Safety and tolerability of fremanezumab in patients with episodic and chronic migraine: a pooled analysis of phase 3 studies

Hans Christoph Diener, Peter McAllister, Tim P Jürgens, Yoel Kessler, Xiaoping Ning, Joshua M Cohen, Verena Ramirez Campos, Steve Barash, Stephen D Silberstein, Hans Christoph Diener, Peter McAllister, Tim P Jürgens, Yoel Kessler, Xiaoping Ning, Joshua M Cohen, Verena Ramirez Campos, Steve Barash, Stephen D Silberstein

Abstract

Background: Fremanezumab, a fully humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, has demonstrated efficacy for preventive treatment of episodic and chronic migraine. Since calcitonin gene-related peptide is expressed within the cardio- and cerebrovascular system and may have cardioprotective effects, it is critical to understand the cardio- and cerebrovascular safety of fremanezumab.

Methods: This was a pooled analysis of three randomized, double-blind, placebo-controlled, phase 3, 12-week trials in which patients with episodic migraine or chronic migraine received quarterly fremanezumab, monthly fremanezumab, or placebo. Incidences of overall and serious adverse events were analyzed. Cardio- and cerebrovascular adverse events (CVAEs) were analyzed in subgroups stratified by cardio- and cerebrovascular medical history, cardiovascular risk factors (CVRFs), and use of cardio- and cerebrovascular medications or triptans.

Results: Two thousand, eight hundred and forty-two patients were included in the study. Overall (58-65%) and serious adverse events (<1-2%) occurred in similar proportions across fremanezumab and placebo groups. CVAEs were infrequent, regardless of cardio- and cerebrovascular medical history (2-6%). CVAEs occurred in low, similar proportions of patients with CVRFs and those using cardio- and cerebrovascular medications or triptans. No cardio- and cerebrovascular signals were identified.

Conclusion: Fremanezumab demonstrated a favorable overall and cardio- and cerebrovascular safety profile in more than 2800 patients with episodic migraine or chronic migraine, regardless of cardio- and cerebrovascular medical history, CVRFs, or medication use.Trial Registrations: NCT02629861 (HALO EM, https://ichgcp.net/clinical-trials-registry/NCT02629861), NCT02621931 (HALO CM, https://ichgcp.net/clinical-trials-registry/NCT02621931), NCT03308968 (FOCUS, https://ichgcp.net/clinical-trials-registry/NCT03308968).

Keywords: calcitonin gene-related peptide; cardiovascular; fremanezumab; safety.

Conflict of interest statement

Declaration of conflicting interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: HCD received honoraria for participation in clinical trials, contribution to advisory boards, or oral presentations from: Alder, Allergan, Amgen, electroCore, Ipsen, Lilly, Medtronic, Novartis, Pfizer, Teva Pharmaceuticals, and Weber & Weber. electroCore provided financial support for research projects. The German Research Council, the German Ministry of Education and Research, and the European Union support his headache research. PM is an employee of the New England Institute for Neurology and Headache. He is an independent contractor and part of speaker bureaus at Teva Pharmaceuticals, Amgen, and Allergan. TPJ received honoraria for contribution to advisory boards or oral presentations from: Allergan, Desitin, Hormosan, Novartis, Lilly, Sanofi, and Teva Pharmaceuticals. His research is supported by Gemeinsame Bundesausschuss – Innovationsfonds and EFRE. YK, XN, VRC, and SB are employees and/or stockholders of Teva Branded Pharmaceutical Product R&D, Inc. JMC is a former employee of Teva Branded Pharmaceutical Product R&D, Inc. SDS provides consultation to Alder, Allergan, Amgen, Autonomic Technologies, Avanir, Curelater, Inc., Depomed, Dr. Reddy’s Laboratories, Ensured, Inc., electroCore, eNeuraTherapeutics, INSYS Therapeutics, Lilly, Supernus Pharmaceuticals, Inc., Teva Pharmaceuticals, Theranica, and Trigemina, Inc.

Figures

Figure 1.
Figure 1.
Systolic (a) and diastolic (b) blood pressure values by hypertension status from the long-term safety study. SBP: systolic blood pressure; DPB: diastolic blood pressure.

References

    1. Global Burden of Disease 2016 Headache Collaborators. Global, regional, and national burden of migraine and tension-type headache, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2018; 17: 954–976.
    1. Messali A, Sanderson JC, Blumenfeld AM, et al.. Direct and indirect costs of chronic and episodic migraine in the United States: A web-based survey. Headache 2016; 56: 306–322.
    1. Jackson JL, Cogbill E, Santana-Davila R, et al.. A comparative effectiveness meta-analysis of drugs for the prophylaxis of migraine headache. PLoS One 2015; 10: e0130733.
    1. Lipton RB, Goadsby PJ, Smith J, et al.. Efficacy and safety of eptinezumab in patients with chronic migraine: PROMISE-2. Neurology 2020; 94: e1365–e1377.
    1. Blumenfeld AM, Bloudek LM, Becker WJ, et al.. Patterns of use and reasons for discontinuation of prophylactic medications for episodic migraine and chronic migraine: Results from the Second International Burden of Migraine Study (IBMS-II). Headache 2013; 53: 644–655.
    1. De Matteis E, Guglielmetti M, Ornello R, et al.. Targeting CGRP for migraine treatment: Mechanisms, antibodies, small molecules, perspectives. Expert Rev Neurother 2020; 20: 627–641.
    1. Edvinsson L. The CGRP pathway in migraine as a viable target for therapies. Headache 2018; 58: 33–47.
    1. Favoni V, Giani L, Al-Hassany L, et al.. CGRP and migraine from a cardiovascular point of view: What do we expect from blocking CGRP? J Headache Pain 2019; 20: 27.
    1. Kee Z, Kodji X, Brain SD. The role of calcitonin gene related peptide (CGRP) in neurogenic vasodilation and its cardioprotective effects. Front Physiol 2018; 9: 1249.
    1. Mulder IA, Li M, de Vries T, et al.. Anti-migraine calcitonin gene-related peptide receptor antagonists worsen cerebral ischemic outcome in mice. Ann Neurol 2020; 88: 771–784.
    1. Dodick D, Lipton RB, Martin V, et al.. Consensus statement: Cardiovascular safety profile of triptans (5-HT agonists) in the acute treatment of migraine. Headache 2004; 44: 414–425.
    1. Alwhaibi M, Deb A, Sambamoorthi U. Triptans use for migraine headache among nonelderly adults with cardiovascular risk. Pain Res Treat 2016; 2016: 8538101.
    1. Roberto G, Raschi E, Piccinni C, et al.. Adverse cardiovascular events associated with triptans and ergotamines for treatment of migraine: Systematic review of observational studies. Cephalalgia 2015; 35: 118–131.
    1. Goldstein JA, Massey KD, Kirby S, et al.. Effect of high-dose intravenous eletriptan on coronary artery diameter. Cephalalgia 2004; 24: 515–521.
    1. Velentgas P, Cole JA, Mo J, et al.. Severe vascular events in migraine patients. Headache 2004; 44: 642–651.
    1. Teva Pharmaceuticals. AJOVY (fremanezumab-vfrm), prescribing information, . North Wales, PA: Teva Pharmaceuticals USA, Inc. (Revised 2020, accessed 1 September 2021).
    1. Dodick DW, Silberstein SD, Bigal ME, et al.. Effect of fremanezumab compared with placebo for prevention of episodic migraine: A randomized clinical trial. JAMA 2018; 319: 1999–2008.
    1. Silberstein SD, Dodick DW, Bigal ME, et al.. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med 2017; 377: 2113–2122.
    1. Ferrari MD, Diener HC, Ning X, et al.. Fremanezumab versus placebo for migraine prevention in patients with documented failure to up to four migraine preventive medication classes (FOCUS): A randomised, double-blind, placebo-controlled, phase 3b trial. Lancet 2019; 394: 1030–1040.
    1. Goadsby PJ, Silberstein SD, Yeung PP, et al.. Long-term safety, tolerability, and efficacy of fremanezumab in migraine: A randomized study. Neurology 2020; 95: e2487–e2499.
    1. Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013; 33: 629–808.
    1. Hepp Z, Bloudek LM, Varon SF. Systematic review of migraine prophylaxis adherence and persistence. J Manag Care Pharm 2014; 20: 22–33.
    1. Hepp Z, Dodick DW, Varon SF, et al.. Persistence and switching patterns of oral migraine prophylactic medications among patients with chronic migraine: A retrospective claims analysis. Cephalalgia 2017; 37: 470–485.
    1. Blumenfeld AM, Bloudek LM, Becker WJ, et al.. Patterns of use and reasons for discontinuation of prophylactic medications for episodic migraine and chronic migraine: Results from the Second International Burden of Migraine Study (IBMS-II). Headache 2013; 53: 644–655.
    1. Yalinay Dikmen P, Kosak S, Ilgaz Aydinlar E, et al.. A single-center retrospective study of onabotulinumtoxinA for treatment of 245 chronic migraine patients: Survey results of a real-world experience. Acta Neurol Belg 2018; 118: 475–484.
    1. Tepper SJ, Ashina M, Reuter U, et al.. Long-term safety and efficacy of erenumab in patients with chronic migraine: Results from a 52-week, open-label extension study. Cephalalgia 2020; 40: 543–553.
    1. Camporeale A, Kudrow D, Sides R, et al.. A phase 3, long-term, open-label safety study of galcanezumab in patients with migraine. BMC Neurol 2018; 18: 188.
    1. Stauffer VL, Dodick DW, Zhang Q, et al.. Evaluation of galcanezumab for the prevention of episodic migraine: The EVOLVE-1 randomized clinical trial. JAMA Neurol 2018; 75: 1080–1088.
    1. Kudrow D, Pascual J, Winner PK, et al.. Vascular safety of erenumab for migraine prevention. Neurology 2020; 94: e497–e510.
    1. Amgen Inc. AIMOVIG (erenumab aooe), prescribing information, . Thousand Oaks, CA: Amgen Inc. (Revised 2019, accessed 1 September 2021).
    1. Lundbeck Seattle BioPharmaceuticals. VYEPTITM (eptinezumab-jjmr), prescribing information, . South Bothell, WA: Lundbeck Seattle BioPharmaceuticals, Inc. (Revised 2020, accessed 1 September 2021).
    1. Eli Lilly and Company. EMGALITY (galcanezumab-gnlm), prescribing information, . Indianapolis, IN: Eli Lilly and Company. (Revised 2019, accessed 1 September 2021).
    1. Oakes TM, Kovacs R, Rosen N, et al.. Evaluation of cardiovascular outcomes in adult patients with episodic or chronic migraine treated with galcanezumab: Data from three phase 3, randomized, double-blind, placebo-controlled EVOLVE-1, EVOLVE-2, and REGAIN studies. Headache 2020; 60: 110–123.
    1. Kounis NG, Soufras GD, Tsigkas G, et al.. Adverse cardiac events to monoclonal antibodies used for cancer therapy: The risk of Kounis syndrome. Oncoimmunology 2014; 3: e27987.

Source: PubMed

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