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Background: Migraine is the second leading cause of disability worldwide. Although many preventive treatments reduce migraine frequency and severity, it is unclear whether these treatments reduce migraine-related disability in a clinically meaningful way. This pooled analysis evaluated the ability of fremanezumab to reduce migraine-related disability, based on responses and shifts in severity in patient-reported disability outcomes. Methods: This pooled analysis included 3 double-blind phase 3 trials (HALO EM, HALO CM, FOCUS) in which patients with episodic or chronic migraine were randomly assigned 1:1:1 to quarterly or monthly fremanezumab or matched placebo for 12 weeks. Migraine-related disability was assessed using the 6-item Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) questionnaires. A clinically meaningful improvement in disability was defined per American Headache Society guidelines: for HIT-6, a ≥ 5-point reduction; for MIDAS, a ≥ 5-point reduction when baseline score was 11 to 20 or ≥ 30% reduction when baseline score was > 20. Proportions of patients who demonstrated shifts in severity for each outcome were also evaluated. Results: For patients with baseline MIDAS scores of 11 to 20 (n = 234), significantly higher proportions achieved 5-point reductions from baseline in MIDAS scores with fremanezumab (quarterly, 71%; monthly, 70%) compared with placebo (49%; both P ≤ 0.01). For patients with baseline MIDAS scores of > 20 (n = 1266), proportions achieving ≥30% reduction from baseline in MIDAS scores were also significantly higher with fremanezumab (quarterly, 69%; monthly, 79%) compared with placebo (58%; both P < 0.001). For HIT-6 scores, proportions of patients achieving 5-point reductions from baseline were significantly higher with fremanezumab (quarterly, 53%; monthly, 55%) compared with placebo (39%; both P < 0.0001). Proportions of patients with shifts of 1 to 3 grades down in MIDAS or HIT-6 disability severity were significantly greater with quarterly and monthly fremanezumab compared with placebo (all P < 0.0001). Conclusion: Fremanezumab demonstrated clinically meaningful improvements in disability severity in this pooled analysis. Trial registrations: HALO CM, NCT02621931; HALO EM, NCT02629861; FOCUS, NCT03308968. [ABSTRACT FROM AUTHOR]

A correction to the article "Efficacy and safety of fremanezumab in clinical trial participants aged ≥60 years with episodic or chronic migraine: Pooled results from 3 randomized, double-blind, placebo-controlled phase 3 studies" that was published in a 2021 issue is presented.

Background: Migraine prevalence is age and sex dependent, predominating in women in early and middle adulthood; however, migraine also represents a substantial burden for men and adults of all ages. Thus, understanding this burden and the efficacy of migraine preventive medications in both sexes and across age groups is critical. The randomized, placebo-controlled, double-blind, phase 3b FOCUS study demonstrated the safety and efficacy of fremanezumab, a fully humanized monoclonal antibody (IgG2∆a) that selectively targets calcitonin gene-related peptide as a migraine preventive treatment for individuals with migraine and prior inadequate response to 2 to 4 migraine preventive medication classes. Here, we assessed the efficacy of fremanezumab in participants from FOCUS subgrouped by age (18–45 years and > 45 years) and sex. Methods: In the FOCUS study, eligible participants were randomized (1:1:1) to 12 weeks of double-blind treatment with quarterly fremanezumab, monthly fremanezumab, or matched monthly placebo. In this post hoc analysis, we evaluated changes from baseline in monthly migraine days (primary endpoint of FOCUS) and other secondary and exploratory efficacy outcomes in prespecified age (18–45 and > 45 years) and sex subgroups. Results: The modified intention-to-treat population (received ≥ 1 dose of study drug and had ≥ 10 days of postbaseline efficacy assessments for the primary endpoint) totaled 837 participants (18–45 years, n = 373; > 45 years, n = 464; male, n = 138; female, n = 699). Consistent reductions in monthly average number of migraine days during 12 weeks were observed, regardless of age (18–45 years: quarterly fremanezumab, − 4.1 days; monthly fremanezumab, − 4.7 days; placebo, − 0.9 days; P < 0.001; > 45 years: quarterly fremanezumab, − 3.6 days; monthly fremanezumab, − 3.7 days; placebo, − 0.3 days; P < 0.001) and sex (male: quarterly fremanezumab, − 4.1 days; monthly fremanezumab, − 4.6 days; placebo, − 0.3 days; P < 0.001; female: quarterly fremanezumab, − 3.6 days; monthly fremanezumab, − 3.9 days; placebo, − 0.6 days; P < 0.001). Fremanezumab also reduced monthly headache days of at least moderate severity, monthly days of acute medication use, and improved Migraine Disability Assessment scores across subgroups. Conclusions: These results demonstrate the efficacy of fremanezumab in patients with difficult-to-treat migraine for reducing migraine and headache days, acute medication use, and disability, regardless of age or sex. Trial registration: ClinicalTrials.gov Identifier NCT03308968 (FOCUS), registered October 13, 2017. [ABSTRACT FROM AUTHOR]

Background: Although migraine is less common in older people, preventive treatment of migraine in these individuals may be more challenging due to the presence of multiple comorbidities and polypharmacy. Additionally, evidence for migraine treatment efficacy, safety, and tolerability is limited in this population. We evaluated efficacy, safety, and tolerability of fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene–related peptide (CGRP), in clinical trial participants aged ≥60 years with episodic migraine (EM) or chronic migraine (CM). Methods: This analysis included data from 3 randomized, double-blind, placebo-controlled phase 3 studies: the HALO EM study, HALO CM study, and FOCUS study in participants with EM or CM and prior inadequate response to 2–4 migraine preventive medication classes. Participants in all studies were randomized 1:1:1 to receive 12 weeks of subcutaneous treatment with quarterly fremanezumab (Months 1/2/3: EM/CM, 675 mg/placebo/placebo), monthly fremanezumab (Months 1/2/3: EM, 225 mg/225 mg/225 mg; CM, 675 mg/225 mg/225 mg), or matched monthly placebo. Results: These pooled analyses included 246 participants aged ≥60 years. Reductions in monthly migraine days from baseline over 12 weeks were significantly greater with fremanezumab (least-squares mean change from baseline [standard error]: quarterly fremanezumab, − 4.3 [0.59]; monthly fremanezumab, − 4.6 [0.54]) versus placebo (placebo, − 2.3 [0.57]; both P < 0.01 vs placebo). As early as Week 1, significant reductions from baseline in weekly migraine days were observed with fremanezumab versus placebo (both P < 0.01). With fremanezumab treatment versus placebo, a significantly higher proportion of participants achieved ≥50% reduction in monthly migraine days, and significant improvements in disability and quality-of-life outcomes were observed (P < 0.05). Proportions of participants experiencing serious adverse events and adverse events leading to discontinuation were low and similar in the fremanezumab and placebo groups. Efficacy and safety results were comparable to the overall pooled population (N = 2843). Conclusions: This pooled subgroup analysis demonstrates that fremanezumab treatment is efficacious and well-tolerated over 12 weeks in participants aged ≥60 years with EM or CM. These data may help healthcare providers with clinical decision making and preventive treatment selection for older patients with migraine. Trial registration: ClinicalTrials.gov identifiers: HALO CM: NCT02621931; HALO EM: NCT02629861; FOCUS: NCT03308968. [ABSTRACT FROM AUTHOR]

Background: Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) selectively targets the calcitonin gene-related peptide and has proven efficacy for the preventive treatment of migraine. In this study, we evaluated the long-term efficacy, safety, and tolerability of monthly and quarterly fremanezumab. Methods: Episodic migraine and chronic migraine patients completing the 12-week double-blind period of the FOCUS trial entered the 12-week open-label extension and received 3 monthly doses of fremanezumab (225 mg). Changes from baseline in monthly migraine days, monthly headache days of at least moderate severity, days of acute headache medication use, days with photophobia/phonophobia, days with nausea or vomiting, disability scores, and proportion of patients achieving a ≥50% or ≥75% reduction in monthly migraine days were evaluated. Results: Of the 807 patients who completed the 12-week double-blind treatment period and entered the open-label extension, 772 patients completed the study. In the placebo, quarterly fremanezumab, and monthly fremanezumab dosing regimens, respectively, patients had fewer average monthly migraine days (mean [standard deviation] change from baseline: − 4.7 [5.4]; − 5.1 [4.7]; − 5.5 [5.0]), monthly headache days of at least moderate severity (− 4.5 [5.0]; − 4.8 [4.5]; − 5.2 [4.9]), days per month of acute headache medication use (− 4.3 [5.2]; − 4.9 [4.6]; − 4.8 [4.9]), days with photophobia/phonophobia (− 3.1 [5.3]; − 3.4 [5.3]; − 4.0 [5.2]), and days with nausea or vomiting (− 2.3 [4.6]; − 3.1 [4.5]; − 3.0 [4.4]). During the 12-week open-label extension, 38%, 45%, and 46% of patients, respectively, achieved a ≥50% reduction and 16%, 15%, and 20%, respectively, achieved a ≥75% reduction in monthly migraine days. Disability scores were substantially improved in all 3 treatment groups. There were low rates of adverse events leading to discontinuation (<1%). Conclusion: Fremanezumab demonstrated sustained efficacy up to 6 months and was well tolerated in patients with episodic migraine or chronic migraine and documented inadequate response to multiple migraine preventive medication classes. Trial registration: ClinicalTrials.gov NCT03308968 (FOCUS). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway have been shown to be effective in migraine prevention. Eptinezumab, erenumab, fremanezumab, and galcanezumb have shown efficacy in clinical trials along with favorable safety and tolerability profiles. Although erenumab is a human mAb and the others have been humanized to varying degrees, they all have the capacity to provoke immune reactions. The present review article aims to discuss the current relationship between mAbs targeting the CGRP pathway (CGRP mAbs) and immunogenicity and their potential clinical implications. Findings: The incidence of patients developing anti-drug antibodies (ADAs), their titer, and clinical significance are highly variable and depend on a variety of different drug and patient factors. Neutralizing ADAs (NAbs) bind to and inhibit or reduce the pharmacologic activity of the biologic drug molecule, whereas non-neutralizing antibodies (Non-NAbs) bind to the biologic drug molecule without affecting pharmacologic activity in an in vitro test, although pharmacokinetics and drug clearance may be affected. A direct comparison of immunogenicity data across clinical trials with different biologics is not possible due to a lack of standardized assays. Several phase 2, phase 3, and long-term studies evaluating CGRP mAbs for migraine prevention have reported immunogenicity data (5 studies each for eptinezumab, erenumab, fremanezumab, and galcanezumab). Across these studies, prevalence of ADAs varied, ranging from < 1% to ~ 18%. Neutralizing ADAs were slightly less common, with a prevalence ranging from 0 to 12%. Adverse events related to ADA formation were rare. Conclusions: As more CGRP mAb studies are conducted and more long-term follow-up data become available, evidence is increasing that immunogenicity rates of biologic therapies for migraine are low, and adverse events related to ADAs are rare. Taken together, these results add to the growing body of evidence for the safety and tolerability of this class of migraine medications. [ABSTRACT FROM AUTHOR]