Home Therapeutic relationship Higher dose erenumab shows better prevention of progression, rationale provided for high...

Higher dose erenumab shows better prevention of progression, rationale provided for high dose initiation

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

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

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 over the whole spectrum of migraine outcomes. Specifically, patients with intractable or difficult-to-treat migraine were identified as those who would benefit the most from initial treatment with the 140 mg dose. The review included 23 relevant articles and abstracts, 5 of which were from randomized double-blind trials. These trials included 3 main studies (NCT02456740; NCT02066415; NCT02630459) and 2 extensions.3-5

“Therapeutic monoclonal antibodies against [CGRP] receptor or its ligand has changed the landscape of migraine treatment options,” 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 the preventive treatment of migraine in adults. The recommended dose of erenumab is 70 mg monthly, with indications that some patients may benefit from the monthly dose of 140 mg. 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 main studies (n=2009) in patients with episodic and chronic migraine, the majority of outcomes assessed, including change from baseline in Monthly Migraine Days (MMD), percentage of patients with at least 50% reduction in MMD and change from baseline in acute migraine-specific treatment days (MSMD) – favored the 140 mg dose.

In these trials, erenumab 140 mg produced reductions of 3.7 MMD (SD, 0.2), 1.83 MMD (95% CI, -2.35 to -1.31), and 6. 6 MMD (SD, 0.4), with 50% (159 of 318), 27.2% (37 of 136), and 41% (77 of 187) of patients in each trial achieving a reduction of at least 50 %, respectively. Additionally, the 140 mg dose resulted in reductions in MSMD of 1.6 (SD, 0.1), 1.16 (95% CI, -1.60 to -0.71), and 4.1 ( SD, 0.3), respectively. These results were consistent with or better than 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 at 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 to the 70 mg dose (week 40: 64.5%; week 52: 69.2%).6

Regarding safety, Tepper and his colleagues noted that “the [FDA] label changes for erenumab, since its introduction to the market, include warnings about the potential for severe constipation and the development or worsening of hypertension, as well as skin rashes, alopecia and mucosal ulceration,” and that providers should closely monitor patients for these adverse events (AEs). However, they noted that “long-term data do not show a clearly higher likelihood of AEs, including constipation and hypertension, for erenumab 140mg than for 70mg.”

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

“While the recommended starting dose of ereumab is 70 mg, the data support the rationale for potential therapeutic gain with an increase to 140 mg of erenumab and for initiation of 140 mg in selected patients. Finally, there is no clear therapeutic penalty with use of the higher dose, so the dose-response relationship likely favors use of the 140 mg monthly dose,” concluded Tepper et al.

REFERENCES
1. Tepper SJ, Sheik HU, Dougherty CO, et al. Erenumab dosing for migraine prevention: an evidence-based narrative review with recommendations. Headache. Published online February 9, 2022. doi:10.1111/head.14266
2. FDA approves new migraine preventative treatment. Press 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, Reuters U, et al. Safety and efficacy of erenumab for the preventive treatment of chronic migraine: a randomized, double-blind, placebo-controlled phase 2 trial. Neurol Lancet. 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 English 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 after treatment with erenumab: results of a post-hoc analysis of a 12-week randomized double-blind study and a 52-week open-label extension. Headache. 2021;41:6-16. doi:10.1177/0333102420973994
7. Ashina M, Goadsby PJ, Reuters U, et al. Sustained efficacy and long-term safety of erenumab in patients with episodic migraine: 4+ results from a 5-year open-label treatment period. Neurology. 202; 94(15Supp):1203.