Effect of Fremanezumab Compared With Placebo for Prevention of Episodic Migraine

Dodick, David W.; Silberstein, Stephen D.; Bigal, Marcelo E.; Yeung, Paul; Goadsby, Peter J.; Blankenbiller, Tricia; Grozinski-Wolff, Melissa; Yang, Ronghua; Ma, Yuju; Aycardi, Ernesto

doi:10.1001/jama.2018.4853

Cited by 414 publications

(526 citation statements)

References 26 publications

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“…“The primary end point was the mean change from baseline (28‐day pretreatment period) in the mean number of monthly migraine days during the 12‐week period after the first injection.” The monthly dosing reduced migraine days by −3.7 to 4.9 monthly migraine days per month compared with −2.2 days to 6.5 days with placebo ( P < .001). The quarterly dose‐reduced migraine days by −3.4 days to 5.3 days ( P < .001) …”

Section: Fremanezumab Pivotal Registration Trialsmentioning

confidence: 96%

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History and Review of anti‐Calcitonin Gene‐Related Peptide (CGRP) Therapies: From Translational Research to Treatment

2018

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Objective – To briefly describe the history of and available data on anti‐calcitonin gene‐related peptide (CGRP) therapies for headache. Background – CGRP was proposed as a target for primary headache therapies. Translational research involved moving from delineating the relationships between CGRP and primary headaches and the clinical development of anti‐CGRP treatments. The first anti‐CGRP treatment, an intravenous CGRP‐receptor antagonist or gepant, olcegepant, was described as effective in terminating migraines in humans in 2004. Methods – The author briefly reviews some of the pathophysiology and translational research that led to the development of the gepants initially and then subsequently to the anti‐CGRP and anti‐CGRP receptor monoclonal antibodies. All accessible randomized controlled trials, abstracts, platform presentations, and press releases on the monoclonal antibody trials are summarized. The trajectory from bench research to the approval of the first anti‐CGRP receptor monoclonal antibody for clinical use in migraine prevention, erenumab, is discussed, as well as potential clinical uses of the anti‐CGRP treatments. Results – The US Food and Drug Administration (FDA) approved erenumab, an anti‐CGRP receptor monoclonal antibody, for prevention of migraine May 17, 2018. At the time of this writing (May 2018), 2 other anti‐CGRP monoclonal antibodies have been submitted to the FDA for the indication of prevention of migraine, galcanezumab and fremanezumab. Galcanezumab has reportedly shown effectiveness in preventing episodic cluster headache as well, although has not yet been submitted to the FDA for this indication. Eptinezumab will likely be submitted to the FDA for prevention of migraine later in 2018. Two gepants, ubrogepant and rimegepant, have completed positive pivotal trials for acute treatment of migraine, but have not yet been submitted to the FDA for this indication. Conclusions – The development of anti‐CGRP therapies opens a new era in the acute and preventive treatment of primary headache disorders.

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Section: Fremanezumab Pivotal Registration Trialsmentioning

confidence: 96%

“…The second arm consisted of a dose of 675 mg given quarterly (placebo given weeks 4 and 8), and the third group received subcutaneous placebo for 3 months. Patients had an average of 9.1 migraine days per month at baseline for placebo, 8.9 days in the monthly group and 9.2 days for the quarterly dose …”

Section: Fremanezumab Pivotal Registration Trialsmentioning

confidence: 99%

History and Review of anti‐Calcitonin Gene‐Related Peptide (CGRP) Therapies: From Translational Research to Treatment

2018

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“…10,12 Fremanezumab is a fully humanized monoclonal antibody (immunoglobulin G2a; IgG2a) that selectively targets calcitonin gene-related peptide (CGRP), a neuropeptide involved in the pathophysiology of migraine. [16][17][18][19] Fremanezumab is approved by the U.S. FDA for the preventive treatment of migraine. [16][17][18][19] Fremanezumab is approved by the U.S. FDA for the preventive treatment of migraine.…”

Section: Introductionmentioning

confidence: 99%

Early Onset of Efficacy With Fremanezumab for the Preventive Treatment of Chronic Migraine

et al. 2019

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Objective.-To assess the onset of efficacy for fremanezumab in chronic migraine by evaluating pain-related clinical measures at different time points.Background.-Faster onset of efficacy of preventive treatments could benefit patients with migraine. Fremanezumab is a fully humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, a neuropeptide involved in the pathophysiology of migraine. In 12-week clinical trials, subcutaneous fremanezumab significantly reduced the frequency of migraine headaches, headache hours, and headaches in general, without serious treatment-related adverse events. New drug classes of migraine preventive treatment demonstrate markedly different clinical profiles from standard-of-care treatments.Methods.-In this double-blind phase III study, eligible patients were randomized 1:1:1 to receive subcutaneous injections of fremanezumab quarterly (675 mg at baseline, placebo at weeks 4 and 8), fremanezumab monthly (675 mg at baseline, 225 mg at weeks 4 and 8), or placebo at each time point. This study included secondary, exploratory, and post hoc analyses of the primary trial, evaluating the change in headache days of at least moderate severity or migraine days during the first 4 weeks of the trial. Results.-A total of 1130 patients were randomized (fremanezumab quarterly, n = 376; fremanezumab monthly, n = 379; or placebo, n = 375). During the 4-week period after the first dose, the mean number of monthly headache days of at least moderate severity was reduced for the all-fremanezumab group (mean reduction [95% confidence interval]: −4.6 days [−5.1, −4.1]) compared with the placebo group (−2.3 days [−2.9, −1.6]; P < .0001). Treatment effects were observed at Week 1 for the all-fremanezumab group (−1.1 days [−1.3, −1.0]) vs placebo (−0.5 days [−0.7, −0.3]; P < .0001), with separation from placebo by Day 2 (P = .003). Similar effects were observed for the monthly average number of migraine days and mean number of monthly headache hours.Conclusions.-The early onset of efficacy of fremanezumab may have the potential to improve patient compliance and clinical outcomes.

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“…In the monthly fremanezumab, quarterly fremanezumab and placebo groups, respectively, of Study 30050 [15], pain occurred in 30.0, 29.6 and 25.9% of patients, induration in 24.5, 19.6 and 15.4%, erythema in 17.9, 18.9 and 14.0% and injection-site haemorrhage in 1.0, 3.1 and 2.0%. In the respective groups of Study 30049 [16], pain occurred in 26.1, 30.3 and 27.7% of patients, induration in 23.7, 19.7 and 18.1%, erythema in 19.8, 21.3 and 16.0% and haemorrhage in 2.1, 1.9 and 2.7%.…”

Section: Scientific Summarymentioning

confidence: 99%

Fremanezumab: First Global Approval

Hoy

2018

Drugs

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Fremanezumab-vfrm (hereafter referred to as fremanezumab) [AJOVY™] is a fully humanized monoclonal antibody (IgG2Δa) developed by Teva Pharmaceuticals to selectively target calcitonin gene-related peptide (a vasodilatory neuropeptide involved in the pathophysiology of migraine). Its use has been associated with significant reductions in migraine frequency, the requirement for acute headache medication use and headache-related disability compared with placebo in multinational, phase III studies, and in September 2018 fremanezumab was approved by the US FDA for the preventive treatment of migraine in adults. A regulatory assessment for fremanezumab as a preventive treatment of migraine in adults is underway in the EU. Fremanezumab is also undergoing phase III development for the preventive treatment of cluster headache (although a phase III chronic cluster headache study has been suspended due to the results of a prespecified futility analysis) and phase II development for the preventive treatment of post-traumatic headache disorder. This article summarizes the milestones in the development of fremanezumab leading to this first approval in the USA for the preventive treatment of migraine in adults.

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Effect of Fremanezumab Compared With Placebo for Prevention of Episodic Migraine

Abstract: clinicaltrials.gov Identifier: NCT02629861.

Cited by 414 publications

References 26 publications

History and Review of anti‐Calcitonin Gene‐Related Peptide (CGRP) Therapies: From Translational Research to Treatment

History and Review of anti‐Calcitonin Gene‐Related Peptide (CGRP) Therapies: From Translational Research to Treatment

Early Onset of Efficacy With Fremanezumab for the Preventive Treatment of Chronic Migraine

Fremanezumab: First Global Approval

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