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Is the monoclonal antibody fremanezumab effective in preventing episodic migraine?
In this randomized clinical trial that included 875 adults with episodic migraine in whom multiple medication classes had not previously failed, fremanezumab compared with placebo resulted in significantly fewer monthly migraine days with monthly dosing (–1.5 days) and with a single higher dose at baseline (–1.3 days) over 12 weeks.
Fremanezumab as a preventive treatment for episodic migraine reduced the mean number of monthly migraine days over a 12-week period compared with placebo. Further research is needed to assess effectiveness against other preventive medications and in patients in whom multiple preventive drug classes have failed and to determine long-term safety and efficacy.
Fremanezumab, a fully humanized monoclonal antibody that targets calcitonin gene-related peptide, may be effective for treating episodic migraine.
To assess the efficacy of fremanezumab compared with placebo for prevention of episodic migraine with a monthly dosing regimen or a single higher dose.
Design and Setting
Randomized, double-blind, placebo-controlled, parallel-group trial conducted at 123 sites in 9 countries from March 23, 2016 (first patient randomized), to April 10, 2017, consisting of a screening visit, 28-day pretreatment period, 12-week treatment period, and final evaluation at week 12.
Study participants were aged 18 to 70 years with episodic migraine (6-14 headache days, with at least 4 migraine days, during 28-day pretreatment period). Patients who had previous treatment failure with 2 classes of migraine-preventive medication were excluded.
Patients were randomized 1:1:1 to receive subcutaneous monthly dosing of fremanezumab (n = 290; 225 mg at baseline, week 4, and week 8); a single higher dose of fremanezumab, as intended to support a quarterly dose regimen (n = 291; 675 mg of fremanezumab at baseline; placebo at weeks 4 and 8); or placebo (n = 294; at baseline, week 4, and week 8).
Main Outcomes and Measures
The primary end point was mean change in mean number of monthly migraine days during the 12-week period after the first dose.
Among 875 patients who were randomized (mean age, 41.8 [SD, 12.1] years; 742 women [85%]), 791 (90.4%) completed the trial. From baseline to 12 weeks, mean migraine days per month decreased from 8.9 days to 4.9 days in the fremanezumab monthly dosing group, from 9.2 days to 5.3 days in the fremanezumab single-higher-dose group, and from 9.1 days to 6.5 days in the placebo group. This resulted in a difference with monthly dosing vs placebo of –1.5 days (95% CI, –2.01 to –0.93 days; P < .001) and with single higher dosing vs placebo of –1.3 days (95% CI, –1.79 to –0.72 days; P < .001). The most common adverse events that led to discontinuation were injection site erythema (n = 3), injection site induration (n = 2), diarrhea (n = 2), anxiety (n = 2), and depression (n = 2).
Conclusions and Relevance
Among patients with episodic migraine in whom multiple medication classes had not previously failed, subcutaneous fremanezumab, compared with placebo, resulted in a statistically significant 1.3- to 1.5-day reduction in the mean number of monthly migraine days over a 12-week period. Further research is needed to assess effectiveness against other preventive medications and in patients in whom multiple preventive drug classes have failed and to determine long-term safety and efficacy.
clinicaltrials.gov Identifier: NCT02629861
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Corresponding Author: David W. Dodick, MD, Department of Neurology, Mayo Clinic, 5777 E Mayo Blvd, Phoenix, AZ 85054 (firstname.lastname@example.org).
Accepted for Publication: April 16, 2018.
Author Contributions: Dr Dodick had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Silberstein, Bigal, Yeung, Goadsby, Yang.
Acquisition, analysis, or interpretation of data: Dodick, Silberstein, Bigal, Yeung, Goadsby, Grozinski-Wolff, Yang, Ma.
Drafting of the manuscript: Dodick, Silberstein, Bigal, Yeung.
Critical revision of the manuscript for important intellectual content: Dodick, Silberstein, Bigal, Yeung, Goadsby, Grozinski-Wolff, Yang, Ma.
Statistical analysis: Dodick, Bigal, Yang, Ma.
Obtained funding: Bigal.
Administrative, technical, or material support: Yeung.
Supervision: Silberstein, Bigal, Yeung, Goadsby.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Dodick has received compensation from serving on advisory boards and/or consulting within the past 5 years for Allergan, Amgen, Novartis, Alder, Arteaus, Pfizer, Colucid, Merck, NuPathe, Eli Lilly & Company, Autonomic Technologies, Ethicon Johnson & Johnson, Zogenix, Supernus, Labrys, Boston Scientific, Medtronic, St Jude, Bristol-Myers Squibb, Lundbeck, Impax, MAP, Electrocore, Tonix, Teva, Alcobra, Zosano, ZP Opco, Insys, Ipsen, Acorda, eNeura, Charleston Laboratories, Core, Biohaven, Biocentric, Magellan, Theranica, Xenon, Dr Reddy’s/Promius Pharma, Vedanta, CC Ford West Group, and Foresite Capital. Dr Dodick also owns equity in Epien, GBS/Nocira, Second Opinion, Healint, and Theranica and has received funding for travel, speaking, editorial activities, or royalty payments from Intramed, SAGE Publishing, Sun Pharma, Allergan, Oxford University Press, American Academy of Neurology, American Headache Society, West Virginia University Foundation, Canadian Headache Society, Healthlogix, Universal Meeting Management, WebMD, UptoDate, Medscape/WebMD, Albert Einstein University, University of Toronto, Starr Clinical, Decision Resources, Synergy, MedNet LLC, Peer View Institute for Medical Education, Medicom, Medlogix, Wolters Kluwer Health, Chameleon Communications, Academy for Continued Healthcare Learning, Haymarket Medical Education, Global Scientific Communications, Miller Medical Communications, MeetingLogiX, and Wiley Blackwell. Through his employer, Dr Dodick has consulting use agreements with Neuro Assessment Systems and Myndshft. Dr Dodick also holds board of director positions with King-Devick Technologies, and Epien Inc and holds patent 17189376.1-1466 on a botulinum toxin dosage regimen for chronic migraine prophylaxis. Dr Silberstein provides consultation to Alder, Allergan, Amgen, Avanir, Curelater Inc, Depomed, Dr Reddy’s Laboratories, Ensured Inc, ElectroCore Medical LLC, INSYS Therapeutics, Lilly USA LLC, Supernus Pharmaceuticals Inc, Teva Pharmaceuticals, Theranica, and Trigemina Inc. Dr Goadsby reports grants and personal fees from Amgen and Eli Lilly and Company and personal fees from Alder Biopharmaceuticals, Allergan, Autonomic Technologies Inc, Dr Reddy’s Laboratories, Electrocore LLC, eNeura, Novartis, Scion, Teva Pharmaceuticals, and Trigemina Inc, personal fees from medicolegal work, Journal Watch, UptoDate, Oxford University Press, Massachusetts Medical Society, and Wolters Kluwer, and a patent on magnetic stimulation for headache assigned to eNeura without fee. Dr Bigal, Dr Yeung, Ms Blankenbiller, Ms Grozinski-Wolff, Dr Yang, Ms Ma, and Dr Aycardi are employees of Teva Pharmaceuticals. No other disclosures were reported.
Funding/Support: This study was funded by Teva Pharmaceuticals, Petach Tikva, Israel.
Role of the Funder/Sponsor: The trial sponsor, Teva Pharmaceuticals, provided the trial medication for trial conduct and manuscript preparation. Teva Pharmaceuticals was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank the study participants and their families; all site personnel and investigators, including the coordinating investigators; and Kristen Hokenson, PhD (Chameleon Communications International with funding from Teva Pharmaceuticals) for editorial assistance in the preparation of the manuscript.
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