Lima, Gabriel Paiva da Silva

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.

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

Background Erenumab (erenumab-aooe in the US) effectively reduces monthly migraine days in episodic and chronic migraine. This traditional outcome does not capture the intensity of headache pain on days with migraine. Methods This post hoc analysis of two pivotal randomized, placebo-controlled studies in patients with episodic migraine and chronic migraine examined the effect of erenumab 70 and 140 mg on migraine pain. Cumulative monthly migraine pain intensity is the sum of the peak pain intensity scores (0 = no migraine to 3 = migraine day with severe pain) on migraine days. Change from baseline in cumulative monthly migraine pain and average monthly pain intensity was assessed over months 4 to 6 for episodic migraine and month 3 for chronic migraine; change in average monthly pain intensity was assessed among monthly migraine days responders/non-responders. Results Efficacy analysis included 946 patients for the episodic migraine study and 656 patients for the chronic migraine study. Cumulative monthly migraine pain decreased significantly with erenumab versus placebo ( p < 0.001, for episodic migraine and chronic migraine). In addition, monthly average migraine pain intensity decreased significantly with erenumab versus placebo for episodic migraine ( p < 0.01); decreases were non-significant for chronic migraine. In comparison with placebo-treated patients, a greater proportion of erenumab-treated patients were pain intensity responders regardless of threshold used. Episodic migraine and chronic migraine patients with a ≥50% reduction in monthly migraine days (responders) had a greater reduction in monthly average pain intensity than non-responders. Conclusions Erenumab reduced cumulative monthly migraine pain in episodic migraine and chronic migraine patients and significantly reduced monthly average migraine pain in episodic migraine, demonstrating treatment benefit beyond reduction in migraine frequency. Clinical Trial Registration: ClinicalTrials.gov, NCT02456740; ClinicalTrials.gov, NCT02066415

AbstractBackground and purposeAlthough erenumab has demonstrated significant reduction in migraine frequency and improved quality of life in studies lasting 3 to 12 months, little is known about long‐term therapy.MethodsThis study was an open‐label, 5‐year treatment phase following a 12‐week, double‐blind, placebo‐controlled trial in adults with episodic migraine. Patients initially received open‐label erenumab 70 mg, which increased to 140 mg following a protocol amendment. Efficacy analyses included change from baseline in monthly migraine days (MMDs), monthly acute migraine‐specific medication (AMSM) days, and health‐related quality of life.ResultsOf 383 patients enrolled, 250 switched to 140 mg; 215 (56.1%) completed open‐label treatment. Mean (standard error) change in MMDs from baseline of 8.7 (0.2) days was −5.3 (0.3) days; an average reduction of 62.3% at year 5. Among patients using AMSM at baseline (6.3 [2.8] treatment days), mean change in monthly AMSM days was −4.4 (0.3) days at the end of 5 years. Patient‐reported outcomes indicated stable improvements in disability, headache impact, and migraine‐specific quality of life. Exposure‐adjusted patient incidence rates of adverse events (AEs) were 123.0/100 patient‐years; AEs were most frequently nasopharyngitis, upper respiratory tract infection, and influenza. Serious AEs (SAEs) reported by 49 patients (3.8/100 patient‐years) were mostly single occurrence. Two fatal adverse events were reported. There were no increases in incidence of AEs, SAEs, or AEs leading to treatment discontinuation over 5 years of exposure.ConclusionsTreatment with erenumab was associated with reductions in migraine frequency and improvements in health‐related quality of life that were maintained for at least 5 years. No new safety signals were observed.