Targeted inhibition of m6A demethylase FTO by FB23 attenuates allergic inflammation in the airway epithelium.

Epithelial cells play a crucial role in asthma, contributing to chronic inflammation and airway hyperresponsiveness. m6A modification, which involves key proteins such as the demethylase fat mass and obesity-associated protein (FTO), is crucial in the regulation of various diseases, including asthma. However, the role of FTO in epithelial cells and the development of asthma remains unclear. In this study, we investigated the demethylase activity of FTO using a small-molecule inhibitor FB23 in epithelial cells and allergic inflammation in vivo and in vitro. We examined the FTO-regulated transcriptome-wide m6A profiling by methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq under FB23 treatment and allergic inflammation conditions. Immunofluorescence staining was performed to assess the tissue-specific expression of FTO in asthmatic bronchial mucosa. We demonstrated that FB23 alleviated allergic inflammation in IL-4/IL-13-treated epithelial cells and house dust mite (HDM)-induced allergic airway inflammation mouse model. The demethylase activity of FTO contributed to the regulation of TNF-α signaling via NF-κB and epithelial-mesenchymal transition-related pathways under allergic inflammation conditions in epithelial cells. FTO was expressed in epithelial, submucosal gland, and smooth muscle cells in human bronchial mucosa. In conclusion, FB23-induced inhibition of FTO alleviates allergic inflammation in epithelial cells and HDM-induced mice, potentially through diverse cellular processes and epithelial-mesenchymal transition signaling pathways, suggesting that FTO is a potential therapeutic target in asthma management.

Effects of fremanezumab on migraine-associated symptoms and medication use in Japanese and Korean patients with episodic migraine: Exploratory endpoint analysis of a multicenter, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To describe exploratory endpoints from a previous phase 2b/3 placebo-controlled trial conducted in Japan and Korea, specifically investigating the effect of fremanezumab or placebo on migraine-associated symptoms and acute headache medication use in patients with episodic migraine (EM). BACKGROUND: EM is associated with non-head pain symptoms, including nausea, vomiting, photophobia, or phonophobia, which contribute substantially to the disease burden, healthcare resource utilization, and impaired quality of life. Current EM treatments include a mix of nonspecific/migraine-specific acute headache medications, but medication overuse can induce headaches and progression from EM to chronic migraine (CM). In multiple phase 2b/3 trials, the monoclonal antibody fremanezumab significantly reduced the average number of monthly migraine days experienced by patients with EM/CM compared with placebo. METHODS: This was a prespecified analysis of exploratory endpoints in a multicenter, randomized, double-blind, placebo-controlled, phase 2b/3 trial conducted in Japanese and Korean patients with EM (NCT03303092). Patients were randomized to receive fremanezumab, either monthly or quarterly, or matching placebo, administered subcutaneously at 4-week/28-day ("monthly") intervals to maintain blinding. Exploratory endpoints reported here were the mean change from baseline in the number of days/month with (i) the use of any acute headache medication, (ii) the use of any migraine-specific acute headache medication, (iii) nausea or vomiting, and (iv) photophobia and phonophobia. RESULTS: Overall, 357 Japanese and Korean patients with EM received either monthly (n = 121) or quarterly (n = 119) fremanezumab or placebo (n = 117). Compared with placebo, fremanezumab administered monthly or quarterly was associated with a significant reduction from baseline in the average number of days/month with acute headache medication use over three months (difference vs. placebo -2.81 [95% confidence interval (CI) -3.52, -2.11]; p < 0.001 and -2.79 [95% CI -3.50, -2.08]; p < 0.001, respectively). Similar findings were observed in the monthly average number of days with migraine-specific acute headache medications (difference vs. placebo with monthly and quarterly fremanezumab, -2.63 [95% CI -3.31, -1.95] for both; p < 0.001), the average number of days/month with nausea or vomiting (difference vs. placebo -1.09 [95% CI -1.60, -0.58]; p < 0.001 for monthly fremanezumab and -1.37 [95% CI -1.88, -0.86]; p < 0.001 for quarterly fremanezumab), and the average number of days with photophobia and phonophobia (difference vs. placebo -1.22 [95% CI -1.80, -0.65]; p < 0.001 and -1.64 [95% CI -2.22, -1.06]; p < 0.001, respectively). CONCLUSION: Monthly and quarterly administered fremanezumab effectively prevented EM in Japanese and Korean patients. Fremanezumab also improved other disease aspects including the need for acute headache medications and the frequency of migraine-associated symptoms.

Improved quality of life with fremanezumab in Japanese and Korean patients with episodic and chronic migraine: Results of two multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trials.

OBJECTIVE: To evaluate quality of life (QoL) endpoints from two 12-week trials investigating fremanezumab efficacy and safety in Japanese/Korean patients with chronic (CM) or episodic (EM) migraine. BACKGROUND: Migraine is a leading cause of disability and affects QoL considerably, interfering with work and daily activities, social and family life, and emotional wellbeing. METHODS: This planned exploratory analysis used data from two multicenter, randomized, double-blind, placebo-controlled, parallel-group studies in which Migraine-Specific QoL (MSQoL; Role Function-Restrictive [RR], Role Function-Preventive [RP], and Emotional Function [EF] domains) scores and Patient Global Impression of Change (PGIC) scores were pre-specified QoL outcomes in individuals receiving monthly or quarterly fremanezumab or placebo. In both trials, MSQoL was assessed at baseline, and MSQoL and PGIC at Weeks 4, 8, and 12. PGIC responders had a score of ≥5 points, indicating significant improvement. RESULTS: Mean baseline MSQoL scores were similar across groups in both CM (N = 565; RR, 60.3-61.5; RP, 78.5-80.0; EF, 69.0-71.4) and EM (N = 353; RR, 68.6-71.1; RP, 83.1-85.7; EF, 76.7-81.9) trials. In the CM trial, all three MSQoL domains improved in both fremanezumab groups at 12 weeks compared with placebo: least squares mean (LSM) and standard error (SE) change from baseline, p versus placebo (quarterly; monthly; placebo): RR 14.9 (1.3), p = 0.030; 15.1 (1.4), p = 0.020; 11.6 (1.3); RP 8.9 (1.1), p = 0.007; 8.6 (1.1), p = 0.013; 5.4 (1.1); EF 13.3 (1.5), p < 0.001; 12.5 (1.5), p = 0.003; 7.5 (1.5). In the EM trial, RR/EF domains improved in both fremanezumab groups compared with placebo: LSM change from baseline, p versus placebo (quarterly; monthly; placebo): RR 16.3 (1.4), p = 0.003; 16.4 (1.3), p = 0.002; 11.6 (1.4); EF 13.0 (1.3), p < 0.001; 11.5 (1.2), p = 0.004; 7.4 (1.3); RP improved in the quarterly group RP 8.6 (1.1), p = 0.010; 7.6 (1.1), p = 0.066; 5.4 (1.1). The proportion of PGIC responders at Week 12 was greater in the monthly and quarterly fremanezumab groups compared with the placebo group in the CM (96/182 [52.7%] and 98/180 [54.4%] vs. 68/179 [38.0%]; p < 0.05) and EM trial (81/118 [68.6%] and 86/113 [76.1%] vs. 38/111 [34.2%]; p < 0.001). CONCLUSION: Patients with EM/CM receiving monthly or quarterly fremanezumab, for a duration of 12 weeks, showed significant improvements in their QoL.

Numbers needed to treat or harm and likelihood of being helped versus harmed for fremanezumab in patients who had prior inadequate response to two to four classes of migraine preventive medications: A post hoc analysis.

OBJECTIVE: This study aimed to determine the number needed to treat (NNT), number needed to harm (NNH), and likelihood of being helped or harmed (LHH) in a post hoc analysis of the phase 3b FOCUS trial. BACKGROUND: Fremanezumab, a humanized monoclonal antibody that selectively targets calcitonin gene-related peptide (CGRP), has demonstrated efficacy, tolerability, and safety in adults with episodic migraine (EM) or chronic migraine (CM), with documented previous inadequate response to two to four classes of migraine preventive medications. METHODS: In the 12-week double-blind period of the FOCUS study, patients were randomized (1:1:1) to quarterly fremanezumab, monthly fremanezumab, or matched monthly placebo. NNT was based on responder analysis, defined as ≥50% reduction in monthly average number of migraine days at 12 weeks. NNH was based on discontinuations due to adverse events (AEs). RESULTS: Among patients with CM (n = 509), response rates and discontinuation rates were 27% (45/169) and 0 for quarterly fremanezumab, 29% (50/173) and 2% (3/173) for monthly fremanezumab, and 8% (13/167) and <1% (1/167) for placebo, respectively. These results translated to NNTs of 5.3 and 4.7, NNHs of 1000 and 88, and LHHs of 188 and 19 for quarterly and monthly fremanezumab, respectively. Among patients with EM (n = 328), response rates were 47% (50/107) for quarterly fremanezumab, 43% (47/110) for monthly fremanezumab, and 10% (11/111) for placebo. Discontinuation rates were <1% (n = 1) in all three groups. These results translated to NNTs of 2.7 and 3.0, NNHs of 1000 and 1000, and LHHs of 368 and 328 for quarterly and monthly fremanezumab, respectively. CONCLUSIONS: The NNT, NNH, and LHH for quarterly and monthly fremanezumab compare favorably with those for traditional oral preventive medications, including topiramate, valproate, and propranolol.

Safety and tolerability of fremanezumab in patients with episodic and chronic migraine: a pooled analysis of phase 3 studies.

BACKGROUND: Fremanezumab, a fully humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, has demonstrated efficacy for preventive treatment of episodic and chronic migraine. Since calcitonin gene-related peptide is expressed within the cardio- and cerebrovascular system and may have cardioprotective effects, it is critical to understand the cardio- and cerebrovascular safety of fremanezumab. METHODS: This was a pooled analysis of three randomized, double-blind, placebo-controlled, phase 3, 12-week trials in which patients with episodic migraine or chronic migraine received quarterly fremanezumab, monthly fremanezumab, or placebo. Incidences of overall and serious adverse events were analyzed. Cardio- and cerebrovascular adverse events (CVAEs) were analyzed in subgroups stratified by cardio- and cerebrovascular medical history, cardiovascular risk factors (CVRFs), and use of cardio- and cerebrovascular medications or triptans. RESULTS: Two thousand, eight hundred and forty-two patients were included in the study. Overall (58-65%) and serious adverse events (<1-2%) occurred in similar proportions across fremanezumab and placebo groups. CVAEs were infrequent, regardless of cardio- and cerebrovascular medical history (2-6%). CVAEs occurred in low, similar proportions of patients with CVRFs and those using cardio- and cerebrovascular medications or triptans. No cardio- and cerebrovascular signals were identified. CONCLUSION: Fremanezumab demonstrated a favorable overall and cardio- and cerebrovascular safety profile in more than 2800 patients with episodic migraine or chronic migraine, regardless of cardio- and cerebrovascular medical history, CVRFs, or medication use.Trial Registrations: NCT02629861 (HALO EM, https://clinicaltrials.gov/ct2/show/NCT02629861), NCT02621931 (HALO CM, https://clinicaltrials.gov/ct2/show/NCT02621931), NCT03308968 (FOCUS, https://clinicaltrials.gov/ct2/ show/NCT03308968).

Efficacy and quality-of-life improvements with fremanezumab treatment in patients with difficult-to-treat migraine with associated neurological dysfunction.

BACKGROUND AND PURPOSE: Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin-gene-related peptide, has demonstrated efficacy as a preventive treatment for adults with episodic migraine or chronic migraine and inadequate response to two to four prior preventive treatment classes in the phase 3b FOCUS study. In this post hoc analysis, efficacy and effects on quality-of-life outcomes for fremanezumab were evaluated in subgroups of patients with and without aura or similar neurological symptoms, here referred to as migraine with or without associated neurological dysfunction. METHODS: In the FOCUS study, 838 patients were randomized (1:1:1) to quarterly fremanezumab, monthly fremanezumab or matched placebo for 12 weeks of double-blind treatment. For this post hoc analysis, subgroups of patients with migraine with and without associated neurological dysfunction at baseline were identified based on patient response to questions about symptoms. RESULTS: In patients with migraine with associated neurological dysfunction at baseline, fremanezumab significantly reduced monthly average days with neurological symptoms (quarterly, -1.7 days; monthly, -1.8 days) compared to placebo (-0.5 days; both p ≤ 0.01). In comparison with placebo, both dosing regimens of fremanezumab yielded greater reductions in monthly migraine days over 12 weeks (p < 0.0001) and improvements in Headache Impact Test 6 and Migraine-Specific Quality of Life scores over the last 4 weeks (p < 0.05), regardless of neurological dysfunction at baseline. CONCLUSIONS: Fremanezumab reduced days with neurological symptoms, effectively prevented migraine, and improved quality of life in patients with migraine with associated neurological dysfunction, including those with previous inadequate response to two to four migraine preventive medication classes.

Transapical Transcatheter Aortic Valve Implantation for Aortic Regurgitation in Takayasu Arteritis.

Transcatheter aortic valve implantation (TAVI) has become a popular treatment for surgical high-risk patients with severe aortic stenosis (AS). Recently, we have applied TAVI to the treatment of aortic regurgitation (AR). Compared with conventional surgical procedures, TAVI is less invasive and considered a useful option for these high-risk patients. In this study, we reported a patient who underwent transapical TAVI. The patient was a 52-year-old female with Takayasu arteritis (TA) for 25 years, as well as with severe aortic regurgitation, porcelain aortas, and heart failure. Transapical TAVI successfully was accomplished without neurological complications, and heart failure immediately improved postoperatively.

Impact of fremanezumab on disability outcomes in patients with episodic and chronic migraine: a pooled analysis of phase 3 studies.

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 .

Early onset of efficacy with fremanezumab in patients with episodic and chronic migraine: subanalysis of two phase 2b/3 trials in Japanese and Korean patients.

BACKGROUND: Early onset of action has become recognized as an important efficacy feature of preventive migraine treatment, which can help overcome adherence issues commonly associated with older medications. Preventive treatments that target the calcitonin gene-related peptide (CGRP) or the CGRP receptor have been previously shown to provide early onset of action. METHODS: This subanalysis of primary endpoints of two separate phase 2b/3 studies sought to determine the onset of action of fremanezumab in Japanese and Korean patients with episodic migraine (EM) and chronic migraine (CM). RESULTS: In EM patients (n = 357), both fremanezumab quarterly and fremanezumab monthly led to greater reductions in weekly migraine days (days/week) than placebo from the first week after the initial injection and thereafter during the remainder of the study period. Similarly, CM patients (n = 571) had a greater reduction in headache days of at least moderate severity (days/week) with fremanezumab (total) than placebo. The percentage of patients with a migraine day (EM) or headache day at least moderate severity (CM) was lower in those treated with fremanezumab than placebo and this effect was apparent from as early as Day 2 (1 day after first injection). CONCLUSIONS: These results suggest that fremanezumab has an early onset of action, as noted in previous post hoc analyses of anti-CGRP monoclonal antibodies. TRIAL REGISTRATION: ClinicalTrials.gov. NCT03303092 , Registered 5 October 2017, NCT03303079 , Registered 5 October 2017.

Fremanezumab for the Preventive Treatment of Migraine: Subgroup Analysis by Number of Prior Preventive Treatments with Inadequate Response.

OBJECTIVE: To evaluate the efficacy of monthly or quarterly fremanezumab in patients with chronic migraine or episodic migraine and documented inadequate response to 2, 3, or 4 classes of prior migraine preventive medications. METHODS: This is an exploratory analysis of a randomized, double-blind, placebo-controlled, phase 3b trial for patients with chronic migraine or episodic migraine and inadequate response to 2 to 4 prior migraine preventive medication classes randomized (1:1:1) to fremanezumab (quarterly or monthly) or placebo. In this exploratory analysis, changes from baseline in the monthly average number of migraine days during 12 weeks of double-blind treatment and adverse events were evaluated for predefined subgroups of patients by number of prior preventive medication classes with inadequate response. RESULTS: Overall, 414, 265, and 153 patients had inadequate response to 2, 3, and 4 preventive medication classes, respectively. Changes from baseline in monthly average migraine days during 12 weeks were significantly greater with fremanezumab compared with placebo for patients with documented inadequate response to 2 classes (least-squares mean difference vs placebo [95% confidence interval]: quarterly, -2.9 [-3.83, -1.98]; monthly, -3.7 [-4.63, -2.75]), 3 classes (quarterly, -3.3 [-4.65, -1.95]; monthly, -3.0 [-4.25, -1.66]), and 4 classes (quarterly, -5.3 [-7.38, -3.22]; monthly, -5.4 [-7.35, -3.48]) of migraine preventive medications (all p < 0.001). No significant treatment-by-subgroup interactions were observed for any outcome (p interaction > 0.20 for all). Adverse events were comparable for placebo and fremanezumab. CONCLUSION: Significant improvements in efficacy were observed with fremanezumab compared with placebo, even in patients who had previously experienced inadequate response to 4 different classes of migraine preventive medications.ClinicalTrials.gov identifier: NCT03308968.

Dose selection for fremanezumab (AJOVY) phase 3 pediatric migraine studies using pharmacokinetic data from a pediatric phase 1 study and a population pharmacokinetic modeling and simulation approach.

BACKGROUND: Potential fremanezumab doses for pediatric patients were evaluated using pharmacokinetic modeling and simulation. An open-label phase 1 pharmacokinetic and safety study was conducted in pediatric patients with migraine. This study's results together with refinement of the adult population pharmacokinetic model were used to determine fremanezumab dose recommendations for phase 3 pediatric studies. METHODS: Initial application of the adult model suggested that a 75 mg dose in pediatric patients would match exposures determined safe and efficacious in adults; thus, in the phase 1 study, 15 patients, aged 6-11 years and weighing 17-45 kg received a single subcutaneous 75 mg fremanezumab dose. The sparse pharmacokinetic data collected were used to refine the adult model and simulate concentration-time profiles for monthly subcutaneous doses (60 to 225 mg) in a virtual pediatric population. RESULTS: In the phase 1 pediatric study, the safety profile was similar to that of adults. A two-compartment model with first-order absorption and elimination and body weight effects on clearance and central volume was found to adequately describe the pediatric pharmacokinetic data. CONCLUSIONS: Using exposure matching to the effective adult fremanezumab dose (225 mg subcutaneous monthly), modeling and simulations predict recommended dose of 120 mg in pediatric patients weighing < 45 kg.Registration: The phase 1 study of this report is registered at EudraCT with the identifier 2018-000734-35.

Improvements in quality of life and work productivity with up to 6 months of fremanezumab treatment in patients with episodic and chronic migraine and documented inadequate response to 2 to 4 classes of migraine-preventive medications in the phase 3b FOCUS study.

BACKGROUND: Migraine is associated with depression as well as negative impact on quality of life and work productivity. Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa), selectively targets the calcitonin gene-related peptide and has proven efficacy for the preventive treatment of migraine. OBJECTIVE: In this open-label extension (OLE) of the phase 3b FOCUS study, we assessed patient-reported outcomes (PROs) over time. METHODS: Patients with episodic migraine (EM) and chronic migraine (CM) completing the 12-week, double-blind (DB) period of the FOCUS trial entered the 12-week OLE and received three monthly doses of fremanezumab (225 mg). PROs included the Migraine-Specific Quality of Life (MSQoL) questionnaire (role function-restrictive [RFR], role function-preventive [RFP], and emotional function [EF] domains), EuroQol-5-Dimension-5-Level (EQ-5D-5L) questionnaire, Patient Global Impression of Change (PGIC) assessment, Work Productivity and Activity Impairment (WPAI) questionnaire, and 9-Item Patient Health Questionnaire (PHQ-9). RESULTS: A total of 838 patients were randomized in the DB period, 807 entered the OLE at 3 months, and 772 were still enrolled at 6 months. At 6 months, patients in the quarterly fremanezumab, monthly fremanezumab, and placebo DB randomization groups, respectively, reported improvements in RFR (mean [standard deviation] change from baseline: 24.6 [21.9]; 22.9 [21.3]; 20.8 [26.5]), RFP (19.6 [20.0]; 18.3 [19.7]; 16.0 [19.9]), and EF (22.5 [24.2]; 19.1 [23.6]; 17.2 [24.7]) domains of the MSQoL questionnaire, the EQ-5D-5L questionnaire (8.0 [19.6]; 7.3 [21.1]; 6.6 [21.0]), all four domains of the WPAI questionnaire, and the PHQ-9 (-2.4 [5.3]; -1.6 [5.5]; -2.0 [4.9]); 77.1% (209/271), 75.4% (205/272), and 68.8% (181/263) of patients were identified as PGIC responders. CONCLUSION: Among patients with EM or CM and prior inadequate response to multiple migraine-preventive medication classes, progressive improvements in MSQoL, depression, and work productivity were achieved during 6 months of fremanezumab treatment.

Efficacy and safety of fremanezumab for episodic migraine prevention: Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in Japanese and Korean patients.

OBJECTIVE: To evaluate the efficacy and safety of two dosing regimens of fremanezumab in Japanese and Korean patients with episodic migraine. BACKGROUND: Episodic migraine, which accounts for more than 90% of migraine cases, is inadequately addressed by widely available preventive therapies. Fremanezumab, a monoclonal antibody that selectively targets the trigeminal sensory neuropeptide calcitonin gene-related peptide involved in migraine pathogenesis, has demonstrated efficacy in international Phase 3 trials of patients with both chronic and episodic migraine. METHODS: This Phase 3 randomized, placebo-controlled trial randomly assigned patients with episodic migraine to receive subcutaneous fremanezumab monthly (225 mg at baseline, week 4, and week 8), fremanezumab quarterly (675 mg at baseline and placebo at weeks 4 and 8), or matching placebo. The primary endpoint was the mean change from baseline in the monthly average number of migraine days during the 12-week treatment period after the first dose. RESULTS: Of 357 patients enrolled (safety set, n = 356; full analysis set, n = 354), the least-squares mean (±standard error) reductions in the average number of migraine days per month during 12 weeks were significantly greater with fremanezumab monthly (-4.0 ± 0.4, n = 121) and fremanezumab quarterly (-4.0 ± 0.4, n = 117) than with placebo (-1.0 ± 0.4, n = 116; p < 0.0001 for both comparisons). The proportion of patients reaching at least a 50% reduction in the monthly average number of migraine days during the 12-week period after initial administration was also significantly improved with fremanezumab (fremanezumab monthly, 41.3%; fremanezumab quarterly, 45.3%; placebo, 11.2%; p < 0.0001 for both comparisons) as were other secondary endpoints (p < 0.001 for all comparisons between fremanezumab and placebo). Injection-site reactions were more common in fremanezumab-treated patients (fremanezumab monthly, 25.6%; fremanezumab quarterly, 29.7%; placebo, 21.4%). CONCLUSION: Fremanezumab prevents episodic migraine in Japanese and Korean patients to a similar extent than in previously reported populations with no new safety concerns.

Efficacy and safety of fremanezumab for chronic migraine prevention: Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in Japanese and Korean patients.

OBJECTIVE: To determine the efficacy and safety of fremanezumab administration in Japanese and Korean patients with chronic migraine (CM). BACKGROUND: Available preventive treatments for CM are limited by various efficacy and safety issues. Fremanezumab, a monoclonal antibody that targets the calcitonin gene-related peptide pathway involved in migraine pathogenesis, has been shown to be effective and well tolerated in large-scale, international Phase 3 trials. METHODS: Randomized, placebo-controlled trial of patients with CM who received subcutaneous fremanezumab monthly (675 mg at baseline and 225 mg at weeks 4 and 8), fremanezumab quarterly (675 mg at baseline and placebo at weeks 4 and 8), or matching placebo. Primary endpoint was the mean change from baseline in the monthly (28-day) average number of headache days of at least moderate severity during the 12 weeks after the first dose. RESULTS: Among 571 patients randomized (safety set, n = 569; full analysis set, n = 566), the least-squares mean (±standard error [SE]) reduction in the average number of headache days of at least moderate severity per month during 12 weeks was significantly greater with fremanezumab monthly (-4.1 ± 0.4) and fremanezumab quarterly (-4.1 ± 0.4) than with placebo (-2.4 ± 0.4). The difference from the placebo group in the mean change (95% confidence interval [CI]) was -1.7 days (-2.54, -0.80) for the fremanezumab monthly group and -1.7 days (-2.55, -0.82) for the fremanezumab quarterly group (p < 0.001 vs. placebo for both fremanezumab groups). The percentage of patients with a ≥50% reduction in the average number of headache days of at least moderate severity per month (response rate) was higher with fremanezumab monthly (29.0%) and fremanezumab quarterly (29.1%) than with placebo (13.2%) in addition to other improvements in secondary endpoints, including reduction of acute medication use (mean change from baseline during 12-week period ± SE: fremanezumab monthly, -3.7 ± 0.4; fremanezumab quarterly, -3.9 ± 0.4; placebo, -2.4 ± 0.4) and improvements in disability scores (mean change from baseline in six-item Headache Impact Test score at 4 weeks after third injection ± SE: fremanezumab monthly, -8.1 ± 0.7; fremanezumab quarterly, -8.0 ± 0.7; placebo, -6.5 ± 0.7). Fremanezumab was well tolerated with a similar incidence of adverse events including injection-site reactions as placebo (patients with at least one treatment-emergent adverse event: fremanezumab total, n = 232 [61.4%]; placebo, n = 118 [61.8%]). CONCLUSION: Fremanezumab effectively prevents CM in Japanese and Korean patients and was well tolerated. No safety signal was detected.

Impact of age and sex on the efficacy of fremanezumab in patients with difficult-to-treat migraine: results of the randomized, placebo-controlled, phase 3b FOCUS study.

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.

Immunogenicity of biologic therapies for migraine: a review of current evidence.

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.

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 .

Efficacy and safety of fremanezumab in patients with episodic and chronic migraine with documented inadequate response to 2 to 4 classes of migraine preventive medications over 6 months of treatment in the phase 3b FOCUS study.

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).

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.

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 .

Fremanezumab versus placebo for migraine prevention in patients with documented failure to up to four migraine preventive medication classes (FOCUS): a randomised, double-blind, placebo-controlled, phase 3b trial.

BACKGROUND: Antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor have shown efficacy in the prevention of migraine attacks. We investigated the efficacy and tolerability of fremanezumab, a fully humanised CGRP antibody, in patients with migraine who had previously not responded to two to four classes of migraine preventive medications. METHODS: The randomised, double-blind, placebo-controlled, parallel-group, phase 3b FOCUS trial was done at 104 sites (including hospitals, medical centres, research institutes, and group practice clinics) across Belgium, the Czech Republic, Denmark, Finland, France, Germany, Italy, the Netherlands, Poland, Spain, Sweden, Switzerland, the UK, and the USA. We enrolled participants aged 18-70 years with episodic or chronic migraine who had documented failure to two to four classes of migraine preventive medications in the past 10 years. Failure was defined as no clinically meaningful improvement after at least 3 months of therapy at a stable dose, as per the treating physician's judgment; discontinuation because of adverse events that made treatment intolerable; or treatment contraindicated or unsuitable for the preventive treatment of migraine for the patient. Participants were randomly assigned (1:1:1) by electronic interactive response technology to subcutaneously administered quarterly fremanezumab (month 1, 675 mg; months 2 and 3: placebo), monthly fremanezumab (month 1: 225 mg in episodic migraine and 675 mg in chronic migraine; months 2 and 3: 225 mg in both migraine subgroups), or matched monthly placebo for 12 weeks. The primary outcome was mean change from baseline in the monthly average number of migraine days during the 12-week treatment period. This trial is registered with ClinicalTrials.gov, number NCT03308968, and is now completed. FINDINGS: Between Nov 10, 2017, and July 6, 2018, 838 participants with episodic (329 [39%]) or chronic (509 [61%]) migraine were randomly assigned to placebo (n=279), quarterly fremanezumab (n=276), or monthly fremanezumab (n=283). Reductions from baseline in monthly average migraine days over 12 weeks were greater versus placebo (least-squares mean [LSM] change -0·6 [SE 0·3]) with quarterly fremanezumab (LSM change -3·7 [0·3]; LSM difference vs placebo -3·1 [95% CI -3·8 to -2·4]; p<0·0001) and with monthly fremanezumab (LSM change -4·1 [0·34]; LSM difference vs placebo -3·5 [-4·2 to -2·8]; p<0·0001). Adverse events were similar for placebo and fremanezumab. Serious adverse events were reported in four (1%) of 277 participants with placebo, two (<1%) of 276 with quarterly fremanezumab, and four (1%) of 285 with monthly fremanezumab. INTERPRETATION: Fremanezumab was effective and well tolerated in patients with difficult-to-treat migraine who had previously not responded to up to four classes of migraine preventive medications. FUNDING: Teva Pharmaceuticals.