Friday, June 23, 2017

Drugs in Clinical Pipeline: Erenumab | AMG 334 | Prevention of Migraines | CGRP Receptor Antagonist Monoclonal Antibody

Erenumab (AMG 334) is the first human monoclonal antibody antagonist against the Calcitonin Gene-Related Peptide Receptor (CGRP) receptor. Like the small-molecule CGRP-receptor antagonists, Erenumab fully antagonizes CGRP-receptor function and is dose-dependently effective in an in vivo target coverage model that exhibits translatability to humans.

Erenumab fully inhibited CGRP-stimulated cAMP production with an IC50 of 2.3 nM in cell-based functional assays (human CGRP receptor) and was 5000-fold more selective for the CGRP receptor than other human calcitonin family receptors, including adrenomedullin, calcitonin, and amylin receptors.

Erenumab is currently in clinical development for the prevention of migraine. On 21st June 2017, Novartis announced that the European Medicines Agency (EMA) has accepted its Marketing Authorization Application (MAA) for Erenumab in the prevention of migraines.

Calcitonin Gene-Related Peptide (CGRP) as a Target for Migraines Treatment
Migraine is a distinct neurological disease which involves recurrent attacks of moderate to severe head pain that is typically pulsating, often unilateral and associated with nausea, vomiting and sensitivity to light, sound and odors.
Migraine has a profound and limiting impact on an individual’s abilities to carry out everyday tasks, and was declared by the World Health Organization (WHO) to be one of the top 10 causes of years lived with disability for men and women. It remains under-recognized, under-treated, associated with disability, reduced quality of life, and financial cost to society.
Existing preventive therapies have been repurposed from other indications and are often associated with poor tolerability and lack of efficacy, which leads to increasing discontinuation rates and dissatisfaction among patients. The cause and triggers of migraine are not fully understood as no two migraines are the same.
Calcitonin gene-related peptide (CGRP) is a 37-aminoacid-long peptide expressed in both the central and peripheral nervous systems. CGRP belongs to the calcitonin family of peptides that also consists of adrenomedullin, calcitonin, and amylin, all of which have important physiologic functions: adrenomedullin is a potent vasodilator, causes prolactin release, and plays a role in diuresis and food intake; calcitonin is involved in the control of bone metabolism; and amylin is thought to be a gut-brain axis hormone that improves glucose metabolism, acts as a trophic factor to promote cell growth, and modulates inflammation.
CGRP is one of the most potent vasodilators discovered to date. It also plays a role in a variety of other activities, including modulation of nociception and neurogenic inflammation. Several lines of evidence suggest a role for CGRP in migraine pathogenesis:
A: Elevated levels of CGRP have been detected in individuals with migraine.
B: Intravenous CGRP infusion produces lasting headaches in healthy individuals and migraine headache in migraineurs.

Most importantly, several small-molecule CGRP-receptor antagonists have shown clinical efficacy in acute migraine and in migraine prevention.