From LBR-101 to Fremanezumab for Migraine
- PDF / 1,173,076 Bytes
- 13 Pages / 595.276 x 790.866 pts Page_size
- 103 Downloads / 191 Views
REVIEW ARTICLE
From LBR‑101 to Fremanezumab for Migraine Marcelo E. Bigal1 · Alan M. Rapoport2 · Stephen D. Silberstein3 · Sarah Walter4 · Richard J. Hargreaves5 · Ernesto Aycardi6 Published online: 11 October 2018 © Springer Nature Switzerland AG 2018
Abstract Calcitonin gene-related peptide (CGRP) is a neuropeptide of importance in migraine pathogenesis. Its central role in migraine was proven pharmacologically by the development of CGRP receptor antagonists. Monoclonal antibodies targeting CGRP or its receptor are effective in the preventive treatment of episodic and chronic migraine and are considered potential breakthroughs in their treatment. Fremanezumab (previously known as TEV-48125, LBR-101, or RN-307) is a humanized IgG2a monoclonal antibody that binds to CGRP. The development of this antibody validated the role of CGRP in chronic migraine and the drug has been recently approved in the US by the FDA, while it continues to be reviewed by other regulatory agencies. Herein we provide an in-depth review of its development. We start by summarizing its in vitro and in vivo pharmacology, and the phase I studies. We then review the late-stage clinical development, with a focus on its efficacy, safety, similarities, and uniqueness relative to other CGRP antibodies. We close by discussing lessons learned on the mechanisms of migraine and areas for future development and exploration.
Key Points
1 Introduction
Fremanezumab was shown to be effective in episodic and chronic migraine, with a monthly and quarterly dose of administration, and was tested as monotherapy and add-on therapy.
Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide that exists in two isoforms, α- and β-CGRP [1, 2], being highly conserved across species [3]. CGRP is derived from the alternate splicing of the gene encoding calcitonin [1, 2]. It is found in every organ system in the body [4], and CGRP-containing sensory nerve fibers and CGRP receptors are widely distributed peripherally and centrally throughout the trigeminovascular system. The physiological actions of CGRP include vasodilatation, trigeminal sensitization, and activation of second-order sensory neurons in the brain stem as part of trigeminal sensory pain signal transmission [5–8]. In addition to being involved in the mechanisms of migraine headache, CGRP has an effect on trigeminal sensitization and may in fact be a risk factor for increased headache frequency, therefore predisposing the progression of migraine from an episodic into a chronic form [9–11]. CGRP is found in literally every organ system in the body [12] and its inhibition by antibodies or small molecules is also ubiquitous. Reviews on the theoretical consequences of inhibiting CGRP have been published [10]. CGRP plays a key role in the pathogenesis of migraine [4], and the work that established it as an anti-migraine drug target has also been recently reviewed [13–15].
Onset of action was remarkably quick, and effect seems to be maintained over time. As with other monoclonal antibodies, no overt
Data Loading...
