Retracted: Calcitonin Gene‐Related Peptide (CGRP) Antagonists: A comprehensive review of safety, efficacy and prescribing information

Abstract

What is known and objectives Migraine is a disabling disorder that affects individuals of all ages. To date, there are multiple limitations to using guidelines‐recommended treatments and preventive therapies. The goal of this review was to provide a comprehensive clinical review of the safety, efficacy and prescribing information of the emerging calcitonin gene‐related peptide (CGRP) antagonists. Agents in this new pharmacologic class were approved by the US Food and Drug Administration (FDA) for the treatment of acute migraine attack pain and the management of episodic and chronic migraine. Methods A total of 12 randomized, placebo‐controlled clinical trials were identified and included in the review utilizing databases such as clinicaltrial.gov, PubMed and EMBASE. The trials collectively evaluated six CGRP antagonists starting from the orally administered CGRPs such as rimegepant and ubrogepant, to the quarterly IV administered CGRP such as eptinezumab, and the monthly/quarterly subcutaneously administered agents such as erenumab, fremanezumab and galcanezumab. Results and discussion All agents displayed significant efficacy compared with placebo, measured by reduction in mean monthly migraine days (MMD). In addition, CGRP antagonists displayed a great tolerability profile with few adverse effects. These medications were neither associated with any cardiovascular‐related adverse effects, nor do they currently have specific contraindications to pre‐existing cardiovascular conditions. This can present a safe alternative to a wide range of patients who cannot be appropriately treated with first‐line treatments such as triptans. No treatment‐related death was reported in any of the clinical trials outlined and discussed. What is new and conclusion Calcitonin gene‐related peptide antagonists are safe and efficacious medications both in treating acute migraine headache pain and the management of episodic and chronic migraine. Head‐to‐head comparative studies with current guideline‐recommended treatments are needed. However, CGRP antagonists are promising agents that present an alternative solution for patients living with migraine.

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

“…However, ubrogepant, rimegepant and atogepant have meanwhile been approved as migraine therapeutics by the US Food and Drug Administration (FDA), and other regulatory authorities including the European Medicines Agency (EMA) were following suit in licensing these gepants. The phase 3 trials of these small molecule CGRP receptor antagonists revealed only rare and transient elevations of serum aminotransferase levels ( Croop et al, 2019 ; Dodick et al, 2019 ; Lipton et al, 2019a , b ; Ailani et al, 2020 ; Omaer et al, 2021 ) that did not lead to clinically manifest liver injury.…”

“…The gepants in clinical use are in general well tolerated as proved in the RCTs during clinical development. Apart from infections of the upper respiratory, urinary and/or gastrointestinal tract, nausea (1.8–4.7% of patients on gepants) was the most common gastrointestinal complaint reported in phase 3 trials of ubrogepant, rimegepant and atogepant ( Croop et al, 2019 ; Lipton et al, 2019a , b ; Ailani et al, 2020 , 2021 ; Omaer et al, 2021 ). Diarrhea was noted in 2.5–2.7% of patients on ubrogepant ( Ailani et al, 2020 ) while constipation was reported in 6.9–7.7% of subjects taking atogepant ( Ailani et al, 2021 ), but were not noticed in the trials of the other gepants.…”

“…Differences in the constipation rates may provide clues as to whether pharmacodynamic and/or pharmacokinetic factors play a role. The two classes of anti-CGRP therapeutics differ profoundly in their pharmacokinetic profile, given that gepants have a comparatively short biological half-life (5–11 h) while the CGRP and CGRP receptor antibodies have a biological half-life of 27–31 d (for reviews see Szkutnik-Fiedler, 2020 ; Omaer et al, 2021 ). Thus it may make a difference if CGRP signaling in the intestine is continuously blocked by antibody therapeutics for a prolonged period of time as compared to a more intermittent receptor blockade caused by gepant therapy.…”

“…Calcitonin gene-related peptide was overtaking many a neuropeptide in its path to clinical exploitation, given that only some 20 years after its discovery ( Rosenfeld et al, 1983 ) a landmark paper ( Olesen et al, 2004 ) provided clinical proof of the concept that a small molecule antagonist of CGRP (code name BIBN4096BS, later given the international non-proprietary name olcegepant) is able to prevent and treat migraine. Since then several small molecule antagonists (as a group termed gepants ) have been developed for use in migraine management, followed by the successful introduction of monoclonal antibodies targeting CGRP or its receptor (for reviews see Edvinsson, 2019 ; Hargreaves and Olesen, 2019 ; Omaer et al, 2021 ). The results of the randomized controlled trials (RCTs) in phase 3 of clinical development attributed not only satisfactory efficacy but also acceptable safety and tolerability to these CGRP-directed migraine therapeutics.…”