Efficacy and safety of fremanezumab in patients with migraine and inadequate response to prior preventive treatment: subgroup analyses by country of a randomized, placebo-controlled trial

Background The FOCUS study evaluated the efficacy of migraine preventive medications across different countries within the same patient population, particularly for patients with difficult-to-treat migraine. These prespecified subgroup analyses evaluated efficacy by country in the FOCUS study of fremanezumab in adults with episodic migraine or chronic migraine and documented inadequate response to 2 to 4 migraine preventive medication classes. Methods Overall, 838 participants were enrolled in the FOCUS study, a randomized, double-blind, placebo-controlled, parallel-group, phase 3b study performed at 104 sites. For 12 weeks of double-blind treatment, patients were randomized (1:1:1) to quarterly fremanezumab, monthly fremanezumab, or matched placebo. The primary efficacy endpoint was the mean change from baseline in monthly average migraine days over 12 weeks of double-blind treatment, evaluated by country in these subgroup analyses. Results Of 14 countries contributing data, the Czech Republic (n = 188/838; 22%), the United States (n = 120/838; 14%), and Finland (n = 85/838; 10%) enrolled the most patients. Changes from baseline in monthly average migraine days over 12 weeks were significantly greater with fremanezumab versus placebo for patients in these countries: Czech Republic (least-squares mean difference versus placebo [95% confidence interval]: quarterly fremanezumab, − 1.9 [− 3.25, − 0.47]; P = 0.009; monthly fremanezumab, − 3.0 [− 4.39, − 1.59]; P < 0.001), the United States (quarterly fremanezumab, − 3.7 [− 5.77, − 1.58]; P < 0.001; monthly fremanezumab, − 4.2 [− 6.23, − 2.13]; P < 0.001), and Finland (quarterly fremanezumab, − 3.0 [− 5.32, − 0.63]; P = 0.014; monthly fremanezumab, − 3.9 [− 6.27, − 1.44]; P = 0.002). Results were comparable for the remaining 9 countries, with the least-squares mean difference versus placebo ranging from – 5.6 to – 2.4 with quarterly fremanezumab and from − 5.3 to − 1.5 with monthly fremanezumab. Incidences of serious adverse events and adverse events leading to discontinuation were low and comparable across countries and treatment groups. Conclusions Monthly and quarterly fremanezumab significantly reduced the monthly average number of migraine days versus placebo regardless of country and continent (North America versus Europe) in migraine patients with documented inadequate response to 2 to 4 migraine preventive medication classes. Trial registration ClinicalTrials.gov Identifier: NCT03308968. Supplementary Information The online version contains supplementary material available at 10.1186/s10194-021-01232-8.


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Conclusions: Monthly and quarterly fremanezumab significantly reduced the monthly average number of migraine days versus placebo regardless of country and continent (North America versus Europe) in migraine patients with documented inadequate response to 2 to 4 migraine preventive medication classes.
Keywords: Migraine, Prevention, Fremanezumab, Anti-CGRP, Efficacy, Country Background Migraine affects > 1 billion people worldwide and is associated with functional impairment and substantial economic burden [1][2][3]. As the leading cause of years lived with disability among individuals < 50 years of age, the burden of migraine and unmet needs are generally higher for patients who have failed ≥ 1 prior preventive treatment [3].
Fremanezumab is a fully humanized monoclonal antibody (IgG isotype 2Δa) that potently and selectively binds to both isoforms of calcitonin gene-related peptide [4]. Fremanezumab has been approved in the United States for the preventive treatment of migraine in adults and in Europe for the prophylaxis of migraine in adults who have ≥ 4 migraine days per month [4,5]. Fremanezumab has demonstrated efficacy, based on reductions in migraine and headache days, in patients with episodic migraine (EM) and chronic migraine (CM) in the 12-week, randomized, double-blind, placbo-controlled, phase 3 HALO studies [6,7]. In a subsequent 12-month extension study, that efficacy was maintained over longterm treatment with fremanezumab [8], with no evidence of a wearing-off effect at the end of the quarterly or monthly dosing intervals [9]. In the FOCUS study, fremanezumab treatment significantly reduced migraine and headache days in patients with EM or CM and documented inadequate response to 2 to 4 prior classes of migraine preventive medications [10].
Given the differences in the epidemiology and burden of migraine across different countries [1], there is the potential that the effectiveness of preventive medications for migraine may differ across different countries. Therefore, in a subgroup analysis of the FOCUS study, we evaluated the efficacy of fremanezumab by country in this population of patients with difficult-to-treat migraine. Based on the favorable efficacy results demonstrated in the overall study population, we hypothesized that treatment with quarterly or monthly fremanezumab would be efficacious in patients regardless of their country of residence.

Methods
This was a preplanned exploratory analysis (for the primary endpoint) of the international, multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3b FOCUS study (ClinicalTrials.gov Identifier: NCT03308968) in patients with EM or CM who had documented inadequate response to 2 to 4 prior classes of migraine preventive medications [10]. The FOCUS study was approved by an independent ethics committee or institutional review board at each study site, and each patient provided written informed consent. The study design, eligibility criteria, methods, and statistical analysis methods for that trial have been reported in detail previously [10] and are summarized briefly here.

Patients
Patients were eligible to participate in the FOCUS study if they were between 18 and 70 years of age, with a diagnosis of migraine (onset ≤ 50 years of age) and a history of migraine for ≥ 12 months prior to screening. Eligible patients also had documented inadequate response within the past 10 years to 2 to 4 migraine preventive medication classes, including angiotensin II receptor blockers (candesartan), anticonvulsants (topiramate), beta blockers (propranolol, metoprolol, atenolol, bisoprolol), calcium channel blockers (flunarizine), onabotulinumtoxinA, tricyclic antidepressants (amitriptyline), or valproic acid. As described previously [10], inadequate response was defined as no clinically meaningful improvement per the treating physician's judgement after ≥ 3 months of therapy at a stable dose, treatment discontinuation due to adverse events, or the treatment was contraindicated or not suitable for the patient. Acceptable documentation of prior inadequate response included the patient's medical record (including the name of the medication, duration of treatment, dose, and reason for discontinuing treatment) or an affidavit that provided confirmation of inadequate response [10].

Study design
The FOCUS study included a screening visit; a 28-day run-in period; a 12-week, double-blind, placebocontrolled treatment period; and a 12-week, open-label treatment period. For the 12-week, double-blind treatment period, patients were randomized (1:1:1) to monthly fremanezumab (Month 1: CM, 675 mg; EM, 225 mg; Months 2 and 3: 225 mg), quarterly fremanezumab (Month 1: 675 mg, Months 2 and 3: placebo), or matched placebo. Efficacy was evaluated using information entered daily by patients in an electronic headache diary throughout the treatment period [10].

Outcomes
For this analysis, all outcomes were evaluated for subgroups of patients divided by country. The primary efficacy outcome for the FOCUS study was the mean change from baseline in the monthly average number of migraine days over 12 weeks of double-blind treatment. Secondary endpoints, prespecified evaluations, and safety analyses are described within the Methods in Additional file 1.

Statistical analyses
For the overall FOCUS study population, a sample size of 705 evaluable patients (235 patients per group) completing the study was needed for 90% power to show a 1.8-day difference in monthly migraine days (based on an assumption of a common standard deviation [SD] of 6 days) at an alpha level of 0.05. Assuming a 12% discontinuation rate, 268 patients per treatment group will be randomized in the study. The safety analysis set included all randomized patients who received ≥ 1 dose of study drug. Efficacy analyses were performed on the modified intention-to-treat analysis set, which included all randomized patients who received ≥ 1 dose of study drug and had ≥ 10 days of post-baseline efficacy assessments for the primary endpoint. Efficacy and safety outcomes were summarized using descriptive statistics (ie, sample size, mean, SD, and frequency counts).
For the change from baseline in the monthly average number of migraine days during 12 weeks (primary endpoint of the study), analyses were performed using an analysis of covariance (ANCOVA) method that included treatment, sex, region, special group of treatment failure (patients who had documented inadequate response to valproic acid and documented inadequate response to 2 to 3 other migraine preventive medication classes), migraine classification, and treatment-by-migraine classification interaction as fixed effects and baseline number of migraine days and years since onset of migraine as covariates. A P value of < 0.05 was considered significant, and tests are 2-tailed. All summaries and statistical analyses were generated using SAS® software (Version 9.4 of SAS System for Windows, SAS Institute Inc., Cary, NC, USA). Statistical analyses for additional efficacy outcomes are described within the eMethods in the Supplement.

Results
Overall, 838 patients were randomized in the FOCUS study and received ≥ 1 dose of study drug; 837 patients had ≥ 10 days of post-baseline diary entries for the primary outcome (modified intention-to-treat analysis set). Of the 14 countries contributing data, the Czech Republic, the United States, and Finland were the 3 toprecruiting countries (with each country recruiting ≥ 10% of the total study population; Table S1 in Additional file 2. These 3 countries together recruited 47% (393/838) of patients for the total study (Czech Republic, n = 188 [22%]; United States, n = 120 [14%]; Finland, n = 85 [10%]; Table  S1 in Additional file 2). Baseline monthly migraine days were similar across treatment groups within the 3 countries. Overall, baseline monthly migraine days in these 3 top-recruiting countries were similar to those of the total population of the study across all countries (Table S2 in Additional file 3).
For the primary endpoint, the reduction from baseline in the monthly average number of migraine days during the 12 weeks after the first dose of study drug was significantly greater with both quarterly and monthly fremanezumab versus placebo and was similar across all 3 toprecruiting countries (P < 0.05; Table 1, Fig. 1a). Similarly, for all countries excluding the Czech Republic, the United States, and Finland, the least-squares mean (LSM) change from baseline was significantly greater with both fremanezumab dosing regimens versus placebo (P < 0.001; Fig. 1a). Among those individual countries, reductions from baseline in the monthly average number of migraine days during the 12 weeks after the first dose of study drug were significantly greater compared with placebo with both dosing regimens of fremanezumab for Germany, Poland, Sweden, Denmark, and the Netherlands; with quarterly fremanezumab for Spain and the United Kingdom; and with monthly fremanezumab for France (P < 0.05; Table 1).
The reduction from baseline in the monthly average number of migraine days at 4 weeks was significantly greater with both quarterly and monthly fremanezumab versus placebo and similar across all top-recruiting countries (P < 0.05; Fig. 1b). For patients in the Czech Republic, the LSM change from baseline in monthly average migraine days at 4 weeks was significantly greater versus placebo with quarterly fremanezumab (P < 0.001) and monthly fremanezumab (P < 0.001). Significantly greater reductions in monthly average migraine days at 4 weeks versus placebo were also observed in patients in the United States with quarterly fremanezumab (P < 0.001) and monthly fremanezumab (P = 0.001), as well as in patients in Finland (quarterly fremanezumab, P = 0.003; monthly fremanezumab, P = 0.007).
Reductions from baseline in the monthly average number of headache days of at least moderate severity during 12 weeks of double-blind treatment were significantly greater with both fremanezumab dosing regimens versus placebo in patients in the Czech Republic, the United States, and Finland (P ≤ 0.01; Table 2). Reductions from   Table 2). The proportion of patients who achieved ≥ 50% reduction in the monthly average number of migraine days during 12 weeks of double-blind treatment was significantly higher with quarterly and monthly fremanezumab versus placebo in patients in the Czech Republic and Finland, and with monthly fremanezumab versus placebo in patients in the United States (Fig. 2). In patients in the Czech Republic, the proportion of patients who achieved ≥ 50% reduction in monthly average migraine days was significantly higher versus placebo with quarterly fremanezumab (odds ratio [ The proportion of patients who achieved ≥ 50% reduction in the monthly average number of migraine days at 4 weeks of double-blind treatment was higher with quarterly and monthly fremanezumab versus placebo in patients in the United States, and Finland and significantly higher in patients in the Czech Republic (Fig. 2) The proportion of patients who achieved ≥ 75% reduction in the monthly average number of migraine days during 12 weeks of double-blind treatment was higher with quarterly and monthly fremanezumab versus placebo in patients in the Czech Republic, the United States, and Finland (Fig. 3). The proportion of patients who achieved ≥ 75% reduction in the monthly average number of migraine days at 4 weeks of double-blind treatment was higher with quarterly and monthly fremanezumab versus placebo in patients in the Czech Republic, the United States, and Finland (Fig. 3).
Reductions from baseline in the monthly average number of days of any acute headache medication use during the 12 weeks after the first dose of study drug were significantly greater with both quarterly and monthly fremanezumab versus placebo in patients in the Czech Republic, the United States, and Finland (P ≤ 0.02; Table 2). Placebo-adjusted reductions in monthly days of any acute headache medication use were approximately 2 to 3 days for patients in the Czech Republic and 3 days for patients in the United States and Finland.
Improvements from baseline in headache-related disability, as measured by reductions in 6-item Headache Impact Test (HIT-6) scores, were higher with both fremanezumab dosing regimens versus placebo, although not all differences reached statistical significance (Table S3 in Additional file 4). Reductions in HIT-6 scores versus placebo of approximately 2 to 3 points were observed for patients in the Czech Republic, 2 to 4.5 points for those in the United States, and 4.5 to 5 points for those in Finland. Improvements in migraine-related disability, as measured by reductions in Migraine Disability Assessment (MIDAS) scores from baseline, were generally higher with fremanezumab versus placebo; however, these betweengroup differences did not reach statistical significance for all comparisons (Table S3 in Additional file 4). Reductions in MIDAS scores versus placebo ranged from approximately 2 to 6.5 points for patients in the Czech Republic, 6 to 12 points for those in the United States, and 20 to 24 points in for those in Finland.
The proportion of responders on the Patient Global Impression of Change (PGIC) scale was higher with both quarterly and monthly fremanezumab versus placebo in patients in the Czech Republic, the United States, and Finland, although all differences did not reach statistical significance (Table S3 in Additional file 4). Approximately 50% to 80% of patients receiving fremanezumab   across these three countries were considered PGIC responders (ie, reported improvements ranging from moderately better to a great deal better), except for patients receiving quarterly fremanezumab in the United States (31%). Incidences of injection-site reaction adverse events, other adverse events, serious adverse events, and adverse events leading to discontinuation were similar across treatment groups in the 3 top-recruiting countries (Table 3). No severe hypersensitivity reactions or cases of anaphylaxis were reported. The most common adverse events across all treatment groups in Europe and the United States were injection-site erythema, injectionsite induration, and injection-site pain (Table S4 in Additional file 5). No deaths were reported. In the 3 top-recruiting countries, serious adverse events were reported for 3 (2%) of 126 patients who received placebo, 1 (< 1%) of 134 who received quarterly fremanezumab, and none of 133 who received monthly fremanezumab. No safety signals were identified in this subgroup analysis.

Discussion
The primary efficacy analysis demonstrated statistical significance in favor of fremanezumab in the 3 top- recruiting countries, the Czech Republic, the United States, and Finland. As compared with placebo, fremanezumab treatment resulted in approximately 2-to 3-day reductions from baseline in monthly migraine days over 12 weeks of treatment (primary endpoint) in the Czech Republic and approximately 3.5-to 4-day reductions in the United States and Finland. Similarly, a reduction of approximately 3.5 days was found for this endpoint for all countries excluding these 3 top-recruiting countries, with reductions ranging from approximately 2 to 8 days across those countries. Fremanezumab also reduced monthly headache days of at least moderate severity by 2.5 to 4.5 days as early as 4 weeks after starting treatment across the 3 top-recruiting countries, with similar results observed during the 12 weeks after the first dose of study drug. For patients in these 3 top-recruiting countries, the observed reductions in days with any acute headache medication use of approximately 2 to 3 days were also similar to the results reported previously for the overall FOCUS population [10]. The consistency among the patient subgroups suggests that these results are generalizable and not limited to a predominant recruiting country. Across different countries, the epidemiology and burden of migraine vary [1], along with the severity of headache pain and migraine-related disability [11]. The use of acute and preventive prescription medications for migraine also differs by country [12]. Furthermore, there is the potential for differences in clinical trial execution in different regions. For example, the prevalence of migraine is higher in Finland than in the Czech Republic or the United States, as are the number of migraineassociated years lived with disability [1,13]. Although each clinical site participating in a clinical trial is expected to closely follow clinical trial protocols and guidelines, the heterogeneity of resource availability, infrastructure, clinical trial regulatory requirements, sociocultural practices, and patient education and support among countries may result in differences in clinical trial execution [14,15].
The results of the FOCUS study provide evidence for the efficacy of fremanezumab in a broad population of patients with difficult-to-treat EM or CM and prior inadequate response to 2 to 4 prior migraine preventive medication classes [10]. The results of the current subgroup analysis, which showed consistent efficacy across countries in this population with inadequate response to multiple prior preventive treatments, are of note given the potential differences in the burden of migraine and the severity of associated headache and disability between countries [1,11]. Although in the current analyses, there were no substantial differences in efficacy across the different countries involved in the clinical trial, the impact of geographic composition on the outcomes of international studies may be an area of future research to determine how to best manage potential differences in trial execution across sites in different countries.
For patients enrolled from the United States, the odds of achieving a ≥ 50% reduction in monthly migraine days were approximately 5 to 6 times higher with fremanezumab than with placebo during the 12 weeks after the first dose of study drug. For the same endpoint, the odds were approximately 3 to 3.5 times higher in the Czech Republic and 6.5 to 7 times higher in Finland. Injection-site erythema 6 (5) 9 (7) 6 (4) Injection-site pain 4 (3) 9 (7) 3 (2) Injection-site induration 3 (2) 4 (3) 7 (5) Injection-site bruising 2 (2) 2 (2) 2 (1) Injection-site pruritus 2 (2) 2 (2) 2 (1) Availability of data and materials Anonymized data, as described in this manuscript, will be shared upon request from any qualified investigator by the author investigators or Teva Branded Pharmaceutical Products R&D, Inc.

Declarations
Ethics approval and consent to participate The study was reviewed and approved by an independent ethics committee or institutional review board at all participating study sites. All participants provided written informed consent before participation in the study.

Consent for publication
Not applicable.