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From LBR-101 to Fremanezumab for Migraine

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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.

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Authors and Affiliations

  1. Purdue Pharma, 201 Tresser Boulevard, Stamford, CT, 06901, USA

    Marcelo E. Bigal

  2. The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Alan M. Rapoport

  3. Jefferson Headache Center, Thomas Jefferson University, Philadelphia, PA, USA

    Stephen D. Silberstein

  4. Antiva Biosciences, San Francisco, CA, USA

    Sarah Walter

  5. Celgene, Summit, NJ, USA

    Richard J. Hargreaves

  6. Xenon Pharmaceuticals, Vancouver, Canada

    Ernesto Aycardi

Authors
  1. Marcelo E. Bigal
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  2. Alan M. Rapoport
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  4. Sarah Walter
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  5. Richard J. Hargreaves
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  6. Ernesto Aycardi
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Correspondence to Marcelo E. Bigal.

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Funding

No funding was provided for writing this manuscript. At the time of writing, former employees of Teva (Bigal and Aycardi) were no longer working with the sponsor.

Conflict of interest

Dr Bigal was a full-time employee of Labrys (Chief Medical Officer) and of Teva (Chief Medical Officer and Chief Scientific Officer) and, as such, received salary and equity from both companies. He was directly involved with the development of fremanezumab at all stages. He is currently at Purdue. Dr Rapoport is a consultant and speaker for Teva Pharmaceuticals and was a consultant to Labrys. He is an author on multiple phase II and phase III publications on the program. Dr Silberstein is a consultant to Teva Pharmaceuticals and was a consultant to Labrys. He is an author on multiple phase II and phase III publications on the program and is the primary investigator on the phase III CM program. Dr Walter was a full-time employee at Labrys (Head of Preclinical Research and Clinical Pharmacology) and supported the transition of the program to Teva. Dr Hargreaves was a consultant to Labrys, was a full-time employee at Merck, and is currently a full-time employee at Celgene. Dr Aycardi was a full-time employee at Teva (Head of Development for Fremanezumab). As such, he received salary and equity compensation from Teva. He is currently at Xenon pharmaceuticals.

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Bigal, M.E., Rapoport, A.M., Silberstein, S.D. et al. From LBR-101 to Fremanezumab for Migraine. CNS Drugs 32, 1025–1037 (2018). https://doi.org/10.1007/s40263-018-0579-4

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