Potential for treatment benefit of small molecule CGRP receptor antagonist plus monoclonal antibody in migraine therapy

Abstract

ObjectiveTo provide the first clinical report that 2 calcitonin gene-related peptide (CGRP) therapies, a small molecule CGRP receptor antagonist and an anti-CGRP receptor antibody, can be used concomitantly to treat refractory migraine.MethodsCase reports are presented of 2 patients participating in a long-term safety study of rimegepant 75 mg oral tablets for acute treatment (NCT03266588). After Food and Drug Administration approval of erenumab, both patients started subcutaneous erenumab monthly as allowed per protocol.ResultsPatients were women 44 and 36 years of age with ≥2 decades of self-reported suboptimal response to multiple migraine medications. Patient 1 used rimegepant for 6 months and then started erenumab 70 mg subcutaneous monthly. Despite a response to preventive treatment with erenumab, she experienced substantial relief treating 7 of 7 acute attacks with rimegepant and eliminated regular, frequent use of ibuprofen and a caffeinated analgesic. Patient 2 used rimegepant for 60 days before starting erenumab 140 mg subcutaneously monthly. While on erenumab, 9 of 9 attacks treated with rimegepant responded. She stopped near-daily use of injectable ketorolac and diphenhydramine. While using rimegepant alone or together with erenumab, patients reported no related adverse events.ConclusionsRimegepant 75 mg may be effective for acute treatment during concomitant erenumab preventive administration. The mechanism underlying the benefits of concomitant use of a small molecule CGRP receptor antagonist and an anti-CGRP receptor antibody is unknown and requires further study.ClinicalTrials.gov identifierNCT03266588.Classification of evidenceThis study provides Class IV evidence that for patients with migraine using erenumab, rimegepant is effective for acute treatment.

Safety of Rimegepant, an Oral CGRP Receptor Antagonist, Plus CGRP Monoclonal Antibodies for Migraine

“…The findings in the present study of 13 safety‐evaluable patients are consistent with those in the case report involving 2 patients who simultaneously received rimegepant for acute treatment and erenumab for preventive treatment 16 . While those patients were being treated with the rimegepant‐CGRP mAb combination, no AEs related to treatment were observed.…”

“…While it is unknown what precise mechanism(s) might underlie the added therapeutic benefit of oral rimegepant acute treatment in combination with injectable CGRP mAb preventive treatment, the presence of up to 55% circulating free CGRP levels each month may increase the propensity for breakthrough attacks in people with migraine, despite ongoing CGRP mAb treatment. As presented previously, 16 other factors contributing to the added benefit of rimegepant may include ~280× smaller physical size; higher inherent membrane permeability, greater functional inhibition of CGRP signaling, differential receptor kinetics, and/or the ability to withstand a wave of CGRP release. Additional studies are needed to determine whether these or other differences are the primary factors underlying the therapeutic benefits of combination therapy with rimegepant and CGRP mAbs.…”

“…Further, the preventive efficacy profile is similar for the receptor‐targeting CGRP mAb erenumab, indicating that CGRP receptor occupancy may also decrease between injections as exposures drop over time, providing an opportunity for added benefit with rimegepant. Support for the potential benefit of a CGRP receptor‐targeting small molecule in combination with a receptor‐targeting mAb comes from a case report showing that open‐label rimegepant consistently and successfully treated breakthrough migraine attacks in 2 patients on preventive erenumab therapy 16 . Taken together, these data suggest that not all CGRP signaling is blocked by preventive treatment with the CGRP mAbs.…”

“…The US Food and Drug Administration has approved 4 CGRP mAbs for the prevention of migraine and 2 gepants for the acute treatment of migraine 15 . A previous case report of 2 patients receiving erenumab suggests that rimegepant (Nurtec ODT, Biohaven Pharmaceutical Holding Company Ltd., New Haven, CT, USA) may be used acutely to relieve attacks without tolerability or safety problems in patients receiving preventive CGRP mAbs 16 …”

Potential for treatment benefit of small molecule CGRP receptor antagonist plus monoclonal antibody in migraine therapy

“…In the article "Potential for treatment benefit of small molecule CGRP receptor antagonist plus monoclonal antibody in migraine therapy" by Mullin et al, 1 first published online January 13, 2020, the last sentence of the abstract's Results should read "While using rimegepant alone or together with erenumab, patients reported no related adverse events." The authors regret the error.…”