Chehrenama, Mahan

Abstract Objective To evaluate the effect of erenumab treatment beyond monthly migraine days in patients with high‐frequency episodic migraine who did not respond to at least one previous migraine preventive treatment. Background Reduction in monthly migraine days has been the efficacy standard for migraine preventive treatments; however, it does not fully capture the holistic benefit of the therapy. Erenumab, a monoclonal antibody targeting the calcitonin gene–related peptide pathway, has demonstrated reduction in monthly migraine days and improvement in function in patients with episodic and chronic migraine. Methods In this phase 4, interventional, double‐blind, randomized, placebo‐controlled, multicenter, global study, treatment with erenumab was assessed over 4 months in adults with high‐frequency episodic migraine. The study was conducted at 61 sites located across North America and Europe between September 2020 and October 2023. Patients with ≥1 qualifying oral triptan‐treated migraine attack at baseline were randomized to receive erenumab 140 mg or placebo subcutaneously once monthly. The primary endpoint was change from baseline in mean monthly hours of at least moderate headache pain intensity over months 1, 2, and 3; secondary endpoints included change from baseline in mean monthly function, mean monthly duration of at least moderate pain intensity in migraine attacks, and mean monthly peak migraine pain intensity. Safety outcomes were also assessed. Results Of 512 randomized patients, 510 received erenumab 140 mg ( n = 254) or placebo ( n = 256) once monthly. Demographics and baseline characteristics were balanced between the two treatment arms. Erenumab 140 mg was superior to placebo in reducing duration of moderate or severe headache pain intensity over months 1, 2, and 3 (least squares mean [95% confidence interval {CI}] difference, −7.95 [−11.45, −4.46]; p < 0.001). Compared with placebo, erenumab significantly reduced migraine functional impact as assessed by the four domains of the Migraine Functional Impact Questionnaire, with a least squares mean (95% CI) difference of −7.36 (−10.80, −3.92) for physical functioning, −7.10 (−10.34, −3.87) for usual activities, −6.82 (−10.37, −3.27) for social functioning, and − 7.05 (−10.76, −3.34) for emotional functioning ( p < 0.001 for all domains). Significant reductions with erenumab compared with placebo were also observed in duration of at least moderate pain intensity in residual or break‐through migraine attacks (least squares mean [95% CI] difference, −1.07 [−1.92, −0.22]; p = 0.013) and peak migraine pain intensity (−0.48 [−0.85, −0.11]; p = 0.011). Incidence of grade 3 adverse events was 1.6% with erenumab and 1.2% with placebo; no grade 4 or fatal adverse events were reported in either treatment arm. Conclusion Findings from the EMBRACE study demonstrated that treatment with erenumab in patients with high‐frequency episodic migraine can provide positive therapeutic effects on ictal burden and pain, with residual migraine attacks tending to be shorter and less painful, with less overall impact.

ABSTRACTBackgroundErenumab‐induced medication overuse headache (MOH) remission in participants with chronic migraine (CM) in a prospective, Phase 4, randomized, placebo‐controlled trial with an open‐label treatment period (OLTP). We present 1‐year results from the combined double‐blind treatment period (DBTP) and OLTP for the stratified nonopioid cohort.MethodsParticipants with CM‐MOH were randomized 1:1:1 to subcutaneous 70 or 140 mg erenumab every 4 weeks (QM) or placebo for the initial 24 weeks (DBTP). Those successfully completing DBTP could continue the 28‐week OLTP, maintaining the same erenumab dose received during DBTP or, if receiving placebo, randomly assigned 1:1 to erenumab 70 or 140 mg QM. OLTP endpoints were exploratory.ResultsOverall, 552 participants received erenumab (70 mg, n = 274; 140 mg, n = 278); 95.3% completed OLTP. One‐year MOH relapse in participants who achieved MOH remission at DBTP Month 6 was 2.7% (3/111) and 2.4% (3/124) with erenumab 70 and 140 mg, respectively; absence of MOH at study end was observed in 69.0% (189/274) and 75.5% (210/278) of participants. Sustained MOH absence over 1 year was reported in 60.5% (107/177) and 68.8% (119/173) of participants, respectively. Sustained improvements in measures of headache days, medication days, and function were observed in both groups. No new safety concerns were identified (grade ≥ 3, 35 [6.3%]; serious, 17 [3.1%]; adverse events leading to treatment discontinuation, 5 [0.9%]).ConclusionsErenumab was effective in inducing and sustaining MOH remission and improving function over 1 year. Treatment compliance remained high, with safety events consistent with erenumab's known safety profile.Trial RegistrationNCT03971071

ImportancePatients with chronic migraine and medication overuse headaches (CM-MOH) represent a particularly burdened subpopulation. This trial provides first, to our knowledge, American Academy of Neurology class I evidence for a preventive therapy in CM-MOH.ObjectiveTo assess erenumab efficacy and safety in patients with nonopioid CM-MOH.Design, Settings, and ParticipantsThis randomized, double-blind, parallel-group, placebo-controlled trial took place at 67 centers in North America, Europe, and Australia from October 7, 2019, to November 2, 2022. This report reflects the primary analysis conducted in January 2023, using a database snapshot from December 1, 2022, which contains the complete dataset of the double-blind treatment period (DBTP). Participants included adults with CM-MOH who had 1 or more preventive treatment failure(s). There were 992 participants screened and 620 participants enrolled (584 in nonopioid cohort and 36 in opioid cohort)InterventionsErenumab, 70 mg, 140 mg, or placebo, once monthly for 24 weeks.Main Outcomes and MeasuresThe primary end point was MOH remission at month 6. Secondary end points included change from baseline in mean monthly acute headache medication days (AHMD) at month 6 and sustained MOH remission throughout the DBTP. Safety end points were adverse events and changes in vital signs.ResultsThe primary analysis population included 584 participants in the nonopioid-treated cohort with a mean age of 44 years and 482 participants were female (82.5%). Baseline demographics and disease characteristics were balanced across groups. At month 6, 134 participants in the erenumab, 140 mg group (69.1%) (odds ratio [OR], 2.01; 95% CI, 1.33-3.05; P &amp;lt; .001 vs placebo) and 117 in the erenumab, 70 mg group (60.3%) (OR, 1.37; 95% CI, 0.92-2.05; P = .13 vs placebo) achieved MOH remission vs 102 participants in the placebo group (52.6%). AHMD use was also reduced in the erenumab groups vs placebo. Least squares mean (standard error) change from baseline in average monthly AHMD was –9.4 (0.4) days in the erenumab, 140 mg group (difference from placebo, –2.7; 95% CI, –3.9 to –1.6; P &amp;lt; .001) and –7.8 (0.4) days in the erenumab, 70 mg group (difference from placebo, –1.2; 95% CI, –2.4 to –0.1; P = .03), vs –6.6 (0.4) days in the placebo group. MOH remission throughout the DBTP was sustained in 119 participants (61.3%,) 96 participants (49.5%), and 73 participants (37.6%) in the erenumab, 140 mg, 70 mg, and placebo groups, respectively. Adverse events were consistent with the known safety profile of erenumab. Treatment-emergent adverse events incidence in the combined erenumab group was 66.8% (259 participants; constipation 15.2% (59 participants) and COVID-19 13.9% (54 participants) were most common.Conclusions and RelevanceIn this study, monthly, 140 mg, erenumab injections safely and effectively achieved MOH remission in patients with nonopioid CM-MOH within 6 months.Trial RegistrationClinicalTrials.gov Identifier: NCT03971071

Abstract Background Treatment wearing‐off has been reported for calcitonin gene‐related peptide‐pathway monoclonal antibodies, including erenumab, specifically in the last week of the monthly dosing cycle. Objective We sought to determine the consistency of erenumab effect throughout the monthly treatment cycle. Methods In this post hoc analysis of four pivotal double‐blind, randomized controlled studies of erenumab in episodic and chronic migraine, we assessed wearing‐off based on change in weekly migraine days at week 4 versus average over weeks 1–3 in each monthly dosing cycle. Analyses were conducted at each monthly dosing cycle in all patients, in responders (≥50% reduction in weekly migraine days), and in consistent responders (response in ≥2monthly cycles). Results There was no evidence of wearing‐off in the full study populations of two global studies (N = 946 and N = 656) and two Japan studies (N = 475 and N = 261). In the full study population, mean change in weekly migraine days at week 4 compared with the average over week 1–3 ranged from 0.15 days improvement to 0.19 days worsening in the placebo group and 0.08 days improvement to 0.20 days worsening in the erenumab groups. A subgroup of responders experienced wearing‐off, but the extent of wearing‐off did not differ between erenumab and placebo groups. The mean change in weekly migraine days at week 4 compared with the average over weeks 1–3 ranged from 0.34 to 0.61 days worsening in the placebo group and 0.27 to 0.78 days worsening in the erenumab groups. Few patients had persistent wearing‐off in ≥2 consecutive monthly treatment cycles. For erenumab‐treated responders, serum erenumab concentrations were similar among patients experiencing wearing‐off and those maintaining response. Conclusion No systematic wearing‐off with erenumab was identified. Further research is needed to determine if wearing‐off reported for some patients in clinical practice reflects a true treatment response pattern or normal fluctuations in migraine frequency.