CGRP Inhibitor Eptinezumab Shows Strong Efficacy in Treating Medication-Overuse Headache

Rigmor Højland Jensen, MD, PhD

Newly presented findings from the RESOLUTION trial (NCT05452239) showed that treatment with 100 mg doses of eptinezumab (Vyepti; Lundbeck) led to statistically significant reductions in frequency of migraine days and monthly acute medication use in patients with chronic migraine (CM) with medication-overuse headache (MOH).^1,2

MOH has been a significant clinical challenge, as it arises paradoxically from the frequent use of acute migraine or headache treatments, including triptans, NSAIDs, and opioids. RESOLUTION was a large-scale trial of 608 patients with CM and MOH who were randomly assigned to eptinezumab 100 mg or placebo, using change in monthly migraine days (MMDs) over a 4-week period as the primary end point. Prior to infusion, all participants received a Brief Educational Intervention about MOH.

Presented at the 2025 American Headache Society (AHS) Annual Meeting and the 11^th Congress of the European Academy of Neurology, eptinezumab met both its primary and secondary end points in the trial. Across the 21-day treatment period, investigators recorded a change of –6.9 MMDs for those on the calcitonin gene-related peptide (CGRP) treatment vs –3.7 days for those on placebo (P <.0001). Some of the secondary end points included change in MMDs from weeks 1-12, percentage of patients no longer fulfilling criteria for CM nor MOH (weeks 1-4; weeks 1-12), change in average daily pain assessment score, and change in monthly days with acute medication use.

"Patient education is often employed as a therapeutic strategy for patients with chronic migraine and medication-overuse headache, while preventive anti-CGRP treatments are reserved for later stages," lead investigator Rigmor Højland Jensen, associate professor at the University of Copenhagen, and Director of the Danish Headache Center, said in a statement.¹ "The RESOLUTION trial demonstrates for the first time, that adding an anti-CGRP treatment early, and alongside patient education about medication-overuse headache, can deliver significant and rapid migraine prevention. This is good news for patients severely impacted by migraine complicated by medication overuse."

During weeks 1-4 of treatment, 37.8% of those on eptinezumab vs 18.1% of those on placebo no longer met the criteria for CM or MOH (P <.0001). This continued through the rest of the trial, as 27.2% of participants on eptinezumab and 12.7% of those on placebo had lost at least one of these designations during weeks 1-12 (P <.0001). Coming into the study, both groups had a baseline mean average daily pain score of 1.7 on a 3-point scale. Within the first 2 weeks of treatment, this score was reduced by –0.6 in the eptinezumab group vs –0.3 for those on placebo (P <.0001).

READ MORE: Phase 4 PEARL Study Confirms Long-Term Effectiveness of Fremanezumab in Preventing Chronic, Episodic Migraine

Additional data from the study showed that patients on active treatment had a mean change of –11.3 in acute medication use days vs –7.7 days for those on placebo, during weeks 1-4 (P <.0001). Notably, the between-group differences were sustained through weeks 1-12 (–11.2 vs –7.8, respectively; P <.0001).

Eptinezumab, approved in 2020 for prevention of migraine, had a similar rate of treatment-emergent adverse events (TEAEs; 41.9%) relative to placebo (36.9%). In RESOLUTION, the most common TEAE observed was nasopharyngitis, occurring in 5.0% of eptinezumab-treated patients and 5.6% of those on placebo.

John Luthman, EVP

"RESOLUTION further reinforces eptinezumab as an effective treatment option for patients severely impacted by migraine,” John Luthman, EVP, head of Research & Development at Lundbeck, said in a statement.¹ "We see robust benefits with eptinezumab, even on top of existing patient education. These results highlight Lundbeck's dedication to raising the bar in migraine treatment expectations, ensuring that even the most difficult-to-treat patients have access to effective solutions."

Eptinezumab’s 2020 approval was backed by findings from 2 phase 3 clinical trials: PROMISE-1 and PROMISE-2, which featured patients with episodic and CM, respectively. A subgroup analysis of PROMISE-2, published in Headache in 2023, first showcased the potential effect of eptinezumab in reducing MOH in patients with CM.^3,4

The subgroup analysis, led by Amaal J. Starling, MD, included 139, 147, and 145 patients randomly assigned to eptinezumab 100 mg, 300 mg, and placebo groups. Patients received up to 2 doses, each 12 weeks apart, for a 24-week treatment period. By week 24, patients treated with eptinezumab showed sustained reductions in HIT-6 scores, with means decreasing from around 65 at baseline to 57.5 (100 mg) and 56.0 (300 mg). Improvements were seen as early as week 4 and continued throughout the study. Notably, the proportion of patients with severe life impact dropped to 39.5% and 38.6% in the 100 mg and 300 mg groups, compared to 65.5% with placebo.

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REFERENCES
1. New data demonstrates robust efficacy of Vyepti® (eptinezumab) in otherwise difficult-to-treat patients with severe migraine. News release. Lundbeck. June 21, 2025. Accessed June 25, 2025. https://www.prnewswire.com/news-releases/new-data-demonstrates-robust-efficacy-of-vyepti-eptinezumab-in-otherwise-difficult-to-treat-patients-with-severe-migraine-302487653.html
2. Jensen R, Lundqvist C, Schytz HW, et al. Eptinezumab and patient education in chronic migraine and medication-overuse headache: results from the randomized, placebo-controlled RESOLUTION trial. Presented at: 2025 AHS Annual Meeting; June 19-22. Minneapolis, MN. P-297
3. Starling AJ, Cowan RP, Buse DC, et al. Eptinezumab improved patient-reported outcomes in patients with migraine and medication-overuse headache: subgroup analysis of the randomized PROMISE-2 trial. Headache. Published January 12, 2023. doi:10.1111/head.14434
4. FDA Approves Lundbeck’s VYEPTI (eptinezumab-jjmr) – The First and Only Intravenous Preventive Treatment for Migraine. News release. Lundbeck; Published February 21, 2020. Accessed June 25, 2025. businesswire.com/news/home/20200221005507/en/FDA-Approves-Lundbeck’s-VYEPTI™-eptinezumab-jjmr-–-Intravenous.