Higher-dose Erenumab Shows Better Prevention of Progression, Rationale Provided for Initiation at High Dose

Cumulative data from an evidenced-based literature review suggest that patients with migraine experience therapeutic gains with a dose increase of erenumab (Aimovig; Novartis) from 70 mg to 140 mg, particularly in preventing progression from episodic to chronic disease. Additionally, the investigators provided a rationale for initiating a 140-mg dose in selected patients.1

Erenumab was originally approved by the FDA for the prevention of migraine in May 2018 in both the 70-mg and 140-mg doses, with the former being the recommended starting dose.2 Since, it has been joined by a variety of other calcitonin gene-related peptide (CGRP) targeting therapies for both the prevention and acute treatment of migraine, and its use in the clinic has been assessed multiple times.

In this literature review, Stewart J. Tepper, MD, professor of neurology, Geisel School of Medicine, and director of research, Dartmouth Headache Clinic, and colleagues observed that the 140-mg dose shows numerically better efficacy across the spectrum of migraine outcomes. More specifically, patients with refractory or difficult to treat migraine were identified among those who would benefit most from initiating therapy with the 140-mg dose. The review included 23 relevant articles and abstracts, of which 5 were from randomized, double-blind trials. These trials included 3 core studies (NCT02456740; NCT02066415; NCT02630459) and 2 extensions.3-5

“Therapeutic monoclonal antibodies against the [CGRP] receptor or its ligand have changed the landscape of treatment options for migraine, ”Tepper and colleagues wrote. Erenumab is the first and only fully human monoclonal antibody designed to target and block the CGRP receptor. It is approved by the [FDA] for preventive treatment of migraine in adults. The recommended dose of erenumab is 70 mg monthly, with guidance that some patients may benefit from the 140 mg monthly dose. There is a need for information to guide clinical practice on the comparative efficacy and safety of these two dosing options. ”

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In the core studies (n = 2009) among patients with both episodic and chronic migraine, the majority of outcomes assessed — including change from baseline in monthly migraine days (MMDs), percentage of patients with at least 50% reduction in MMD, and the change from baseline in acute migraine-specific medication days (MSMDs) —favored the 140-mg dose.

In those trials, 140-mg erenumab resulted in decreases of 3.7 MMDs (SE, 0.2), 1.83 MMDs (95% CI, –2.35 to –1.31), and 6.6 MMDs (SE, 0.4), with 50% (159 of 318 ), 27.2% (37 of 136), and 41% (77 of 187) of patients in each trial achieving at least a 50% reduction, respectively. Additionally, the 140-mg dose resulted in reductions in MSMDs of 1.6 (SE, 0.1), 1.16 (95% CI, –1.60 to –0.71), and 4.1 (SE, 0.3), respectively. These results were in-line with or better than those for the 70-mg dose in all 3 studies.3-5

Notably, data from a post hoc analysis of the phase 2 study by Tepper et al suggest that by weeks 40 and 52 of the open-label period, patients experienced a higher rate of reversion to episodic migraine with the 140-mg dose (week 40 : 75.9%; week 52: 75.8%) compared with the 70-mg dose (week 40: 64.5%; week 52: 69.2%).6

As for safety, Tepper and colleagues noted that “the [FDA] label changes for erenumab, since it was introduced to the market, do include warnings of the potential for severe constipation and the development or worsening of hypertension, as well as rash, alopecia, and oral mucosal ulceration, ”and that providers must closely monitor patients for these adverse events (AEs). Although, they noted that “long-term data do not show a clearly higher likelihood of AEs, including constipation and hypertension, for erenumab 140 mg than 70 mg.”

In the regulatory clinical studies, the therapy has shown a favorable safety and tolerability profile, with long-term data suggesting that the exposure-adjusted incidence rate for AEs was 124.9 per 100 person-years, and for serious AEs was 3.8 per 100 person- years.7

“While the recommended starting dosage of erneumab is 70 mg, the data support the rationale for a potential therapeutic gain with an increase to erenumab 140 mg and for initiating 140 mg in selected patients. Finally, there is not a clear therapeutic penalty with using the higher dose, so the dose-response relationship likely favors the use of the 140-mg monthly dose, ”Tepper et al concluded.

REFERENCES
1. Tepper SJ, Sheik HU, Dougherty CO, et al. Erenumab dosage for migraine prevention: An evidence-based narrative review with recommendations. Headache. Published online February 9, 2022. doi: 10.1111 / head.14266
2. FDA approves novel preventive treatment for migraine. News release. FDA. May 17, 2018. Accessed April 15, 2022. https://www.fda.gov/news-events/press-announcements/fda-approves-novel-preventive-treatment-migraine
3. Tepper SJ, Ashina M, Reuter U, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomized, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2017; 16 (6): 425-434. doi: 10.1016 / S1474-4422 (17) 30083-2
4. Sakai F, Takeshima T, Tatsuoka Y, et al. A Randomized Phase 2 Study of Erenumab for the Prevention of Episodic Migraine in Japanese Adults. Headache. 2019; 59 (10): 1731-1742. doi: 10.1111 / head.13652
5. Goadsby PJ, Reuter U, Hallström Y, et al. A Controlled Trial of Erenumab for Episodic Migraine. N Engl J Med. 2017; 377: 2123-2132 doi: 10.1056 / NEJMoa1705848
6. Lipton RB, Tepper SJ, Silberstein SD, et al. Reversion from chronic migraine to episodic migraine following treatment with erenumab: results of a post-hoc analysis of a randomized, 12-week, double-blind study and a 52-week, open-label extension. Cephalagia. 2021; 41: 6-16. doi: 10.1177 / 0333102420973994
7. Ashina M, Goadsby PJ, Reuter U, et al. Sustained efficacy and long-term safety or erenumab in patients with episodic migraine: 4+ results of a 5-year, open-label treatment period. Neurology. 202; 94 (15Suppl): 1203.

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