Assessment of prolonged safety and tolerability of erenumab in migraine patients in a long-term open-label study (APOLLON).

BACKGROUND: Efficacy and safety of human monoclonal antibody erenumab used for migraine prophylaxis have been shown in clinical studies. APOLLON is an open-label, multi-center, single arm study, which permits dose adjustments of erenumab and includes an option for a drug holiday. The findings contribute to the accumulating long-term evidence regarding erenumab's tolerability and safety profile in individuals experiencing episodic and chronic migraines. METHODS: The study population consisted of adult patients with episodic or chronic migraine, who had successfully completed the HER-MES study (NCT03828539). Patients were treated with erenumab for 128 weeks at a flexible dose of either 70 mg or 140 mg. Treatment discontinuation attempts were allowed as voluntary single treatment interruption ('drug holiday') of up to 24 weeks. RESULTS: 701 patients were enrolled in APOLLON. The exposure associated incidence rate (EAIR) of adverse events (AEs) (N = 601) per 100 subject years was 101.71 (95% CI [92.28; 111.14]) meaning a patient could expect having about one adverse event per each year of treatment. EAIR was higher in females (n = 524, EAIR: 104.40, 95% CI [93.93; 114.86]) than in males (n = 77, EAIR: 86.55, 95% CI [65.39; 107.71]) and increased with initial monthly migraine days (MMD) and prior prophylactic treatment failures. A total of 155 patients discontinued erenumab treatment during open-label treatment phase. Of these, 29 were due to AEs (4.1% of total cohort) and out of these 65.5% (N = 19) were considered treatment-related. Safety parameters were in line with HER-MES data and did not reveal new safety signals. Drug holidays were realized by 108 patients (15.4%), of which 64.8% (N = 70) returned to treatment. The mean number of monthly headache days (MHDs), MMDs, and days with acute headache medication significantly increased during drug holiday. After resumption of erenumab treatment, a rapid reduction of the migraine parameters was observed. CONCLUSIONS: APOLLON provides long-term safety and tolerability data confirming the beneficial safety profile of erenumab over a period of 128 weeks. In addition, reversibility of migraine deterioration during drug holiday was shown and most patients returned to their treatment with similar response rates compared to initial treatment. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04084314 ( https://clinicaltrials.gov/study/NCT04084314 ), First submitted: 2019-09-06.

First real-world study on the effectiveness and tolerability of rimegepant for acute migraine therapy in Chinese patients.

BACKGROUND: Rimegepant, a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist, is indicated for acute and preventive migraine treatment in the United States and other countries. However, there is a lack of prospective real-world evidence for the use of rimegepant in Chinese migraine patients. METHODS: This was a single-arm, prospective, real-world study. While taking rimegepant to treat migraine attacks as needed, eligible participants were asked to record their pain intensity, functional ability, and accompanying symptoms for a single attack at predose and 0.5, 1, 2, 24, and 48 h postdose via a digital platform. Adverse events (AEs) during the rimegepant treatment period were recorded and analysed. The percentages of participants who experienced moderate to severe pain at predose and 0.5, 1, 2, 24, and 48 h postdose were assessed. Additionally, the percentages of participants who reported better/good outcomes in terms of pain intensity, functional ability, and accompanying symptoms at 0.5, 1, 2, 24, and 48 h postdose were analysed. In addition, the total cohort (full population, FP) was stratified into a prior nonresponder (PNR) group to observe the effectiveness and safety of rimegepant for relatively refractory migraine and a rimegepant and eptinezumab (RE) group to observe the effectiveness and safety of the combination of these drugs. RESULTS: By November 24th, 2023, 133 participants (FP, n = 133; PNR group, n = 40; RE group, n = 28) were enrolled, and 99 participants (FP, n = 99; PNR group, n = 30; RE group, n = 23) were included in the analysis. Rimegepant was effective in treating migraine in the FP and both subgroups, with a significant decreasing trend in the percentages of participants experiencing moderate to severe pain postdose (p < 0.05) and a marked increase in the percentages of participants who reported better/good outcomes in terms of pain intensity, functional ability, and accompanying symptoms at 0.5, 1, 2, 24, and 48 h postdose compared with predose. AEs were reported by 6% of participants in the FP, and all AEs were mild. CONCLUSIONS: In the real world, rimegepant is effective in the acute treatment of migraine patients in China. The low incidence rate of AEs highlighted the favourable tolerability profile of rimegepant. TRIAL REGISTRATION: Clinicaltrials.gov NCT05709106. Retrospectively registered on 2023-02-01.

Case series on monoclonal antibodies targeting calcitonin gene-related peptide in migraine patients during pregnancy: Enhancing safety data.

BACKGROUND: Monoclonal antibodies targeting calcitonin gene-related peptide (CGRP-mAbs) are approved for adult migraine prevention but pose safety concerns in pregnancy. We assess the safety of CGRP-mAbs in the periconceptional period through a case series and literature review. METHODS: Six migraine-diagnosed women received CGRP-mAbs; treatment ceased upon pregnancy. We collected data and conducted safety assessments. To provide a comprehensive context, we performed a literature review. RESULTS: The series includes three erenumab, two fremanezumab and one galcanezumab case. A fremanezumab recipient experienced miscarriage; severe perinatal asphyxia linked to dystocia occurred with erenumab (140 mg). Database reviews revealed 63 spontaneous abortions, eight premature births, and seven birth defects among 286 World Health Organization and 65 European Medicines Agency cases. These rates align with untreated population rates. CONCLUSIONS: CGRP-mAbs use in the periconceptional period does not lead to clinically significant increase in pregnancy-related pathology or adverse effects on newborns within our case series and the literature reviewed.

Long-term safety of zavegepant nasal spray for the acute treatment of migraine: A phase 2/3 open-label study.

BACKGROUND: Zavegepant is the first small molecule calcitonin gene-related peptide receptor antagonist for intranasal administration for the acute treatment of migraine. The objective of this study was to evaluate the safety and tolerability of zavegepant in the acute treatment of migraine under repeated, as-needed dosing for up to one year. METHODS: This phase 2/3, one-year open-label safety study of zavegepant 10 mg nasal spray for the acute treatment of migraine enrolled adults aged ≥18 years with a history of two to eight moderate to severe monthly migraine attacks. Participants used one dose of zavegepant as needed to self-treat migraine attacks of any severity, up to eight times per month, for 52 weeks. RESULTS: Participants were enrolled between 29 June and 4 December 2020. Of the 608 participants entering long-term treatment, 603 were treated with study drug. Participants administered a mean (SD) of 3.1 (1.55) zavegepant doses per month. There were no deaths. Of the seven serious adverse events reported, none was considered related to treatment. Altogether, 6.8% (41/603) of treated participants had an adverse event leading to study drug discontinuation. The most frequent adverse event leading to discontinuation was dysgeusia (1.5% [9/603]). The most common treatment-emergent adverse events (≥5% of participants) were dysgeusia (39.1% [236/603]); nasal discomfort (10.3% [62/603]); COVID-19 (7.5% [45/603]); nausea (6.1% [37/603]); nasal congestion and throat irritation (5.5% [33/603] each); and back pain (5.3% [32/603]). Aminotransferases >3x the upper limit of normal occurred in 2.6% [16/603] of participants; none had concurrent elevations in bilirubin >2x upper limit of normal. CONCLUSIONS: One year of zavegepant 10 mg nasal spray up to eight times per month was safe and well tolerated.Trial registration: Clinicaltrials.gov: NCT04408794.

Effect of Ubrogepant on Patient-Reported Outcomes When Administered During the Migraine Prodrome: Results From the Randomized PRODROME Trial.

BACKGROUND AND OBJECTIVES: Ubrogepant is a calcitonin gene-related peptide receptor antagonist approved for the acute treatment of migraine. The PRODROME trial previously demonstrated that ubrogepant treatment during prodrome prevents the onset of moderate or severe headache. In this analysis of the PRODROME trial, the benefits of ubrogepant treatment during the prodrome on patient-reported outcomes (PROs) are evaluated. METHODS: PRODROME was a multicenter, randomized, double-blind, placebo-controlled, crossover trial that enrolled adults who experienced 2-8 migraine attacks per month with moderate-severe headache pain. Eligible participants treated 2 qualifying prodrome events, defined as a migraine attack with prodromal symptoms when the participant was confident a headache would follow within 1-6 hours. Participants were randomized to treatment sequence A (placebo then ubrogepant 100 mg) or sequence B (ubrogepant 100 mg then placebo). This analysis evaluated the ability to function normally over 24 hours (secondary end point) and at specific time points after dose (additional end point). Other PRO end points included activity limitation over 24 hours and satisfaction with study medication at 8 and 24 hours. RESULTS: Of 518 randomized participants, 477 comprised the modified intent-to-treat population. After treatment of qualifying prodrome events, a significantly greater ability to function normally over 24 hours was observed for participants after treatment with ubrogepant 100 mg compared with placebo (odds ratio [OR] 1.66, 95% CI 1.40-1.96; p < 0.0001). As early as 2 hours after dose, a greater proportion of ubrogepant-treated participants reported "no disability, able to function normally" compared with placebo (OR 1.76, 95% CI 1.32-2.35; nominal p = 0.0001). Ubrogepant administered during the prodrome was also associated with a greater reduction in activity limitations over 24 hours after dose (OR 2.07, 95% CI 1.61-2.67; nominal p < 0.0001). At 8 and 24 hours after dose, rates of being "satisfied" or "extremely satisfied" were greater for ubrogepant than for placebo (8 hours: OR 2.37, 95% CI 1.78-3.15; nominal p < 0.0001; 24 hours: OR 2.32, 95% CI 1.78-3.02; nominal p < 0.0001). DISCUSSION: Ubrogepant 100 mg administered during the prodrome was associated with significantly greater ability to function normally, greater reduction in activity limitations over 24 hours, and greater satisfaction with study medication, compared with placebo. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT04492020. Submitted: July 27, 2020; first patient enrolled: August 21, 2020. clinicaltrials.gov/ct2/show/NCT04492020. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that taking ubrogepant 100 mg during a migraine prodrome allows more patients to function normally over the next 24 hours.

Efficacy and safety of atogepant, a small molecule CGRP receptor antagonist, for the preventive treatment of migraine: a systematic review and meta-analysis.

BACKGROUND: Migraine is one of the most common diseases worldwide while current treatment options are not ideal. New therapeutic classes of migraine, the calcitonin gene-related peptide (CGRP) antagonists, have been developed and shown considerable effectiveness and safety. The present study aimed to systematically evaluate the efficacy and safety of atogepant, a CGRP antagonist, for migraine prophylaxis from the results of randomized controlled trials (RCTs). METHODS: The Cochrane Library, Embase, PubMed and https://www. CLINICALTRIALS: gov/ were searched for RCTs that compared atogepant with placebo for migraine prophylaxis from inception of the databases to Feb 1, 2024. Outcome data involving efficacy and safety were combined and analyzed using Review Manager Software version 5.3 (RevMan 5.3). For each outcome, risk ratios (RRs) or standardized mean difference (SMD) were calculated. RESULTS: 4 RCTs with a total of 2813 subjects met our inclusion criteria. The overall effect estimate showed that atogepant was significantly superior to placebo in terms of the reduction of monthly migraine (SMD - 0.40, 95% CI -0.46 to -0.34) or headache (SMD - 0.39, 95% CI -0.46 to -0.33) days, the reduction of acute medication use days (SMD - 0.45, 95% CI -0.51 to -0.39) and 50% responder rate (RR 1.66, 95% CI 1.46 to 1.89), while no dose-related improvements were found between different dosage groups. For the safety, significant number of patients experienced treatment-emergent adverse events (TEAEs) with atogepant than with placebo (RR 1.10, 95% CI 1.02-1.21) while there was no obvious difference between the five dosage groups. Most TEAEs involved constipation (RR 2.55, 95% CI 1.91-3.41), nausea (RR 2.19, 95% CI 1.67-2.87) and urinary tract infection (RR 1.49, 95% CI 1.05-2.11). In addition, a high dosage of atogepant may also increase the risk of treatment-related TEAEs (RR 1.64, 95% CI 1.02-2.63) and fatigue (RR 3.07, 95% CI 1.13-8.35). CONCLUSIONS: This meta-analysis suggests that atogepant is effective and tolerable for migraine prophylaxis including episodic or chronic migraine compared with placebo. It is critical to weigh the benefits of different doses against the risk of adverse events in clinical application of atogepant. Longer and multi-dose trials with larger sample sizes are required to verify the current findings.

Persistent effectiveness of CGRP antibody therapy in migraine and comorbid medication overuse or medication overuse headache - a retrospective real-world analysis.

BACKGROUND: Management of patients with migraine who have concomitant medication overuse (MO) or medication overuse headache (MOH) is a major problem in clinical practice. Detoxification of acute analgesics before or during initiation of prophylactic therapy has long been recommended although this concept has recently been questioned. Additionally, relapse after detoxification is a common problem. This real-world study analyses the initial and sustained effectiveness of prophylactic migraine therapy with CGRP (receptor) antibodies without prior detoxification in patients with comorbid MO or MOH for up to one year. METHODS: A retrospective real-world analysis was performed on 291 patients (episodic migraine (EM) with MO (EM-MO; n = 35), EM without MO (EM-noMO; n = 77), chronic migraine (CM) with MOH (CM-MOH; n = 109), CM without MOH (CM-noMOH; n = 70). All patients began treatment with either erenumab (n = 173), fremanezumab (n = 70) or galcanezumab (n = 48) without prior detoxification. Data were available for up to 12 months of treatment. Responder rates for monthly headache days (MHD), monthly migraine days (MMD) and monthly acute medication intake (AMD) were analysed. RESULTS: All groups showed a significant reduction in MHD, MMD and AMD at the last observed time point compared to baseline. In patients with CM and MOH, 60.6% (66/109) no longer fulfilled the definition of MO or MOH and a further 13.8% (15/109) had only EM-MO. In the EM cohort, 89% (31/35) of MO patients lost their MO during therapy. MHD and AMD 30% responder rates were comparable for CM-MOH and CM-noMOH (MHD: CM-MOH: 56.0% vs. CM-noMOH: 41.4%, p = 0.058, AMD: CM-MOH: 66.1% vs. CM-noMOH: 52.9%, p = 0.077). MMD responder rate did not differ significantly (after Bonferroni adjustment) (CM-MOH: 62.4% vs. CM-noMOH: 47.1%, p = 0.045, α = 0.017). After successful initiation of therapy, 15.4% of the initial CM-MOH patients relapsed and met the criterion for CM-MOH at the end of follow-up. There were no antibody specific differences in response to therapy. CONCLUSIONS: Our data confirms the effectiveness of CGRP antibody treatment in migraine patients with additional MOH or MO in a real-world setting. Low relapse rates after initial successful therapy support an early start of CGRP antibody treatment in patients with MOH or MO. TRIAL REGISTRATION: No registration, retrospective analysis.

Reduced hepatic impairment study to evaluate pharmacokinetics and safety of zavegepant and to inform dosing recommendation for hepatic impairment.

Zavegepant, a high-affinity, selective, small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, is approved in the United States for acute treatment of migraine in adults. The effects of moderate hepatic impairment (8 participants with Child-Pugh score 7-9 points) on the pharmacokinetics of a single 10-mg intranasal dose of zavegepant versus eight matched participants with normal hepatic function were evaluated in a phase I study. Pharmacokinetic sampling determined total and unbound plasma zavegepant concentrations. Moderate hepatic impairment increased the exposure of total zavegepant (~2-fold increase in AUC0-inf and 16% increase in Cmax) versus normal hepatic function, which is not considered clinically meaningful. The geometric least squares mean ratios (moderate impairment/normal) of plasma zavegepant AUC0-inf and Cmax were 193% (90% confidence interval [CI]: 112, 333; p = 0.051) and 116% (90% CI: 69, 195; p = 0.630), respectively. The geometric mean fraction unbound of zavegepant was similar for participants with moderate hepatic impairment (0.13; coefficient of variation [CV] 13.71%) versus those with normal hepatic function (0.11; CV 21.43%). Similar exposure findings were observed with unbound zavegepant versus normal hepatic function (~2.3-fold increase in AUC0-inf and 39% increase in Cmax). One treatment-emergent adverse event (mild, treatment-related headache) was reported in a participant with normal hepatic function. No dosage adjustment of intranasal zavegepant is required in adults with mild or moderate hepatic impairment.

Situational prevention: Pharmacotherapy during periods of increased risk for migraine attacks.

The small molecule calcitonin gene-related peptide receptor antagonists (gepants) are the only drug class with medicines indicated for both the acute and preventive treatment of migraine. Given this dual capacity to both treat and prevent, along with their favorable tolerability profiles and lack of an association with medication-overuse headache, headache specialists have begun to use gepants in ways that transcend the traditional categories of acute and preventive treatment. One approach, called situational prevention, directs patients to treat during the interictal phase, before symptoms develop, in situations of increased risk for migraine attacks. Herein, we present three patients to illustrate scenarios of gepant use for situational prevention. In each case, a gepant was started in anticipation of a period of increased headache probability (vulnerability) and continued for a duration of 1 day to 5 consecutive days. Although this approach may expose patients to medication when headache may not have developed, the tolerability and safety profile and preventive effect of gepants may represent a feasible approach for some patients. Situational prevention is an emerging strategy for managing migraine before symptoms develop in individuals who can identify periods when the probability of headache is high. This paper is intended to increase awareness of this strategy and stimulate future randomized, placebo-controlled trials to rigorously assess this strategy.

The preclinical discovery and development of atogepant for migraine prophylaxis.

INTRODUCTION: Atogepant is a selective calcitonin gene-related peptide (CGRP) receptor antagonist that is utilized in adults for the prevention of episodic and chronic migraine. Cumulative findings support the involvement of CGRP in migraine pathophysiology, and atogepant functions by competitively antagonizing CGRP receptors, which results in the inhibition of trigeminovascular nociception. The mechanism of action addresses the cause of migraine pain, providing an effective preventive treatment option. AREAS COVERED: The key milestones in its development, including preclinical achievements, phase I, II, and III clinical trials, and regulatory approvals are reviewed. Additionally, clinical efficacy, safety profile, and tolerability of atogepant are discussed. The literature review is based on a comprehensive search of English peer-reviewed articles from various electronic databases, including PubMed and ClinicalTrials.gov. EXPERT OPINION: The development of atogepant represents a significant breakthrough in migraine prevention, particularly due to its improved safety profile that reduces the risk of liver injury, which was a major limitation of first-generation gepants. Drug-drug interaction studies with atogepant highlight the necessity for more inclusive study populations. Given that migraine disproportionately affects females, future clinical development programs should include diverse patient demographics to ensure the findings are generalizable to all individuals suffering from migraine.

Real-world effectiveness and safety of erenumab for the treatment of migraine: A systematic review and meta-analysis.

BACKGROUND: Migraine is a common and disabling primary headache disorder. Several drugs targeting calcitonin gene-related peptide (CGRP), such as erenumab (an anti-CGRP receptor mAb), have been developed recently. However, the real-world effects of erenumab are not well understood. OBJECTIVE: To assess the clinical effectiveness and safety of erenumab for reducing migraine intensity and frequency in the real world. METHODS: A systematic search of PubMed, Scopus, Web of Science and the Cochrane Library was conducted from inception to December 2023. Studies estimating the real-world effect of erenumab on monthly migraine days (MMD), monthly headache days (MHD), headache impact test (HIT-6), number of days in medication (NDM), acute monthly intake (AMI), pain intensity (PI) and safety outcomes were included. Meta-analyses of proportions or mean differences were performed. RESULTS: Fifty-three studies were included. At 3-months, the effect was -7.18 days for MMD, -6.89 days for MHD, -6.97 for HIT-6, -6.22 days for NDM, -15.75 for AMI, and -1.71 for PI. Generally, the effect at 6- and 12-months increased slightly and gradually. The MMD/MHD response rates revealed that approximately one-third of patients exhibited a response greater than 30%, while one-sixth demonstrated a response exceeding 50%. Additionally, 3-4% of patients achieved a response rate of 100%. Adverse event rates were 0.34 and 0.43 at 6- and 12-months, respectively. CONCLUSION: This study provides strong evidence of the effectiveness and safety of erenumab in the real world; to our knowledge, this is the first real-world meta-analysis specific to erenumab. Erenumab represents a solid therapeutic option for physicians.

Effectiveness and safety of pharmacological prophylaxis for chronic migraine: a systematic review and network meta-analysis.

BACKGROUND: Chronic migraine (CM) significantly impacts both the physical and mental health of patients. Current studies on the safety and effectiveness of different pharmacological prophylaxis interventions for CM are limited. To address this gap, we conducted a network meta-analysis (NMA) to compare and rank the efficacy and safety of various drugs in preventing CM. METHODS: Two independent researchers systematically searched four databases from their inception to August 1, 2023, to identify eligible randomized controlled trials (RCTs). Subsequently, they performed data extraction and assessed the risk of bias. A NMA was then performed. Continuous outcomes and binary outcomes were displayed as weighted mean difference (WMD) and risk ratio (RR), respectively, and corresponding 95% confidence intervals (CI) were reported. The surface under the cumulative ranking curve (SUCRA) was used to rank each intervention separately. RESULTS: 24 RCTs involving 8789 patients were included. Compared to placebo, Botulinum toxin A demonstrated the most significant effect in reducing the monthly migraine days for CM patients (MD = 3.88, 95% CI 0.48, 7.28); in terms of improving the response rate by a 50% reduction in monthly migraine days, Topiramate (RR = 50.06, 95% CI 3.18, 787.30) was the most effective; there was no statistically significant difference between all preventive drugs and placebo in improving the migraine disability assessment (MIDAS) score; in terms of the incidence of adverse events, Eptinezumab (RR = 1.09, 95% CI 0.8, 1.54) exhibited the highest safety profile. CONCLUSION: Among all the drugs for the preventive drugs for CM, Botulinum toxin A has the best efficacy and safety profile, closely followed by calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs).

A real-world prospective observational study of eptinezumab in Asian patients with migraine.

OBJECTIVE: To evaluate the real-world effectiveness of eptinezumab for migraine prevention in Asian patients. BACKGROUND: Eptinezumab is a monoclonal antibody that targets calcitonin gene-related peptide (CGRP), a potent vasodilator with an important role in migraine pathophysiology. Although there is robust clinical evidence from pivotal Phase 3 placebo-controlled trials of the efficacy of eptinezumab for migraine prevention, there are limited data on the real-world effectiveness of eptinezumab in Asian patient cohorts. METHODS: This was a non-interventional, prospective, multisite cohort study of adults with migraine (International Classification of Headache Disorders, 3rd edition criteria) in Singapore who were prescribed eptinezumab (100 mg at baseline and Month 3, administered intravenously) and were followed until Month 6. The primary endpoint was change from baseline in monthly migraine days (MMDs) at Month 3 and Month 6. Secondary endpoints were ≥30% and ≥50% responder rates, and change from baseline in the Headache Impact Test-6 (HIT-6), Migraine Disability Assessment (MIDAS), Migraine-Specific Quality of Life (MSQ), patient-identified most bothersome symptom (PI-MBS), acute medication use at Month 3 and Month 6, and safety. RESULTS: Enrolled patients (completed = 29/30) had on average 3.4 (SD 2.9) previous preventive treatments; 29/30 of the patients had trialed at least one previous preventive treatment without benefit. Most had previously trialed oral preventives (87%, 26/30) and anti-CGRP (70%, 21/30). Relative to baseline, mean MMDs decreased by 4.3 days (95% CI 2.1-6.4; p < 0.001) at Month 3 and 4.9 days (95% CI 2.1-7.7; p < 0.001) at Month 6. At Month 3 and Month 6, 14/30 (47%) and 15/29 (52%) of the patients were ≥30% responders, and 6/30 (20%) and 8/29 (28%) patients were ≥50% responders, respectively. The number of patients with severe life impairment based on the HIT-6 score (total score 60-78) decreased from 24/30 (80%) at baseline to 19/30 (63%) at Month 3 and 19/29 (66%) at Month 6. The mean MIDAS score decreased by 24.6 points (95% CI 2.82-46.38; p = 0.028) at Month 6, and the mean MSQ score increased by 12.2 points (95% CI 5.18-19.20; p = 0.001) at Month 3 and 13.6 points (95% CI 4.58-22.66; p = 0.004) at Month 6. Most patients reported improvement in the PI-MBS at Month 3 (73%, 22/30) and Month 6 (55%, 16/29). Acute medication use for headache relief decreased by 3.3 days/month (95% CI 1.0-5.6; p = 0.007) at Month 3 and 4.7 days/month (95% CI 1.7-7.7; p = 0.003) at Month 6. Treatment-emergent adverse events (TEAEs) were reported in 16/30 (54%) patients, mostly mild/moderate in severity. No serious TEAEs led to treatment discontinuation. CONCLUSION: Quarterly eptinezumab administration was effective and well-tolerated in Asian patients with chronic migraine.

Sustained response to atogepant in episodic migraine: post hoc analyses of a 12-week randomized trial and a 52-week long-term safety trial.

BACKGROUND: Atogepant is an oral calcitonin gene-related peptide receptor antagonist approved for the preventive treatment of migraine in adults. These analyses evaluated the proportions of clinical trial participants who experienced sustained responses to atogepant over 12 or 52 weeks of treatment. METHODS: These were post hoc analyses of ADVANCE, a 12-week, double-blind, randomized trial of atogepant 10, 30, and 60 mg once daily vs. placebo for the preventive treatment of episodic migraine, and a separate open-label long-term safety (LTS) trial of atogepant 60 mg once daily over 52 weeks. The 60 mg dose of atogepant was used to detect safety issues. An initial response was defined as ≥50%, ≥75%, or 100% reduction from baseline in MMDs in month 1 for ADVANCE or quarter 1 for the LTS trial. The proportions of participants who continued to experience a response above each response-defining threshold through each subsequent month (for ADVANCE) or each quarter (for LTS) were calculated. RESULTS: In ADVANCE, sustained response rates during months 2 and 3 varied with dose and were as follows: 70.8-81.1% following an initial ≥50% response, 47.3-61.9% following an initial ≥75% response, and 34.8-41.7% following an initial 100% response. Of those who experienced an initial ≥75% or 100% response during month 1, more than 79% continued to experience at least a 50% response during both months 2 and 3. During the LTS trial, sustained response rates through quarters 2, 3, and 4 were 84.7% following an initial ≥50% response, 72.6% following an initial ≥75% response, and 37.8% following an initial 100% response. Of those who experienced an initial ≥75% or 100% response during quarter 1, more than 90% continued to experience at least a 50% response through quarters 2, 3, and 4. CONCLUSION: Over 70% of participants who experienced an initial response with atogepant treatment had a sustained response with continued treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03777059 (submitted: December 13, 2018); NCT03700320 (submitted: September 25, 2018).

Case reports: Could sexual dysfunction in women with migraine be a side effect of CGRP inhibition?

BACKGROUND: The development and approval of antibodies targeting calcitonin gene-related peptide or its receptor mark a revolutionary era for preventive migraine treatment. Real-world evidence sheds light on rare, stigmatized or overlooked side effects of these drugs. One of these potential side effects is sexual dysfunction. CASE REPORTS: We present two cases of one 42-year-old and one 45-year-old female patient with chronic migraine who both reported sexual dysfunction as a possible side effect of treatment with galcanezumab, a monoclonal antibody targeting calcitonin gene-related peptide. DISCUSSION: As calcitonin gene-related peptide is involved in vaginal lubrication as well as genital sensation and swelling, inhibiting the calcitonin gene-related peptide pathway may lead to sexual dysfunction as a potential side effect. CONCLUSION: Sexual dysfunction in female migraine patients might be a rare and overlooked side effect of monoclonal antibodies targeting the calcitonin gene-related peptide pathway. Considering the discomfort and stigma surrounding both migraine and sexual dysfunction, we advocate for an open attitude and awareness among clinicians toward such side effects.

Effectiveness and tolerability of eptinezumab in treating patients with migraine resistant to conventional preventive medications and CGRP (receptor) antibodies: a multicentre retrospective real-world analysis from Germany.

BACKGROUND: Eptinezumab is a monoclonal antibody that targets calcitonin gene-related peptide (CGRP mAb) and is used for migraine prophylaxis. Efficacy data are mainly from clinical trials, real-world data are hardly available yet. Reimbursement policy in Germany leads to eptinezumab mainly being used in patients having failed pre-treatment with other CGRP mAb. To date, it is unclear whether eptinezumab is efficacious and well tolerated in this population and how the treatment response differs from patients who are naive to CGRP mAbs. METHODS: We analysed clinical routine data of 79 patients (episodic migraine (EM): n = 19; chronic migraine (CM): n = 60) from four different centres in Germany. All patients were treated with eptinezumab (100mg). Differences in monthly headache (MHD), migraine (MMD) and acute medication days (AMD) after three months were analysed. The correlation of response with the number of CGRP mAb failures was evaluated. Significance level has been corrected (alpha = 0.017). RESULTS: After three months MHD, MMD and AMD were significantly reduced. In EM, the median reduction for MHD was 4.0 days (IQR: -6.5 to -1.0; p = 0.001), for MMD 3.0 days (IQR: -5.5 to -1.5; p < 0.001) and for AMD 2.0 days (IQR: -5.0 to -0.5; p = 0.006). In CM, median reduction of MHD was 4 days (IQR: -8.0 to 0.0; p < 0.001), 3.0 days (IQR: -6.0 to-1.0; p < 0.001) for MMD and 1.0 day (IQR: -5.0 to 0.0; p < 0.001) for AMD. All patients were resistant to conventional preventive therapies and most to CGRP mAbs. Fourteen patients had never received a CGRP mAb and 65 patients had received at least one mAb without sufficient effectiveness and/or intolerability (one: n = 20, two: n = 28, three: n = 17). There was a significant association between the number of prior therapies and the 30% MHD responder rate (none: 78.6%, one: 45.0%, two: 32.1%, three: 23.5%, p = 0.010). Regarding tolerability, 10.4% (8/77) reported mild side effects. CONCLUSIONS: The effectiveness of eptinezumab is significantly reduced in patients who have not previously responded to other CGRP mAbs. However, limitations such as the retrospective nature of the analysis, the small sample size and the short treatment period with only the lower dose of eptinezumab must be considered when interpreting the results.

Erenumab for Treatment of Persistent Erythema and Flushing in Rosacea: A Nonrandomized Controlled Trial.

Importance: Treatment of erythema and flushing in rosacea is challenging. Calcitonin gene-related peptide (CGRP) has been associated with the pathogenesis of rosacea, raising the possibility that inhibition of the CGRP pathway might improve certain features of the disease. Objective: To examine the effectiveness, tolerability, and safety of erenumab, an anti-CGRP-receptor monoclonal antibody, for the treatment of rosacea-associated erythema and flushing. Design, Setting, and Participants: This single-center, open-label, single-group, nonrandomized controlled trial was conducted between June 9, 2020, and May 11, 2021. Eligible participants included adults with rosacea with at least 15 days of either moderate to severe erythema and/or moderate to extreme flushing. No concomitant rosacea treatment was allowed throughout the study period. Visits took place at the Danish Headache Center, Copenhagen University Hospital, Rigshospitalet in Copenhagen, Denmark. Participants received 140 mg of erenumab subcutaneously every 4 weeks for 12 weeks. A safety follow-up visit was performed at week 20. Data analysis occurred from January 2023 to January 2024. Intervention: 140 mg of erenumab every 4 weeks for 12 weeks. Main Outcomes and Measures: The primary outcome was mean change in the number of days with moderate to extreme flushing during weeks 9 through 12, compared with the 4-week run-in period (baseline). The mean change in number of days with moderate to severe erythema was a secondary outcome. Adverse events were recorded for participants who received at least 1 dose of erenumab. Differences in means were calculated with a paired t test. Results: A total of 30 participants (mean [SD] age, 38.8 [13.1] years; 23 female [77%]; 7 male [23%]) were included, of whom 27 completed the 12-week study. The mean (SD) number of days with moderate to extreme flushing was reduced by -6.9 days (95% CI, -10.4 to -3.4 days; P < .001) from 23.6 (5.8) days at baseline. The mean (SD) number of days with moderate to severe erythema was reduced by -8.1 days (95% CI, -12.5 to -3.7 days; P < .001) from 15.2 (9.1) days at baseline. Adverse events included transient mild to moderate constipation (10 participants [33%]), transient worsening of flushing (4 participants [13%]), bloating (3 participants [10%]), and upper respiratory tract infections (3 participants [10%]), consistent with previous data. One participant discontinued the study due to a serious adverse event (hospital admission due to gallstones deemed unrelated to the study), and 2 participants withdrew consent due to lack of time. Conclusions and Relevance: These findings suggest that erenumab might be effective in reducing rosacea-associated flushing and chronic erythema (participants generally tolerated the treatment well, which was consistent with previous data), and that CGRP-receptor inhibition holds potential in the treatment of erythema and flushing associated with rosacea. Larger randomized clinical trials are needed to confirm this finding. Trial Registration: ClinicalTrials.gov Identifier: NCT04419259.

A multicenter, open-label long-term safety study of rimegepant for the acute treatment of migraine.

BACKGROUND: The present study evaluated the long-term safety and tolerability of rimegepant, an orally administered small molecule calcitonin gene-related peptide receptor antagonist, in people with migraine. METHODS: This multicenter, long-term, open-label safety study included adults (≥18 years) with ≥1 year history of migraine who were sequentially enrolled into three groups: participants in the first two groups had either 2-8 or 9-14 moderate to severe migraine attacks per month by history and treated as needed (pro re nata [PRN]) with one rimegepant 75 mg oral tablet up to once per calendar day for 52 weeks (PRN 2-8 and PRN 9-14); a third group, included to collect safety data during higher-frequency dosing, had 4-14 moderate to severe migraine attacks per month by history and who took one rimegepant tablet every other day as scheduled dosing plus PRN dosing of one rimegepant tablet for migraine attacks of any severity on nonscheduled dosing days for 12 weeks (every other day (EOD) + PRN). RESULTS: Overall, 1800 participants self-administered rimegepant (PRN 2-8: n = 1033; PRN 9-14: n = 481; EOD + PRN: n = 286). The most common on-treatment adverse events (AEs) were upper respiratory tract infection (8.8%), nasopharyngitis (6.8%) and sinusitis (5.1%). Most AEs were mild or moderate and considered unrelated to rimegepant. Serious AEs considered possibly (n = 1) or unlikely (n = 9) related to rimegepant were reported in ten (0.6%) participants. No signal of drug-induced liver injury because of rimegepant was identified. CONCLUSIONS: Rimegepant 75 mg up to once per day as EOD + PRN for 12 weeks or PRN for up to 52 weeks was safe and well tolerated. No signal of hepatotoxicity, potential drug abuse, or medication-overuse headache was identified.Trial registration: Clinicaltrials.gov: NCT03266588.

Efficacy and Safety of Erenumab in Participants With Episodic Migraine in Whom 2-4 Prior Preventive Treatments Had Failed: LIBERTY 3-Year Study.

BACKGROUND AND OBJECTIVES: The LIBERTY study assessed the efficacy and safety of erenumab in participants with episodic migraine (EM) and 2-4 prior preventive treatment failures. The results have been presented after 3 years of erenumab exposure in its open-label extension phase (OLEP). METHODS: Participants completing the 12-week double-blind treatment phase (DBTP) of the LIBERTY study could enter the OLEP and receive 140 mg of erenumab once monthly for 3 years. The main outcomes included the proportion of participants achieving ≥50% reduction in monthly migraine days (MMDs), the mean MMD change from baseline, and tolerability and safety. RESULTS: Overall, 240/246 (97.6%) participants entered the OLEP and 168/240 (70.0%) completed the study (85/118 continuing erenumab [n = 1 lost during follow-up]; 83/122 switching from placebo [n = 2 lost during follow-up]). In the overall population, 79/151 participants (52.3%) with valid data points achieved ≥50% reduction in MMDs at week 168 (i.e., responders). In the continuous erenumab group, 35/117 participants (29.9%) were ≥50% responders at week 12 of the DBTP and 26/35 (74.3%) remained ≥50% responders in at least half of OLEP visits. Of the 82/117 participants (70.1%) not achieving responder status at week 12 in the continuous erenumab group, 17/82 (20.7%) converted to ≥50% responders in at least half of OLEP visits. Of 103/120 participants (85.8%) not achieving responder status at week 12 in the placebo-erenumab group, 42/103 (40.8%) converted to ≥50% responders in at least half of OLEP visits after switching to erenumab. Overall, the mean (SD) MMD change from baseline showed sustained improvement over 3 years (-4.4 [3.9] days at week 168). The most common treatment-emergent AEs (per 100 person-years) were nasopharyngitis (28.8), influenza (7.5), and back pain (5.8). Overall, 9.6% (3.9 per 100 person-years) and 6.7% (2.7 per 100 person-years) of participants reported events of treatment-emergent hypertension and constipation, respectively. The safety and tolerability profile remained consistent with earlier studies. DISCUSSION: Erenumab (140 mg) showed sustained efficacy over 3 years in participants with EM and 2-4 prior preventive treatment failures. No new safety signals were observed. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03096834.