Efficacy, Tolerability, and Safety of Eptinezumab in Patients With a Dual Diagnosis of Chronic Migraine and Medicationoveruse Headache

Subgroup analysis of PROMISE-2

Hans-Christoph Diener MD, PhD; Michael J. Marmura MD; Stewart J. Tepper MD; Robert Cowan MD, FAAN; Amaal J. Starling MD; Merle L. Diamond MD; Joe Hirman PhD; Lahar Mehta MD; Thomas Brevig MD, PhD; Bjørn Sperling MD; Roger Cady MD


Headache. 2021;61(1):125-136. 

In This Article

Abstract and Introduction


Objective: To evaluate the efficacy, tolerability, and safety of eptinezumab 100 and 300 mg compared with placebo in patients with the dual diagnosis of chronic migraine (CM) and medication-overuse headache (MOH).

Background: Eptinezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide, may be effective for treating patients with a dual diagnosis of CM and MOH.

Methods: PROMISE-2 (NCT02974153) was a double-blind, randomized, placebo-controlled, phase 3 study that comprised a screening visit, a 28-day pretreatment period, and a 32-week study duration. Patients in this exploratory analysis of a prespecified subgroup had confirmed diagnoses of both CM and MOH at screening. Patients were randomly assigned to receive intravenous eptinezumab 100, 300 mg, or placebo every 12 weeks. Efficacy outcomes included mean changes from baseline in monthly migraine days (MMDs) during weeks 1–12, migraine responder rates at week 12, and percentages of patients below International Classification of Headache Disorders thresholds for CM and MOH over weeks 1–24.

Results: There were 431 patients who were diagnosed with CM and MOH as specified in the protocol and received eptinezumab 100 mg (n = 139), 300 mg (n = 147), or placebo (n = 145). During the baseline period, these patients experienced an average of 16.7 migraine days across treatment arms. Over weeks 1–12, eptinezumab-treated patients experienced greater reductions from baseline in MMDs than placebo patients (100 mg, change from baseline = −8.4, difference from placebo [95% confidence interval (CI)] = −3.0 [−4.56, −1.52], p < 0.0001 vs. placebo; 300 mg, change from baseline = −8.6, difference from placebo [95% CI] = −3.2 [−4.66, −1.78], p < 0.0001 vs. placebo; placebo, −5.4). Compared with placebo, more eptinezumab-treated patients were ≥50% migraine responders (100 mg, 84/139 [60.4%]; 300 mg, 91/147 [61.9%]; placebo, 50/145 [34.5%]) or ≥75% responders (100 mg, 38/139 [27.3%]; 300 mg, 44/147 [29.9%]; placebo, 21/145 [14.5%]) over weeks 1–12. Therapeutic benefits with eptinezumab were observed from day 1 after dosing, and improvements were sustained with an additional dose. For the full 24-week treatment period, 71/139 (51.1%), 80/147 (54.4%), and 47/145 (32.4%) of 100, 300 mg, and placebo-treated patients, respectively, were below CM thresholds, and of the patients who provided sufficient acute medication data, 47/93 (50.5%), 53/107 (49.5%), and 26/96 (27.1%), respectively, were below medication-overuse thresholds.

Conclusions: In patients diagnosed with both CM and MOH, eptinezumab treatment resulted in greater reductions in MMDs, higher responder rates, and fewer patients meeting CM and MOH criteria, thus demonstrating the efficacy and clinical utility of eptinezumab in this patient population.


Medication-overuse headache (MOH) is a secondary headache disorder associated with overuse of analgesics or specific drugs (e.g., triptans) to treat acute migraine attacks. The overuse of medication may also result in an exacerbation of headache-related symptoms, including an increase in the frequency, duration, and/or intensity of headache.[1,2] The criteria for MOH include patients with a preexisting primary headache disorder (at least 15 headache days/month)—usually chronic migraine (CM) or chronic tension-type headache[3–5]—who develop a new type of headache or a significant worsening of their preexisting headache in association with the use of acute or symptomatic headache medication at least 15 days/month (simple analgesics) or at least 10 days/month (triptans, ergots, and opioid/combination analgesics) for at least 3 months.[6,7] MOH develops as patients increase the quantity and frequency of their medication usage in an effort to gain or maintain control of their headache disorder. This vicious cycle of symptoms often improves after reducing the intake of acute or symptomatic medication or discontinuing the medication followed by preventive therapy of the primary headache disorder.[8]

The worldwide prevalence of MOH is estimated to be 1%–2% of the general population or more, depending on the country and study.[2,9] MOH affects three to four times more women than men,[10] which could be partly attributable to the higher prevalence of migraine and tension-type headaches in women compared with men.[11] MOH creates a global economic burden and disability for patients;[12] the indirect costs caused by reduced productivity and the absence from work are significant, accounting for approximately 92% of the overall costs of MOH.[13] In addition to the economic burden, patients with MOH have an increased prevalence of depression and anxiety, which has a negative impact on quality of life for these patients.[14,15]

Calcitonin gene-related peptide (CGRP) is a neuropeptide implicated in the pathophysiology of migraine.[16,17] Eptinezumab (Vyepti™, Lundbeck Seattle BioPharmaceuticals, Inc., Bothell, WA, USA) is a humanized monoclonal antibody that selectively binds to and inhibits the activity of the CGRP ligand, resulting in selective and sustained inactivation of CGRP.[18] Eptinezumab is administered every 12 weeks via 30-minute intravenous (IV) infusion, achieving 100% bioavailability following administration, with a half-life of 27 days,[18] and has been approved by the US Food and Drug Administration for the preventive treatment of migraine in adults. The efficacy, tolerability, and safety of eptinezumab for migraine prevention was established in two phase 3 clinical studies in patients with episodic migraine (PROMISE-1)[19] and CM (PROMISE-2).[20] In both trials, eptinezumab significantly reduced migraine days during weeks 1 through 12, with an onset of preventive effect as early as the first day after administration. The patients included in the PROMISE-2 trial had CM with or without MOH. Due to its mechanism of action, administration as an IV infusion, and potential early onset of efficacy,[21] we hypothesized that eptinezumab would be an effective migraine preventive treatment for patients with MOH, and hence MOH was prespecified as an efficacy subgroup in the protocol. The objective of this subgroup analysis was to investigate the efficacy, tolerability, and safety of eptinezumab for the prevention of migraine in patients with a dual diagnosis of CM and MOH.