Adv Ther (2021) 38:3154–3165 https://doi.org/10.1007/s12325-021-01708-8 ORIGINAL RESEARCH Galcanezumab Provides Consistent Efficacy Throughout the Dosing Interval Among Patients with Episodic and Chronic Migraine: A Post Hoc Analysis Patricia Pozo-Rosich . Karen H. Samaan . Todd J. Schwedt . Robert A. Nicholson . Mallikarjuna Rettiganti . Eric M. Pearlman Received: December 9, 2020 / Accepted: March 12, 2021 / Published online: May 5, 2021 Ó The Author(s) 2021 ABSTRACT headache days, averaged across all months for each week of the dosing interval, was compared Introduction: The consistency of the treatment between groups and within the galcanezumab effect of galcanezumab throughout the dosing group during weeks 1 and 4. Additional analyses interval is examined in patients with episodic examined the mean difference from placebo in and chronic migraine. weekly migraine headache days and a day-by- Methods: This study was a post hoc analysis of day analysis. clinical trial data from episodic (EVOLVE-1; Results: Weekly migraine headache day reduc- EVOLVE-2; both 6-month duration) and tion was significantly greater with gal- chronic (REGAIN; 3-month duration) migraine canezumab relative to placebo every week double-blind trials evaluating the efficacy of a (P \ 0.001) and did not differ during weeks 1 once-monthly injection of galcanezumab and 4 for those with episodic (P = 0.740) or 120 mg relative to placebo. Adults with episodic chronic migraine (P = 0.231) taking gal- (placebo, n = 894; galcanezumab, n = 444) or canezumab. Estimated probabilities of migraine chronic migraine (placebo, n = 558; gal- on day 2 and day 30 did not differ for those with canezumab, n = 278) were included. Mean episodic (P = 0.61) or chronic migraine change from baseline in weekly migraine (P = 0.616) taking galcanezumab. Conclusion: This analysis demonstrates once monthly galcanezumab exhibits consistent P. Pozo-Rosich efficacy throughout the dosing interval among Headache Unit, Neurology Department, Vall the population of patients with migraine in d’Hebron University Hospital, Barcelona, Spain three clinical trials evaluating the efficacy of P. Pozo-Rosich galcanezumab. There is no evidence from these Headache and Neurological Pain Research Group, trials that the effect of galcanezumab ‘‘wears off’’ Department de Medicine, Vall d’Hebron Research at the end of the dosing interval. Institute, Universitat Autònoma de Barcelona, Barcelona, Spain Trial Registration: ClinicalTrials.gov identifier: EVOLVE-1 (NCT02614183); EVOLVE-2 K. H. Samaan (&)  R. A. Nicholson  M. Rettiganti (NCT02614196); REGAIN (NCT02614261).  E. M. Pearlman Eli Lilly and Company, LTC-South, Indianapolis, IN, USA Keywords: Chronic; Efficacy; Episodic; e-mail: karen.samaan@lilly.com Galcanezumab; Migraine; Wear off T. J. Schwedt Mayo Clinic, Scottsdale, AZ, USA Adv Ther (2021) 38:3154–3165 3155 INTRODUCTION Key Summary Points Migraine is a neurologic disease that affects Migraine is a neurologic disease that is a about 12% of the population worldwide and is a major cause of diminished quality of life major cause of diminished quality of life and and years lost to disability. A lack of years lost to disability [1, 2]. Despite a large consistent response to preventive percentage of patients meeting criteria to treatment may contribute to patient non- receive preventive treatment for migraine [2, 3], compliance and early discontinuation of only a fraction of prevention-eligible patients preventive therapy with migraine receive appropriate treatment [4, 5]. Among these patients, a lack of consistent This post-hoc analysis examined the response to treatment may contribute to patient consistency of the treatment effect of non-compliance and early discontinuation of galcanezumab throughout the dosing preventive therapy [6, 7]. interval in patients with chronic and Galcanezumab, a humanized monoclonal episodic migraine antibody that binds to the calcitonin gene-re- Compared to placebo, patients treated lated peptide (CGRP) ligand and blocks its with galcanezumab had greater reduction binding to the CGRP receptor [8], is approved in weekly migraine headache days every for the preventive treatment of migraine in week over 3 months in patients with adults. The efficacy of galcanezumab 120 mg chronic migraine and 6 months in administered once monthly (with an initial patients with episodic migraine loading dose of 240 mg) has been established for the preventive treatment of episodic During the dosing interval, there was no (EVOLVE-1 and EVOLVE-2 studies) and chronic difference in weekly migraine headache (REGAIN study) migraine in three phase 3 days when the first week was compared to studies where galcanezumab significantly the fourth week, and the estimated reduced the number of monthly migraine probability of having a migraine headache headache days compared to placebo [9–11]. on days 2 and 30 were not different In patients with episodic migraine, gal- Among the population of patients in the canezumab has demonstrated a significant dif- phase 3 studies, galcanezumab 120 mg ference relative to placebo as early as the first once monthly (with a 240 mg loading day after treatment and a superiority in C 50% dose) exhibits consistent efficacy reduction in migraine headache days as early as throughout the dosing interval week 1 [12]. Although a clinically meaningful persistence of efficacy with galcanezumab in the treatment of episodic and chronic migraine has been demonstrated across consecutive months [13], the consistency of galcanezumab efficacy within the monthly dosing interval has not DIGITAL FEATURES been investigated beyond the first month. The objective of this post hoc analysis was to This article is published with digital features, examine the consistency of treatment effect of including a summary slide, to facilitate under- galcanezumab 120 mg once monthly (with an standing of the article. To view digital features initial loading dose of 240 mg) throughout the for this article go to https://doi.org/10.6084/ dosing interval. m9.figshare.14195273. 3156 Adv Ther (2021) 38:3154–3165 METHODS International Classification of Headache Disor- ders—3rd edition, beta version [14]. for at least In this post hoc analysis of three phase 3, ran- 1 year prior to enrollment and with migraine domized, double-blind, placebo-controlled onset prior to age 50. Patients in the episodic studies, 1338 adult patients with episodic migraine studies had 4–14 migraine headache migraine (placebo, n = 894; galcanezumab days per month with an average of no less than 120 mg, n = 444) and 836 adult patients with 2 migraine attacks per month during the pre- chronic migraine (placebo, n = 558; gal- vious 3 months. In the chronic migraine study, canezumab 120 mg, n = 278) were included. patients had at least 15 headache days per Data from the two episodic migraine studies month, of which 8 or more had migraine fea- were pooled, and the chronic migraine study tures, with at least 1 or more headache-free days was analyzed separately. The pooled studies, per month for 3 months prior to enrollment. EVOLVE-1 (NCT02614183) [9] and EVOLVE-2 Full exclusion criteria for these studies are (NCT02614196) [10], were designed to examine described in the primary manuscripts [9–11]. Of whether galcanezumab dosed at 120 mg per note, patients were excluded from the studies if month with a 240-mg loading dose or dosed at three or more classes of adequately dosed 240 mg per month was superior to placebo in migraine preventive treatments had failed to the preventive treatment of episodic migraine. provide adequate efficacy. In EVOLVE-1, 858 randomized patients received at least 1 dose of study drug; 433, 213, and 212 Statistical Analyses patients received placebo, galcanezumab 120 mg, and galcanezumab 240 mg, respec- The primary objective of the statistical analysis tively. In EVOLVE-2, 915 randomized patients was to determine the consistency of the treat- received at least 1 dose of study drug; 461, 231, ment effect of galcanezumab during each week and 223 patients received placebo, gal- of the dosing interval, starting with the week canezumab 120 mg, and galcanezumab 240 mg, immediately after dosing (week 1) and ending respectively. The third study, REGAIN with the week immediately prior to the next (NCT02614261) [11], was designed to determine dose (week 4). The analysis aimed to determine whether galcanezumab dosed at 120 mg per whether the effect of galcanezumab remained month with a 240-mg loading dose or dosed at consistent throughout the month, starting from 240 mg per month was superior to placebo in the first day after dosing to the day(s) prior to the preventive treatment of chronic migraine. the next dose. These analyses were done for In REGAIN, 1113 randomized patients received patients in the episodic (pooled data from at least 1 dose of study drug; 558, 278, and 277 EVOLVE-1 and EVOLVE-2) and chronic patients received placebo, galcanezumab migraine (REGAIN) studies. Mean changes from 120 mg, and galcanezumab 240 mg, respec- baseline in weekly migraine headache days tively. The primary outcome measure for each during each week of the dosing interval aver- of these studies was the overall mean change aged across all months were estimated and from baseline in monthly migraine headache compared between the galcanezumab and pla- days. The study protocols were approved by the cebo groups using a mixed-model repeated institutional review board for each study site, measures (MMRM) analysis. This model inclu- and patients provided written informed consent ded the following fixed effects variables: base- prior to study procedures. More information line migraine headache days, treatment, week, regarding these trials is available in the primary month, study (for episodic only), pooled manuscripts [9–11]. This analysis evaluated the region/country (nested within study), and the galcanezumab 120 mg and placebo treatment treatment-by-week and baseline-by-week inter- arms of the phase 3 studies. action effects. The probability of having a Patients were between 18 and 65 years, with migraine over each day within the month, from a diagnosis of migraine as defined by the day 2 (first day after dosing) through day 30, Adv Ther (2021) 38:3154–3165 3157 was modeled using a generalized linear mixed- Guide version 7.1. All statistical tests conducted effects model. This model included the follow- were two-sided, assuming a significance level of ing fixed effects variables: baseline migraine 5%. All analyses conducted were post hoc in headache days, treatment, day, month, study nature, and thus results should be considered (for episodic data only), and treatment-by-day exploratory. interaction effect. All multilevel models included patient-level random effects for inter- cept, week/day, and month variables using a RESULTS variance components correlation structure to account for the correlation introduced because Baseline Characteristics of repeated measures on each patient measured on each day of each month. There were no significant differences in baseline Consistency of treatment effect throughout characteristics between the patient groups ran- the dosing interval was evaluated in two ways. domized to galcanezumab or to placebo in the First, the treatment-effect difference of gal- episodic or chronic migraine studies, with the canezumab relative to placebo was estimated at exception of age (mean age [SD]: galcanezumab the weekly or day-by-day level and averaged 120-mg group = 39.7 [11.9] years, placebo across all months. This allowed evaluation of group = 41.6 [12.1] years; P \ 0.05). At baseline, whether the treatment effect of galcanezumab prior to randomization, there were no signifi- later in the dosing interval, relative to placebo, cant differences between the galcanezumab and was consistent with its effect early in the dosing placebo groups in the number of migraine interval. Second, within-treatment-group dif- headache days per week or per month (Table 1). ferences were compared. This allowed evalua- In the episodic trials, the average weekly tion of whether the effect of galcanezumab migraine headache days was 2.1 ± 0.7 days, and remained consistent later in the dosing interval in the chronic trial, patients treated with gal- relative to earlier in the dosing interval. For the canezumab averaged 4.5 ± 1 weekly migraine weekly analysis, mean weekly migraine head- headache days versus 4.6 ± 1.1 days in the pla- ache days were compared between the first and cebo group. last weeks within each treatment group. For the daily analysis, the estimated probabilities of Consistency of Treatment Effect having a migraine on day 2 (first day after administration) and day 30 were compared to Episodic Migraine evaluate consistency of effect. These compar- In the weekly analysis of the pooled episodic isons were done within the context of the studies (Fig. 1), the mean reduction from base- multilevel models using contrasts for the least- line in weekly migraine headache days, aver- squares (LS) means for the treatment-by-period aged across all 6 months, was significantly (day or week) interaction effect. greater for the galcanezumab group relative to the placebo group in each of the 4 weeks General Considerations (P \ 0.001). The mean differences (95% CI) in Baseline demographics were summarized using change from baseline of weekly migraine summary statistics, which included means and headache days between the galcanezumab standard deviations (SDs) for continuous vari- group and placebo group were - 0.49 (- 0.59, ables and frequencies and percentages for cate- - 0.39) in weeks 1 and 2, - 0.44 (- 0.54, gorical variables. Effects from linear mixed- - 0.34) in week 3, and - 0.45 (- 0.55, - 0.35) effects models were presented using the differ- in week 4. The mean treatment differences in ences in LS means, whereas effects from gener- weekly migraine headache days were not sig- alized linear mixed-effects models were nificantly different between week 1 and week 4 presented as odds ratios (ORs) along with 95% (difference = - 0.04; 95% CI - 0.12, 0.04; confidence intervals (CIs). All analyses were P = 0.321). Treatment-effect estimates were not conducted using the software SASÒ Enterprise 3158 Adv Ther (2021) 38:3154–3165 Table 1 Baseline characteristics of phase 3 studies Episodic Migraine (EVOLVE-1 and Chronic Migraine (REGAIN) EVOLVE-2) Placebo, GMB Placebo, GMB n = 894 120 mg, n = 558 120 mg, n = 444 n = 278 Age, years, mean (SD) 41.9 (11.4) 40.9 (11.5) 41.6 (12.1) 39.7 (11.9)* Female, n (%) 755 (84.5) 378 (85.1) 483 (86.6) 237 (85.3) Race, white, n (%) 681 (76.2) 335 (75.5) 432 (77.4) 223 (80.2) North America residence, n (%) 657 (73.5) 325 (73.2) 321 (57.5) 161 (57.9) Years since migraine diagnosis, mean (SD) 20.5 (12.5) 20.5 (12.3) 21.9 (12.9) 20.4 (12.7) MIDAS total score, mean (SD) 33.1 (29.3) 31.9 (28.0) 68.7 (57.4) 62.5 (49.5) Number of migraine headache days, mean (SD) Per month 9.1 (3.0) 9.1 (3.0) 19.6 (4.6) 19.4 (4.3) Per week 2.1 (0.7) 2.1 (0.7) 4.6 (1.1) 4.5 (1.0) Summary statistics for migraine headache days per week at baseline were obtained by converting migraine headache days per month (30 days) summaries into a 7-day period by dividing them by 30 and multiplying by 7 GMB galcanezumab, MIDAS Migraine Disability Assessment, n number, SD standard deviation *P \ 0.05 versus placebo Fig. 1 Episodic migraine: LS mean change from baseline baseline migraine headache days, week, month, study, in weekly migraine headache days across all months pooled region/country (nested within study), and the (EVOLVE-1 and EVOLVE-2 pooled). aP \ 0.001 versus treatment-by-week and baseline-by-week interaction placebo based on MMRM analysis. Mean changes from effects. GMB galcanezumab, LS least-squares, MMRM baseline for each treatment group were estimated using an mixed-model repeated measures, SE standard error MMRM model for repeated measures after adjusting for Adv Ther (2021) 38:3154–3165 3159 meaningfully different between other combi- day, averaged across all 6 months from day 2 nations of weeks (results not shown). Within through day 30, was significantly lower in the the galcanezumab group, LS mean changes galcanezumab group compared to the placebo from baseline in weekly migraine headache group (P B 0.001 for all days). The gal- days during week 1 (- 1.06) and week 4 canezumab group had a significantly lower (- 1.07) were not significantly different (differ- probability of having a migraine headache ence = 0.01; 95% CI - 0.05, 0.07; P = 0.740), compared to the placebo group on day 2 (OR suggesting the treatment effect of gal- 0.61; 95% CI 0.51, 0.72; P \ 0.001) and day 30 canezumab was not ‘‘wearing off’’ during the (OR 0.65; 95% CI 0.51, 0.85; P = 0.001), sug- last week of the dosing interval relative to the gesting the treatment effect relative to placebo first week. The fixed effect of week (P = 0.705) is not likely to be different from the beginning and the treatment-by-week interaction effect to the end of the dosing interval. Within the (P = 0.148) from the MMRM model were not galcanezumab group, the estimated probabili- statistically significant, suggesting no signifi- ties of having a migraine headache on day 2 and cant trend in mean changes from baseline in day 30 were not statistically significantly dif- weekly migraine headache days throughout the ferent (OR 0.94; 95% CI 0.74, 1.19; P = 0.61), dosing interval. suggesting the treatment effect of gal- In the day-by-day analysis of the pooled canezumab was not ‘‘wearing off’’ at the end of episodic studies (Fig. 2), the estimated proba- the dosing interval relative to the first day fol- bility of having a migraine headache on each lowing dosing. In addition, the main effect of Fig. 2 Episodic migraine: estimated probability of generalized linear mixed-effects model for repeated mea- migraine by day averaged across all 6 months (EVOLVE- sures adjusting for baseline migraine headache days, day, 1 and EVOLVE-2 pooled). aP B 0.001 versus placebo month, study, and treatment-by-day interaction effect. (P values comparing probability of migraine between the GMB galcanezumab two groups was significant for all days). Probabilities shown for each treatment group were estimated using a 3160 Adv Ther (2021) 38:3154–3165 day (P = 0.498) and the interaction effect of the galcanezumab group, LS mean changes treatment by day (P = 0.485) were not statisti- from baseline in weekly migraine headache cally significant, suggesting no evidence of days during week 1 (- 1.07) and week 4 treatment-effect inconsistency during the dos- (- 1.15) were not significantly different (differ- ing interval. ence = 0.08; 95% CI - 0.05, 0.20; P = 0.231), suggesting the effect of galcanezumab did not Chronic Migraine ‘‘wear off’’ during the last week of the dosing In the weekly analysis of the chronic migraine interval relative to the first week. The fixed study (Fig. 3), the mean reduction from baseline effect of week (P = 0.162) and the treatment-by- in weekly migraine headache days, averaged week interaction effect (P = 0.403) from the across all 3 months, was significantly greater for MMRM model were not statistically significant, the galcanezumab group compared to the pla- suggesting no significant trend in mean chan- cebo group for each of the 4 weeks (P \ 0.001). ges from baseline in migraine headache days The mean differences (95% CI) in weekly from week to week within the month. migraine headache day change from baseline In the day-by-day analysis of those with between the galcanezumab group and placebo chronic migraine (Fig. 4), the estimated proba- group were - 0.49 (- 0.69, - 0.28) in week 1, bility of having a migraine headache on each - 0.56 (- 0.78, - 0.34) in week 2, - 0.52 day, from day 2 through day 30, averaged across (- 0.74, - 0.31) in week 3, and - 0.40 (- 0.62, all 3 months, was significantly lower in the - 0.19) in week 4. Treatment differences in galcanezumab group compared to the placebo weekly migraine headache days were not sig- group on most days (P \ 0.05) except for days nificantly different between week 1 and week 4 10 (P = 0.091), 23 (P = 0.096), 29 (P = 0.125), (difference = - 0.08; 95% CI - 0.24, 0.07; and 30 (P = 0.226). The galcanezumab group P = 0.301). Treatment-effect estimates were not had a significantly lower probability of having a meaningfully different between other combi- migraine headache compared to the placebo nations of weeks (results not shown). Within group on day 2 (OR 0.71; 95% CI 0.56, 0.90; P = 0.005) but not on day 30 (OR 0.80; 95% CI Fig. 3 Chronic migraine: LS mean change from baseline in repeated measures after adjusting for baseline migraine weekly migraine headache days across all months (REGAIN) headache days, week, month, pooled region/country, and for each treatment group. aP \ 0.001 versus placebo based on the treatment-by-week and baseline-by-week interaction MMRM analysis. Mean changes from baseline for each effects. GMB galcanezumab, LS least squares, MMRM treatment group were estimated using an MMRM model for mixed-model repeated measures, SE standard error Adv Ther (2021) 38:3154–3165 3161 Fig. 4 Chronic migraine: estimated probability of mixed-effects model for repeated measures adjusting for migraine by day averaged across all 3 months (REGAIN). baseline migraine headache days, day, month, and treat- a P B 0.001 versus placebo, bP B 0.010 versus placebo, ment-by-day interaction effect. GMB galcanezumab c P \ 0.050 versus placebo. Probabilities shown for each treatment group were estimated using a generalized linear 0.55, 1.15; P = 0.226). Within the gal- galcanezumab in healthy patients have shown canezumab group, the estimated probabilities of that galcanezumab has a half-life of 27 days [8] having a migraine headache on day 2 and day and support treating patients with a once- 30 were not statistically significantly different monthly subcutaneous injection of gal- (OR 1.08; 95% CI 0.80, 1.48; P = 0.616), sug- canezumab. Previous phase 3 studies have gesting the treatment effect of galcanezumab shown that galcanezumab at doses of 120 mg was not ‘‘wearing off’’ at the end of the dosing and 240 mg significantly reduces the number of interval relative to the first day following dos- mean monthly migraine headache days over ing. The main effect of day (P = 0.389) and the 6 months compared to placebo in adults with interaction effect of treatment-by-day episodic migraine [9, 10] and over 3 months in (P = 0.241) were not statistically significant, adults with chronic migraine [11]. suggesting no evidence that the treatment effect Here, we examined whether galcanezumab within the galcanezumab group was inconsis- 120 mg once monthly (with an initial loading tent during the dosing interval. dose of 240 mg) maintained consistent efficacy during the dosing interval in patients with epi- sodic or chronic migraine. Clinical trials evalu- DISCUSSION ating the reduction of migraine headache days in response to a treatment typically use longer Maintenance of benefit throughout the dosing durations of time (e.g., months rather than interval is an important attribute for migraine weeks or days) to evaluate treatment efficacy preventive therapy. Pharmacokinetic studies of because the natural variation of migraine 3162 Adv Ther (2021) 38:3154–3165 headache in individuals may impact outcomes may be more likely to occur near the end of the when comparing treatment to placebo effect. month among patients with higher headache This post hoc analysis attempted to mitigate day frequency [15, 16]. This may be especially this variability by averaging data across all relevant for the placebo group who had more months of the phase 3 trials. We evaluated headache days to report throughout the month. mean reduction of weekly migraine headache Finally, the absence of statistical significance days and the day-to-day likelihood of having a does not rule out a clinically meaningful effect. migraine headache to determine whether the This may help substantiate the message that the population of those taking galcanezumab effect of galcanezumab does not diminish at the showed a consistent response from the first to end of the dosing interval relative to the the last day of the dosing interval. beginning of the dosing interval for those with This post hoc analysis demonstrates that chronic migraine. efficacy of galcanezumab remains consistent The strengths of the study include the large throughout the monthly dosing interval for sample size and the complementary methods both chronic and episodic migraine. The mean used to investigate the consistency of effect. reduction from baseline of weekly migraine These were necessary since there is no standard headache days averaged across all months was definition for the loss of effect or ‘‘wearing off’’ significantly greater in the galcanezumab group during the dosing interval of migraine preven- compared to the placebo group, and the change tive medication. This analysis was performed on in average weekly migraine headache days a post hoc basis and thus should be considered among those in the galcanezumab group was exploratory, so failure to find a statistically sig- consistent from the first week to the last week of nificant difference may not provide conclusive the dosing interval. These findings suggest that, evidence of absence of effect. In addition, the at a treatment-population level, the effect of analysis is treatment population based, and it galcanezumab remains consistent throughout cannot be interpreted that every individual will the dosing interval (i.e., does not ‘‘wear off’’) for have a consistent response to galcanezumab those with episodic or chronic migraine. throughout the dosing interval every month. It In the day-by-day analysis, the results among is possible to evaluate consistency of effect at an those with episodic migraine show a similar individual level, but that was not in line with pattern to the weekly data, with the likelihood the scope and aims of the current study. Future of having a migraine headache lower among studies might consider whether individual-level those in the galcanezumab group relative to factors (e.g., migraine headache day variability, placebo for all days of the dosing interval and comorbidities, migraine disease-related, care- no difference in the likelihood of having a related, sociodemographic, psychographic) migraine headache within the galcanezumab influence the consistency of effect throughout group at day 2 and day 30. Among those with the month. Identifying a subset of patients chronic migraine in the galcanezumab group, inclined to experience inconsistent effect there were also no differences in the likelihood throughout the month would provide clinicians of having a migraine headache at day 2 and day insight that might influence treatment 30 of the dosing interval. When comparing the decisions. day-to-day likelihood of having a migraine These results demonstrate that gal- headache between the galcanezumab and pla- canezumab has consistent efficacy throughout cebo groups, the differences were significant at the monthly dosing interval and there is no 25 of 29 days. Possible reasons for the lack of indication of ‘‘wearing off’’ or loss of effect for statistical significance on other days include the patients with episodic or chronic migraine. smaller sample size in the chronic study and a These results expand the information available smaller sample size reporting headache days to providers and patients about the expected towards the end of the month, which could lead outcomes when using galcanezumab for the to higher variability. In addition, the burden of preventive treatment of migraine. diary entry (participant fatigue) during the trial Adv Ther (2021) 38:3154–3165 3163 ACKNOWLEDGEMENTS consultant and speaker for Allergan, Amgen, Almirall, Biohaven, Chiesi, Eli Lilly and Com- The authors thank the study participants for pany, Medscape, Novartis, and Teva Pharma- their involvement in the study. ceuticals. Her research group has received research grants from Allergan, Novartis, Insti- tuto de Salud Carlos III, La Caixa Foundation, Funding. This study (design and conduct of EraNet Neuron, Migraine Research Foundation, the study; collection, management, analysis, and International Headache Society, and has and interpretation of the data, preparation of received funding for clinical trials from Alder, the manuscript, and decision to submit the Boehringer Ingelheim, MSD, electroCore, Eli manuscript for publication) was funded by Eli Lilly and Company, Janssen Cilag, Novartis, Lilly and Company, Indianapolis, IN, USA. The and Teva. She is a trustee member of the board journal’s Rapid Service and Open Access Fees are of the International Headache Society, a mem- also funded by the study sponsor (Eli Lilly and ber of the Council of the European Headache Company, Indianapolis, IN, USA). Federation, a member of the Scientific Advisory Medical writing, editorial, and other assis- Committee of the Migraine Research Founda- tance. Editorial assistance in the preparation of tion and Lilly Spain Foundation. She is on the the manuscript was provided by Antonia Baldo. editorial board of Revista de Neurologia. She is Medical writing assistance in the preparation of an editor for Cephalalgia, Headache, Frontiers the manuscript was provided by Deborah in Neurology, Neurologia and is on the advisory D’Souza. Support for this assistance was funded Committee of The Journal of Headache and by Eli Lilly and Company. Pain. She is a member of the Clinical Trials Guidelines Committee of the International Authorship. All named authors meet the Headache Society. She has edited the Guidelines International Committee of Medical Journal for the Diagnosis and Treatment of Headache of Editors (ICMJE) criteria for authorship for this the Spanish Neurological Society. She is the article, take responsibility for the integrity of founder of www.midolordecabeza.org. She does the work as a whole, and have given their not own stocks in any pharmaceutical com- approval for this version to be published. pany. Todd J. Schwedt reports research grants from the American Migraine Foundation, Prior presentation. This manuscript is based Amgen, Henry Jackson Foundation, National on work that has been previously presented at Institutes of Health, the Patient Centered Out- 19th Congress of International Headache Soci- comes Research Institute, and United States ety, Dublin, Ireland, September 5–8, 2019; 13th Department of Defense. He has received per- Annual Headache Cooperative of the Pacific, sonal fees for consulting from Allergan, Alder, California, USA, January 24–25, 2020; Presented Amgen, Biohaven, Cipla, Click Therapeutics, at the 2020 American Academy of Neurology Dr. Reddy’s, Eli Lilly and Company, Equinox, Science Highlights Platform (Annual Meeting Ipsen Bioscience, Lundbeck, Novartis, Teva, On Demand 2020), May 18, 2020; Presented at Weber and Weber, and XoC. He has stock 2020 American Association of Nurse Practi- options from Aural Analytics and Nocira, and tioners (AANPconnect), September 10–Decem- receives royalties from UpToDate. ber 31, 2020; Spanish Society of Neurology Annual Meeting, Seville, Spain, November Compliance with ethics guidelines. The 17–21, 2020. study protocols were approved by the institu- tional review board for each study site and Disclosures. Karen H. Samaan, Robert A. patients provided written informed consent Nicholson, Mallikarjuna Rettiganti, and Eric M. prior to study procedures. More information Pearlman are full time employees and minor regarding these trials is available in the primary stockholders of Eli Lilly and Company. Patricia manuscripts [9–11]. Pozo-Rosich has received honoraria as a 3164 Adv Ther (2021) 38:3154–3165 Data availability. Data Sharing State- 2. Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ment—Lilly provides access to all individual ML, Stewart WF, AMPP Advisory Group. Migraine prevalence, disease burden, and the need for pre- participant data collected during the trial, after ventive therapy. Neurology. 2007;68:343–9. anonymization, with the exception of pharma- cokinetic or genetic data. Data are available to 3. Lipton RB, Araujo AB, Nicholson RA, et al. Patterns request 6 months after the indication studied of diagnosis, consultation, and treatment of migraine in the US: results of the OVERCOME has been approved in the US and EU and after study. In: 61st Annual Scientific Meeting American primary publication acceptance, whichever is Headache SocietyÒ 2019 Headache. 2019;59:2–3. later. No expiration date of data requests is https://doi.org/10.1111/head.13549. currently set once data are made available. 4. Ashina S, Nicholson RA, Buse DC, et al. Identifying Access is provided after a proposal has been barriers to care-seeking, diagnosis, and preventive approved by an independent review committee medication among those with migraine: results of identified for this purpose and after receipt of a the OVERCOME study [abstract]. Headache. signed data sharing agreement. Data and docu- 2020;60(S1):127–8. ments, including the study protocol, statistical 5. Nicholson RA, Lipton RB, Reed ML, et al. Charac- analysis plan, clinical study report, blank or teristics of individuals with migraine who are eli- annotated case report forms, will be provided in gible for novel CGRP monoclonal antibodies: a secure data sharing environment. For details results of the OVERCOME study [abstract]. Head- ache. 2020;60(S1):126–7. on submitting a request, see the instructions provided at www.vivli.org. 6. Hepp Z, Bloudek LM, Varon SF. Systematic review of migraine prophylaxis adherence and persistence. Open Access. This article is licensed under a J Manag Care Pharm. 2014;20:22–33. Creative Commons Attribution-NonCommer- 7. D’Amico D, Tepper SJ. Prophylaxis of migraine: cial 4.0 International License, which permits general principles and patient acceptance. Neu- any non-commercial use, sharing, adaptation, ropsychiatr Dis Treat. 2008;4:1155–67. distribution and reproduction in any medium or format, as long as you give appropriate credit 8. EMGALITY (Prescribing Information). Indianapolis, IN: Eli Lilly and Company, 2019. https://pi.lilly. to the original author(s) and the source, provide com/us/emgality-uspi.pdf. a link to the Creative Commons licence, and indicate if changes were made. The images or 9. Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani other third party material in this article are J, Conley RR. Evaluation of galcanezumab for the prevention of episodic migraine: the EVOLVE-1 included in the article’s Creative Commons randomized clinical trial. JAMA Neurol. 2018;75: licence, unless indicated otherwise in a credit 1080–8. line to the material. If material is not included in the article’s Creative Commons licence and 10. Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim B-K, Yang JY. Efficacy and safety of gal- your intended use is not permitted by statutory canezumab for the prevention of episodic migraine: regulation or exceeds the permitted use, you results of the EVOLVE-2 phase 3 randomized con- will need to obtain permission directly from the trolled clinical trial. Cephalalgia. 2018;38:1442–54. copyright holder. To view a copy of this licence, 11. Detke HC, Goadsby PJ, Wang S, Friedman DI, Sel- visit http://creativecommons.org/licenses/by- zler KJ, Aurora SK. Galcanezumab in chronic nc/4.0/. migraine: the randomized, double-blind, placebo- controlled REGAIN study. Neurology. 2018;19: e2211–21. 12. Detke HC, Millen BA, Zhang Q, et al. Rapid onset of REFERENCES effect of galcanezumab for the prevention of epi- sodic migraine: analysis of the EVOLVE studies. 1. Woldeamanuel YW, Cowan RP. Migraine affects 1 Headache. 2020;60:348–59. in 10 people worldwide featuring recent rise: a systematic review and meta-analysis of community- 13. Förderreuther S, Zhang Q, Stauffer VL, Aurora SK, based studies involving 6 million participants. Lainez MJA. Preventive effects of galcanezumab in J Neurol Sci. 2017;372:307–15. adult patients with episodic or chronic migraine are Adv Ther (2021) 38:3154–3165 3165 persistent: data from the phase 3, randomized, 15. O’Connor S, Hanlon P, O’Donnell CA, Garcia S, double-blind, placebo controlled EVOLVE-1, Glanville J, Mair FS. Understanding factors affecting EVOLVE-2, and REGAIN studies. J Headache Pain. patient and public engagement and recruitment to 2018;19:121. digital health interventions: a systematic review of qualititave studies. BMC Med Inform Decis Mak. 14. Headache Classification Committee of the Inter- 2016;16:120. national Headache Society (IHS). The international classification of headache disorders, 3rd edition 16. Reynolds BM, Robles TF, Repetti RL. Measurement (beta version). Cephalalgia. 2013;33:629–808. reactivity and fatigue effects in daily diary research with families. Dev Psychol. 2016;52:442–56.