erenumab

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erenumab

GtoPdb Ligand ID: 9250

Synonyms: Aimovig® | AMG 334 | AMG-334 | erenumab-aooe

erenumab is an approved drug (FDA & EMA (2018))

Comment: Erenumab (erenumab-aooe, AMG-334) is a first-in-class fully human monoclonal antibody targeting the calcitonin gene-related peptide receptor (CGRPR) [7] (and the first approved GPCR targeted monoclonal). Antibody production was initiated by immunising mice with polypeptides from the N-terminal extracellular domains of human CRLR and human RAMP1, which are subunits of the CGRPR protein complex. Erenumab is used clinically to prevent migraine headache. The selectivity of erenumab for the CGRPR vs. the AMY₁ receptor has not been fully established.

Anti-CGRPR antagonistic monoclonals are being developed in place of non-peptide small molecule CGRPR antagonists as these have suffered from hepatotoxicity liability (although this has been largely overcome by using different chemotypes) when tested as migraine prophylactics. Antibodies have the positive attributes of being able to span the relatively large binding domain across the CGRPR complex to provide effective blockade, offer the potential for selectivity given the similarity with other receptors in the family, and exhibit a prolonged serum half-life which facilitates longer dosing intervals [1].

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Summary of Clinical Use
Erenumab received US FDA approval in May 2018 as a once-monthly injection as a preventative treament for migraine sufferers. One of the determining clinical trials leading to this marketing authorisation was the Phase 3 ARISE trial, NCT02483585, for which results were published in May 2018 [2]. Phase 2 trial results were published in [8] and reported a significant reduction in migraine episodes in the patient group receiving the highest erenumab dose (70mg; monthly subcutaneous administration) compared to the placebo control group. EMA approval was granted in August 2018 for the treament of patients who suffer 4 or more mirgaines/month.

Summary of Clinical Use

Erenumab received US FDA approval in May 2018 as a once-monthly injection as a preventative treament for migraine sufferers. One of the determining clinical trials leading to this marketing authorisation was the Phase 3 ARISE trial, NCT02483585, for which results were published in May 2018 [2]. Phase 2 trial results were published in [8] and reported a significant reduction in migraine episodes in the patient group receiving the highest erenumab dose (70mg; monthly subcutaneous administration) compared to the placebo control group. EMA approval was granted in August 2018 for the treament of patients who suffer 4 or more mirgaines/month.

Mechanism Of Action and Pharmacodynamic Effects
Calcitonin gene-related peptide (CGRP) is a neuropeptide involved in migraine pathophysiology [3-5]. Antagonism of CGRP's interaction with its cognate receptor CGRPR by small molecules proved that this was a valid pathway for migraine intervention. However, small molecule CGRPR antagonists showed considerable hepatotoxicity which precluded futher clinical development. More recently, anti-CGRPR antibodies with antagonist activity have entered clinical development pipelines as an alternative to small molecule antagonists. Erenumab is one such monoclonal. Anti-CGRP ligand antibodies are also in development to target this same migraine pathway (for example, galcanezumab, fremanezumab and ALD403) [6].

Mechanism Of Action and Pharmacodynamic Effects

Calcitonin gene-related peptide (CGRP) is a neuropeptide involved in migraine pathophysiology [3-5]. Antagonism of CGRP's interaction with its cognate receptor CGRPR by small molecules proved that this was a valid pathway for migraine intervention. However, small molecule CGRPR antagonists showed considerable hepatotoxicity which precluded futher clinical development. More recently, anti-CGRPR antibodies with antagonist activity have entered clinical development pipelines as an alternative to small molecule antagonists. Erenumab is one such monoclonal.
Anti-CGRP ligand antibodies are also in development to target this same migraine pathway (for example, galcanezumab, fremanezumab and ALD403) [6].

Clinical Trials
Clinical Trial ID	Title	Type	Source	Comment	References
NCT02483585	Study to Evaluate the Efficacy and Safety of Erenumab (AMG 334) Compared to Placebo in Migraine Prevention	Phase 3 Interventional	Amgen