Halker Singh, Rashmi B

Abstract Objective This study was conducted to review and synthesize current evidence on anti‐calcitonin gene‐related peptide (CGRP) therapies in women with menstrual‐related migraine, during pregnancy and lactation, and while using hormonal contraception. Background Migraine disproportionately affects women, with prevalence peaking during reproductive years when hormonal fluctuations modulate neurovascular and nociceptive pathways, including CGRP signaling, that contribute to migraine susceptibility. Despite the established efficacy of anti‐CGRP therapies—including monoclonal antibodies (erenumab, fremanezumab, galcanezumab, and eptinezumab) and gepants (ubrogepant, rimegepant, atogepant, and zavegepant)—evidence regarding their use across critical reproductive health contexts remains limited. Methods A systematic search of MEDLINE and Embase was conducted using MeSH terms and keywords related to migraine, CGRP‐targeted therapies, and reproductive health contexts. Studies were screened independently by two reviewers. Data were extracted using standardized forms and synthesized narratively by clinical domain. Results Sixteen studies met inclusion criteria. For menstrual‐related migraine, post hoc analyses and observational studies demonstrate that CGRP monoclonal antibodies reduce migraine frequency both during and outside the perimenstrual window (galcanezumab: −5.1 vs. −3.2 days, p < 0.001), although the perimenstrual period remains a time of relatively higher headache burden despite treatment. Pregnancy data are limited to pharmacovigilance analyses and case reports of unintended exposures, which have not identified specific patterns of maternal, fetal, or neonatal toxicity. Phase 1 pharmacokinetic studies demonstrate minimal gepant transfer into breast milk (relative infant doses, 0.04%–0.19%), well below the 10% safety threshold, although no human lactation data exist for CGRP monoclonal antibodies. No studies specifically evaluated anti‐CGRP therapies in women using hormonal contraceptives. Conclusion Substantial evidence gaps exist across all reproductive health contexts examined. Prospective trials in menstrual‐related migraine, pregnancy registries, lactation studies assessing infant outcomes, and research examining interactions with hormonal contraceptives are needed to optimize migraine care for women.

Abstract Objective To estimate the number needed to treat and cost per additional responder for atogepant and rimegepant versus placebo for the preventive treatment of episodic migraine (EM) in the United States. Background Migraine has an enormous impact on a person's daily activities and quality of life, and results in significant clinical and economic burden to both individuals and society. It is important to understand the comparative efficacy and economic value of oral calcitonin gene–related peptide receptor antagonists (gepants) for preventive treatment of EM. Currently, atogepant and rimegepant are US Food and Drug Administration approved for preventive treatment of migraine (rimegepant for EM and atogepant for EM and for chronic migraine). In the absence of head‐to‐head trials, we utilized an indirect treatment comparison on efficacy data from clinical trials conducted for the preventive treatment of EM. We estimated number needed to treat, a valuable metric used in clinical practice to compare treatment efficacy, and cost per additional responder, which can be used to establish the cost effectiveness of a treatment. Methods An indirect treatment comparison was conducted to compare the efficacy of atogepant 60 mg once daily and rimegepant 75 mg once every other day as preventive treatments for EM using published data from the registrational trials of atogepant (ADVANCE) and rimegepant (BHV3000‐305). The efficacy outcome of interest was ≥50% reduction from baseline in mean monthly migraine/headache days (≥50% responder rate), which was variably defined for a base case and two scenario analyses. Number needed to treat and cost per additional responder versus placebo were calculated and compared between both treatments (weeks 9–12 in the base case analysis; weeks 1–12 and 9–12 for atogepant and during weeks 9–12 for rimegepant in the scenario analyses). Results In the base case analysis, ≥50% responder rates were 64.9% (95% confidence interval [CI], 53.9–74.5) for atogepant and 51.8% (95% CI, 42.9–60.6) for rimegepant, compared to 44.1% (95% CI, 39.4–49.0) for placebo. The median number needed to treat versus placebo in the base case scenario was 4.8 (95% CI, 3.1–9.0) for atogepant compared to 13.0 (95% CI, 5.9–75.1) for rimegepant. The cost per additional responder versus placebo in the base case scenario was estimated to be $15,823 (95% CI, $11,079–$29,516) for atogepant compared to $73,029 (95% CI, $32,901–$422,104) for rimegepant. Results of the two scenario analyses were consistent with the base case analysis. Conclusions Atogepant had substantially lower numbers needed to treat and costs per additional responder versus placebo than rimegepant for the preventive treatment of EM across all evaluated scenarios. These analyses suggest that atogepant may be more cost effective than rimegepant for the preventive treatment of EM. Limitations include differences in inclusion/exclusion criteria and in reporting of the ≥50% responder rates between trials.

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.