New Insights into the Regulation of CGRP-Family Receptors.

The calcitonin gene-related peptide (CGRP) receptor system has emerged as an important drug target for migraine. This is highlighted by the recent regulatory approval of the first drug targeting the CGRP signalling pathway, the CGRP receptor antibody erenumab. The cellular compartments in which receptors are found affects drug access and whether they can exert their effects. G protein-coupled receptors (GPCRs) were thought to signal only at the cell surface, but it is now recognised that some GPCRs, including the CGRP receptor, undergo sustained signalling from endosomes, once internalised in response to ligand. What does this mean for drugs like erenumab? This review covers recent insights into the regulation of CGRP family receptors and examines what implications this may have on drug activity.

Gingell JJ ，Hendrikse ER ，Hay DL 《-》

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

To 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. Case 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. Patients 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. Rimegepant 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. NCT03266588. This study provides Class IV evidence that for patients with migraine using erenumab, rimegepant is effective for acute treatment.

Mullin K ，Kudrow D ，Croop R ，Lovegren M ，Conway CM ，Coric V ，Lipton RB ... -  《-》

CGRP and Migraine: The Role of Blocking Calcitonin Gene-Related Peptide Ligand and Receptor in the Management of Migraine.

Maasumi K ，Michael RL ，Rapoport AM 《-》

Pharmacological characterisation of erenumab, Aimovig, at two calcitonin gene-related peptide responsive receptors.

Calcitonin gene-related peptide (CGRP) is involved in migraine pathophysiology. CGRP can signal through two receptors. The canonical CGRP receptor comprises the calcitonin receptor-like receptor and receptor activity-modifying protein 1 (RAMP1); the AMY1 receptor comprises the calcitonin receptor with RAMP1. Drugs that reduce CGRP activity, such as receptor antagonists, are approved for the treatment and prevention of migraine. Despite being designed to target the canonical CGRP receptor, emerging evidence suggests that these antagonists, including erenumab (a monoclonal antibody antagonist) can also antagonise the AMY1 receptor. However, it is difficult to estimate its selectivity because direct comparisons between receptors under matched conditions have not been made. We therefore characterised erenumab at both CGRP-responsive receptors with multiple ligands, including αCGRP and βCGRP. Erenumab antagonism was quantified through IC50 and pKB experiments, measuring cAMP production. We used SK-N-MC cells which endogenously express the human CGRP receptor, and HEK293S and Cos7 cells transiently transfected to express either human CGRP or AMY1 receptors. Erenumab antagonised both the CGRP and AMY1 receptors with an ~20-120-fold preference for the CGRP receptor, depending on the cells, agonist, analytical approach and/or assay format. Erenumab antagonised both forms of CGRP equally, and appeared to act as a competitive reversible antagonist at both receptors. Despite being designed to target the CGRP receptor, erenumab can antagonise the AMY1 receptor. Its ability to antagonise CGRP activity at both receptors may be useful in better understanding the clinical profile of erenumab.

Garelja ML ，Alexander TI ，Bennie A ，Nimick M ，Petersen J ，Walker CS ，Hay DL ... -  《-》

History and Review of anti-Calcitonin Gene-Related Peptide (CGRP) Therapies: From Translational Research to Treatment.

Objective - To briefly describe the history of and available data on anti-calcitonin gene-related peptide (CGRP) therapies for headache. Background - CGRP was proposed as a target for primary headache therapies. Translational research involved moving from delineating the relationships between CGRP and primary headaches and the clinical development of anti-CGRP treatments. The first anti-CGRP treatment, an intravenous CGRP-receptor antagonist or gepant, olcegepant, was described as effective in terminating migraines in humans in 2004. Methods - The author briefly reviews some of the pathophysiology and translational research that led to the development of the gepants initially and then subsequently to the anti-CGRP and anti-CGRP receptor monoclonal antibodies. All accessible randomized controlled trials, abstracts, platform presentations, and press releases on the monoclonal antibody trials are summarized. The trajectory from bench research to the approval of the first anti-CGRP receptor monoclonal antibody for clinical use in migraine prevention, erenumab, is discussed, as well as potential clinical uses of the anti-CGRP treatments. Results - The US Food and Drug Administration (FDA) approved erenumab, an anti-CGRP receptor monoclonal antibody, for prevention of migraine May 17, 2018. At the time of this writing (May 2018), 2 other anti-CGRP monoclonal antibodies have been submitted to the FDA for the indication of prevention of migraine, galcanezumab and fremanezumab. Galcanezumab has reportedly shown effectiveness in preventing episodic cluster headache as well, although has not yet been submitted to the FDA for this indication. Eptinezumab will likely be submitted to the FDA for prevention of migraine later in 2018. Two gepants, ubrogepant and rimegepant, have completed positive pivotal trials for acute treatment of migraine, but have not yet been submitted to the FDA for this indication. Conclusions - The development of anti-CGRP therapies opens a new era in the acute and preventive treatment of primary headache disorders.

Tepper SJ 《-》