, 3 (1.2%) patients reported AEs, which included peri-labial numbness and cough, nausea and vomiting, and constipation (each 1). None of these reported AEs led to discontinuation of combined treatment. The patient cohort was on treatment for an average of 2.55 months, although 1 patient remained on combined treatment for an extended period of 22 months. This patient, who consumed 168 pills throughout that time, reported no AEs while on treatment. As for the 3 patients who reported AEs, 2 were on a combined treatment of erenumab and rimegepant.

"Although in clinical practice specialists are considering this combination therapy for migraine treatment on the basis of a limited number of studies that endorse its safety, only case series so far have documented its effectiveness," Alsaaki et al wrote. "Delving into the pharmacodynamic perspective, because gepants can potentially penetrate the blood–brain barrier while CGRP monoclonal antibodies function in the peripheral system, it is logical to contemplate that combining the two could result in a synergistic impact, potentially enhancing effectiveness."

The use of gepants was for acute attacks, and as such they were used infrequently on an as-needed basis, while mAbs, as indicated for preventive therapy, were used for long-term therapy. Authors noted that this raises the question of the validity of the findings; however, the average number of utilized gepant pills in the study, along with the average months of follow-up, would support the safety and tolerability findings of this combination treatment.

"Gepants selectively block CGRP receptors while on the other hand CGRP mAbs such as eptinezumab and galcanezumab directly target the CGRP ligand. Both pathways aim to regulate the CGRP pathway,” the study authors wrote. “However, the potential synergy in combining gepants and CGRP mAbs in migraine treatment depends on points of intervention within the CGRP pathway. Blockade of ligand and receptor could possibly lead to complex outcomes that are challenging to predict accurately."

1. Alsaadi T, Suliman R, Santos V, et al. Safety and tolerability of combining CGRP monoclonal antibodies with gepants in patients with migraine: a retrospective study. Neurol & Ther. Published online February 15, 2024. doi:10.1007/s40120-024-00586-w
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