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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. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusions Erenumab is a fully human monoclonal antibody that selectively targets the calcitonin gene–related peptide receptor. It has been proven to be safe and efficacious in patients with episodic migraine (EM) and chronic migraine (CM) as demonstrated in phase 2 and 3 clinical trials including patients from Europe, Japan, and the United States. Reversion from CM to EM, as indicated by a reduction in the frequency of headache days, is an important indicator for efficacy outcome, though it has not been analyzed widely in patients with CM to date.Primary results of the DRAGON study demonstrated the efficacy and safety of erenumab in patients with CM from China and other Asian countries. This post hoc analysis evaluated the rate of reversion from CM to EM in the overall population and in subgroups of patients defined by baseline demographic and clinical characteristics (age, body mass index, gender, prior preventive treatment failure, medication overuse status, and disease duration).Reversion from CM to EM was defined as a reduction in headache frequency to < 45 headache days over the 12 weeks of the double‐blind treatment period. In addition, migraine‐related disability and disease impact on functional impairment were assessed within each treatment group in reverters and non‐reverters using the Headache Impact Test‐6 (HIT‐6), Migraine Physical Function Impact Diary (MPFID), and modified Migraine Disability Assessment (mMIDAS).Overall, 557 patients with CM were randomized to monthly erenumab 70 mg (n = 279) or placebo (n = 278), of whom 52.3% (146 of 279) treated with erenumab reverted from CM to EM compared to 41.0% (114 of 278) in the placebo group (odds ratio [OR] 1.59, 95% confidence interval: 1.1–2.2; p = 0.007). Treatment with erenumab resulted in a greater mean change (standard error) from baseline in the HIT‐6 total score for reverters versus non‐reverters compared to placebo (erenumab: −9.5 [0.6] vs. −5.1 [0.5]; placebo: −8.9 [0.7] vs. −4.9 [0.5]). A similar pattern was observed for mMIDAS score in erenumab treatment groups versus placebo (erenumab: −22.1 [1.2] vs. −6.3 [1.8]; placebo: −19.9 [1.3] vs. −7.9 [1.6]). Substantial improvements were reported in MPFID‐Physical Impairment (PI) and Everyday Activities (EA) scores in reverters versus non‐reverters in erenumab treatment groups (MPFID‐PI: −5.9 [0.3] vs. −1.9 [0.6]; MPFID‐EA: −7.9 [0.4] vs. −3.4 [0.6]) and in placebo (MPFID‐PI: −5.4 [0.4] vs. −1.0 [0.5]; MPFID‐EA: −7.1 [0.5] vs. −3.2 [0.5]).This analysis demonstrated that a greater proportion of patients treated with erenumab reverted from CM to EM compared to patients treated with placebo. The reversion from CM to EM was reflected by the greater improvements in patient‐reported outcomes in the erenumab group. [ABSTRACT FROM AUTHOR]

Objective: To investigate if calcitonin gene-related peptide infusion induces migraine-like attacks in chronic migraine patients. Methods: Fifty-eight patients with chronic migraine, either with or without headache on the experimental day, were assessed for the incidence of migraine-like attacks after an intravenous infusion with calcitonin gene-related peptide 1.5 µg/min over 20 min. The primary endpoint was the incidence of migraine-like attacks after calcitonin gene-related peptide. Exploratory endpoints were the association between the incidence of migraine-like attacks and presence of headache on the experimental day, and headache frequency in the past month. Migraine-like attack data was compared to a historic cohort of 91 episodic migraine patients without headache on the experimental day. Total tenderness score, pressure-pain threshold and supra-threshold pressure pain at baseline were investigated in relation to incidence of migraine-like attacks and presence of headache on the experimental day. Results: In total, 83% of the 58 chronic migraine patients developed migraine-like attacks after calcitonin gene-related peptide infusion. Migraine-like attacks were found in 92% of chronic migraine patients with headache on the experimental day compared to 65% of chronic migraine patients without headache on the experimental day (p = 0.035). No differences were observed in total tenderness score and pressure-pain threshold between chronic migraine patients with and without headache on the experimental day. The incidence of migraine-like attacks following calcitonin gene-related peptide in chronic migraine patients without headache (65%) was equal to the historic cohort of 91 episodic migraine patients without headache (67%) on the experimental day. Conclusions: Chronic migraine patients are hypersensitive to calcitonin gene-related peptide. The potency of calcitonin gene-related peptide as a migraine inductor is increased in chronic migraine patients with ongoing headache. We suggest that calcitonin gene-related peptide, besides being a migraine trigger also acts as a modulator of nociceptive transmission in the trigeminal system. [ABSTRACT FROM AUTHOR]

Introduction: Preclinical data implicate large conductance calcium-activated potassium (BKCa) channels in the pathogenesis of headache and migraine, but the exact role of these channels is still unknown. Here, we investigated whether opening of BKCa channels would cause headache and vascular effects in healthy volunteers.Methods: In a randomized, double-blind, placebo-controlled, cross-over study, 21 healthy volunteers aged 18-39 years were randomly allocated to receive an intravenous infusion of 0.05 mg/min BKCa channel opener MaxiPost and placebo on two different days. The primary endpoints were the difference in incidence of headache and the difference in area under the curve (AUC) for headache intensity scores (0-12 hours) and for middle cerebral artery blood flow velocity (VMCA) (0-2 hours) between MaxiPost and placebo. The secondary endpoints were the differences in area under the curve for superficial temporal artery and radial artery diameter (0-2 hours) between MaxiPost and placebo.Results: Twenty participants completed the study. Eighteen participants (90%) developed headache after MaxiPost compared with six (30%) after placebo (p = 0.0005); the difference of incidence is 60% (95% confidence interval 36-84%). The area under the curve for headache intensity (AUC0-12 hours, p = 0.0003), for mean VMCA (AUC0-2 hours, p = 0.0001), for superficial temporal artery diameter (AUC0-2 hours, p = 0.003), and for radial artery diameter (AUC0-2 hours, p = 0.03) were significantly larger after MaxiPost compared to placebo.Conclusion: MaxiPost caused headache and dilation in extra- and intracerebral arteries. Our findings suggest a possible role of BKCa channels in headache pathophysiology in humans. ClinicalTrials.gov, ID: NCT03887325. [ABSTRACT FROM AUTHOR]

Background: The present study aimed to investigate the predictive value of calcitonin gene-related peptide (CGRP)-induced migraine attacks for effectiveness to erenumab treatment in people with migraine., Methods: In total, 139 participants with migraine underwent a single experimental day involving a 20-min infusion with CGRP. Following this, the participants entered a 24-week treatment period with erenumab. The primary endpoints were the predictive value of CGRP-induced migraine attacks on the effectiveness of erenumab, defined as ≥50% reduction in monthly migraine days, or ≥ 50% reduction in either monthly migraine or monthly headache days of moderate to severe intensity., Results: Among participants with CGRP-induced migraine attacks, 60 of 99 (61%) achieved ≥50% reduction in monthly migraine days during weeks 13-24 with erenumab. Conversely, 13 of 25 (52%) where CGRP infusion did not induce a migraine achieved the same endpoint ( p  = 0.498). There were no significant differences between the ≥50% reduction in either monthly migraine or monthly headache days of moderate to severe intensity between CGRP-sensitive and non-sensitive participants ( p  = 0.625)., Conclusions: Our findings suggest that the CGRP-provocation model cannot be used to predict erenumab's effectiveness. It remains uncertain whether this finding extends to other monoclonal antibodies targeting the CGRP ligand or to gepants. Trial Registration: The study was registered at ClinicalTrials.gov (NCT04592952).

Background: The cAMP and cGMP pathways are implicated in the initiation of migraine attacks, but their interactions remain unclear. Calcitonin gene-related peptide (CGRP) triggers migraine attacks via cAMP, whereas the phosphodiesterase-5 inhibitor sildenafil induces migraine attacks via cGMP. Our objective was to investigate whether sildenafil could induce migraine attacks in individuals with migraine pre-treated with the CGRP-receptor antibody erenumab., Methods: In this randomized, double-blind, placebo-controlled, cross-over study, adults with migraine without aura received a single subcutaneous injection of 140 mg erenumab on day 1. They were then randomized to receive sildenafil 100 mg or placebo on two experimental days, each separated by at least one week, between days 8 and 21. The primary endpoint was the difference in the incidence of migraine attacks between sildenafil and placebo during the 12-h observation period after administration., Results: In total, 16 participants completed the study. Ten participants (63%) experienced a migraine attack within 12 h after sildenafil administration compared to three (19%) after placebo ( p  = 0.016). The median headache intensity was higher after sildenafil than after placebo (area under the curve (AUC) for the 12-h observation period, p  = 0.026). Furthermore, sildenafil induced a significant decrease in mean arterial blood pressure (AUC, p  = 0.026) and a simultaneous increase in heart rate (AUC, p  < 0.001) during the first hour after administration compared to placebo., Conclusion: These findings provide evidence that migraine induction via the cGMP pathway can occur even under CGRP receptor blockade., Trial Registration: ClinicalTrials.gov: Identifier NCT05889455., Competing Interests: Declaration of conflicting interestsWe declare the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: BR reports personal fees from AbbVie/Allergan, Eli Lilly, Lundbeck, Novartis and Teva, as well as research grants from Novartis and Lundbeck, all outside of the submitted work. BR reports serving as junior associate editor of The Journal of Headache and Pain, and associate editor of Frontiers In Neurology. TPD has nothing to disclose. HA reports personal fees from Lundbeck and Teva, outside of the submitted work. JS and TMT are full-time employees and shareholders of Novartis Pharma AG, Basel, Switzerland. MA reports receiving personal fees from AbbVie, Amgen, Eli Lilly, GlaxoSmithKline, Lundbeck, Novartis, Pfizer and Teva Pharmaceuticals, all outside of the submitted work. MA reports serving as associate editor of The Journal of Headache and Pain, and associate editor of Brain.

Introduction: Preclinical data implicate large conductance calcium-activated potassium (BK Ca ) channels in the pathogenesis of headache and migraine, but the exact role of these channels is still unknown. Here, we investigated whether opening of BK Ca channels would cause headache and vascular effects in healthy volunteers., Methods: In a randomized, double-blind, placebo-controlled, cross-over study, 21 healthy volunteers aged 18-39 years were randomly allocated to receive an intravenous infusion of 0.05 mg/min BK Ca channel opener MaxiPost and placebo on two different days. The primary endpoints were the difference in incidence of headache and the difference in area under the curve (AUC) for headache intensity scores (0-12 hours) and for middle cerebral artery blood flow velocity (V MCA ) (0-2 hours) between MaxiPost and placebo. The secondary endpoints were the differences in area under the curve for superficial temporal artery and radial artery diameter (0-2 hours) between MaxiPost and placebo., Results: Twenty participants completed the study. Eighteen participants (90%) developed headache after MaxiPost compared with six (30%) after placebo ( p  = 0.0005); the difference of incidence is 60% (95% confidence interval 36-84%). The area under the curve for headache intensity (AUC 0-12 hours , p  = 0.0003), for mean V MCA (AUC 0-2 hours , p  = 0.0001), for superficial temporal artery diameter (AUC 0-2 hours , p  = 0.003), and for radial artery diameter (AUC 0-2 hours , p  = 0.03) were significantly larger after MaxiPost compared to placebo., Conclusion: MaxiPost caused headache and dilation in extra- and intracerebral arteries. Our findings suggest a possible role of BK Ca channels in headache pathophysiology in humans. ClinicalTrials.gov, ID: NCT03887325.