New Trends in Migraine Pharmacology: Targeting Calcitonin Gene-Related Peptide (CGRP) With Monoclonal Antibodies

Abstract

Migraine is a common neurologic disorder characterized by attacks consisting of unilateral, throbbing headache accompanied by photophobia, phonophobia, and nausea which remarkably reduces the patients' quality of life. Not migraine-specific non-steroidal anti-inflammatory drugs (NSAIDs) are effective in patients affected by mild episodic migraine whilst in moderate or severe episodic migraine and in chronic migraineurs triptans and preventative therapies are needed. Since these treatments are endowed with serious side effects and have limited effectiveness new pharmacological approaches have been investigated. The demonstrated pivotal role of calcitonin gene-related peptide (CGRP) has fostered the development of CGRP antagonists, unfortunately endowed with liver toxicity, and monoclonal antibodies (mAbs) toward circulating CGRP released during migraine attack or targeting its receptor. Currently, four mAbs, eptinezumab, fremanezumab, galcanezumab for CGRP and erenumab for CGRP canonical receptor, have been studied in clinical trials for episodic and chronic migraine. Apart from the proven effectiveness, these antibodies have resulted well tolerated and could improve the compliance of the patients due to their long half-lives allowing less frequent administrations. This study aims at investigating the still poorly clear pathogenesis of migraine and the potential role of anti-CGRP mAbs in the scenario of prophylaxis of migraine.

Keywords: CGRP; anti-CGRP; migraine; monoclonal antibodies anti-CGRP; pharmacology of migraine; treatment.

FIGURE 1

CGRP occurrence and pathway in migraine. Expression of CGRP, CLR, and RAMP1 in human dura vessels: (A) CGRP immunoreactivity is found in thin fibers in the adventitia; (B) cross and longitudinal sections showing RAMP1 expression in the cytoplasm of smooth muscle cells; (C) coexpression of CLR and RAMP1 in the smooth muscle cell layer. (D) CGRP receptor components and important residues for receptor signaling and internalization. The CGRP receptor is formed by CLR (blue), RAMP1 (yellow), and RCP (orange). Functionally important residues are shown as single letter abbreviations. Amino acid residues are numbered from the start of the predicted N-terminal signal peptide (Swiss-Prot Q16602). Several amino acids within the CLR C-terminus (∼N400-C436) and I312 at the ICL3/TM5 junction are required for effective CGRP-mediated internalization. Important features of the CGRP receptor, including the TM6 “kink” (P343) and the putative eighth helix (∼G388-W399) in CLR are illustrated. C′, C-terminal; ECL, extracellular loop; ICL, intracellular loop; N′, N-terminal; TM, transmembrane. (E) CGRP receptor-mediated intracellular signaling: Gα_s signaling increases AC (green) activity, elevating intracellular cAMP, activating PKA and subsequently many potential downstream effectors. Panels (A–C) are adapted from Eftekhari et al. (2013) and panel (D,E) from Walker et al. (2010), respectively, with permission.