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Patients with long-term tricuspid regurgitation (TR) are mostly accompanied by hepatic, cardiac, and venous remodeling. Transcatheter tricuspid valve replacement (TTVR) device has emerged as a promising alternative to open-heart surgery for TR patients. No study has assessed the impact of TTVR on hepatic, cardiac, and venous remodeling.Twenty-two patients with TR enrolled in this study underwent TTVR between October 2020 and January 2021. Liver, heart, and veins were reconstructed by three-dimensional computed tomography reconstruction software at baseline and 6 months follow-up.Twenty-two patients were enrolled in this study. The mean age was 64.8 ± 8.2 years, and all patients had severe or greater TR with multiple comorbidities. The left hepatic lobe volume decreased from 518.8 ± 171.9 ml to 470.4 ± 179.6 ml at 6 months during follow-up (p = 0.049). Evidence of a decrease in three hepatic veins parameters and splenic vein parameters was noted from baseline to 6 months. And a significant decrease in right atrial volume (317.5 ml [interquartile range: 216.1 to 497.3 ml] vs. 266.7 ml [interquartile range: 178.7 to 480.7 ml]; p = 0.003) were observed in the study.Six-month outcomes show that TR elimination by LuX-Valve is associated with the reverse remodeling of liver, heart, and veins. Accordingly, LuX-Valve is a promising alternative for patients presenting with severe TR.

Fremanezumab is a humanized monoclonal antibody against calcitonin gene-related peptide for subcutaneous use to suppress migraine attacks. A phase 3 study was conducted to investigate the safety of autoinjector (AI)-assisted self-injection of fremanezumab 225 mg.The multicenter, open-label study involving 71 patients with migraine was conducted between June 2020 and November 2020 at ten institutions in Japan. The study consisted of a 4-week (28-day) screening period and an 8-week (57-day) treatment period. According to the investigator's instructions, all patients successfully performed self-injection for 4 weeks at the institutional site and at home and maintained eDiaries of their headaches. The primary endpoint was safety of the drug based on treatment-emergent adverse events (TEAEs).Treatment-emergent adverse events were more frequent after at-home injection than after at-site injection, but they were mainly injection site reactions and mostly mild. The safety profile was comparable, raising no concerns compared with what has been reported in previous studies. Both migraine days and headache days were decreased considerably.Overall, AI-assisted, at-home self-injection of fremanezumab was found to be generally safe and well-tolerated. This injection strategy is considered clinically meaningful in view of improved utility of and adherence to the drug.

Kazumasa Saigoh,1 Takao Takeshima,2 Masami Nakai,3 Yoshiyuki Shibasaki,4 Miki Ishida,5 Xiaoping Ning,6 Steve Barash,6 Yuki Isogai,4 Nobuyuki Koga7 1Department of Neurology, Kindai University School of Medicine, Osaka, Japan; 2Headache Center, Department of Neurology, Tominaga Hospital, Osaka, Japan; 3Medical Affairs, Otsuka Pharmaceutical Co., Ltd., Osaka, Japan; 4Medical Affairs, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan; 5Headquarters of Clinical Development, Otsuka Pharmaceutical Co., Ltd., Osaka, Japan; 6Teva Branded Pharmaceutical Products R&D, Inc., West Chester, PA, USA; 7Medical Affairs, Otsuka Pharmaceutical Co., Ltd., Tokushima, JapanCorrespondence: Masami Nakai, Medical Affairs, Otsuka Pharmaceutical Co., Ltd., 3-2-27 Otedori, Chuo-ku, Osaka, 540-0021, Japan, Tel +81-80-9026-3806, Email nakai.masami@otsuka.jpPurpose: Fremanezumab monoclonal antibody therapy has demonstrated efficacy for chronic migraine (CM) with rapid onset and good tolerability. This subgroup analysis of two clinical trials (Japanese and Korean CM Phase 2b/3 [NCT03303079] and HALO CM Phase 3 [NCT02621931]) aimed to evaluate the efficacy and safety of fremanezumab in Japanese patients.Patients and Methods: Both trials randomly assigned eligible patients at baseline (1:1:1 ratio) to subcutaneous monthly fremanezumab, quarterly fremanezumab, or placebo at 4-week intervals. The 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-week period after the first dose of study medication (analyzed by ANCOVA over 12 weeks and MMRM over initial 4 weeks). Secondary endpoints examined other aspects of efficacy, including medication use and disability.Results: A total of 479 and 109 patients were Japanese in the Japanese and Korean CM Phase 2b/3 and HALO CM trials, respectively. Baseline and treatment characteristics were generally similar between treatment groups for both trials. Results of subgroup analyses for the primary endpoint according to ANCOVA demonstrated the superiority of fremanezumab over placebo in Japanese patients (quarterly fremanezumab, p=0.0005; monthly fremanezumab, p=0.0002 in both trials). Results using the MMRM analysis confirmed the rapid onset of action in this population. Results of the secondary endpoints further supported the efficacy of fremanezumab in Japanese patients. Fremanezumab was well tolerated with nasopharyngitis and injection-site reactions representing the most common adverse events in all treatment groups.Conclusion: Despite the limitations of subgroup analyses, these consistent results confirm the efficacy and tolerability of fremanezumab in Japanese patients with CM.Keywords: calcitonin gene-related peptide, chronic migraine, fremanezumab, Japanese

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.

Introduction Early discontinuation and poor adherence are common limitations of conventional preventive migraine medications that limit their long-term efficacy. Therefore, a migraine preventive medication with favorable long-term safety is warranted. Objective This study aimed to evaluate the long-term safety and tolerability of fremanezumab for the preventive treatment of chronic or episodic migraine in Japanese patients. Methods In this 52-week, randomized, open-label, parallel-group study, fremanezumab monthly or quarterly was administered in newly enrolled Japanese patients with chronic migraine or episodic migraine. Safety was assessed by monitoring of treatment-emergent adverse events, including injection-site reactions, laboratory and vital sign assessments. Newly enrolled patients and rollover patients from previous phase IIb/III trials who did not receive fremanezumab in this study were included in the immunogenicity testing cohort (n = 587). Efficacy outcomes included changes from baseline in the average monthly migraine days and headache days of at least moderate severity. Other efficacy outcomes included changes in disability scores. Results A total of 50 patients were enrolled with chronic migraine (monthly, n = 17; quarterly, n = 17) or episodic migraine (monthly, n = 8; quarterly, n = 8). The most commonly reported treatment-emergent adverse events were nasopharyngitis (64.0%) and injection-site reactions (erythema, 24.0%; induration, 10.0%; pain, 8.0%; pruritus, 6.0%). The discontinuation rate was low (4.0% from adverse events, 2.0% from a lack of efficacy) and no deaths were reported. The incidence of anti-drug antibody development was low (2.4%). Fremanezumab reduced monthly migraine days and headache days of at least moderate severity from 1 month after initial administration, and this effect was maintained with no worsening throughout 12 months. Fremanezumab also led to sustained reductions in any acute headache medication use and headache-related disability at 12 months. Conclusions Fremanezumab administered monthly and quarterly was well tolerated in patients with chronic migraine and episodic migraine and led to sustained improvements in monthly migraine days and headache days of at least moderate severity throughout 12 months. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT03303105. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01119-2.

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.

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

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

ObjectiveTo assess the long-term safety, tolerability, and efficacy of fremanezumab, a fully humanized monoclonal antibody approved for the preventive treatment of migraine.MethodsA 52-week, multicenter, randomized, double-blind, parallel-group study evaluated fremanezumab monthly or quarterly in adults with chronic migraine (CM) or episodic migraine (EM). Safety and tolerability were assessed by adverse event (AE) monitoring (performed by the investigators), systematic local injection-site assessments (immediately and 1 hour after injection), laboratory/vitals assessments, and immunogenicity testing. Prespecified exploratory evaluations included change from baseline in the monthly number of migraine days, headache days of at least moderate severity, and days with any acute headache medication use. Change from baseline in headache-related disability (6-item Headache Impact Test scores) was also measured.ResultsOf 1,890 patients enrolled, 551 and 559 patients with CM received quarterly and monthly dosing; 394 and 386 patients with EM received quarterly or monthly, respectively. The most commonly reported AEs were injection-site reactions (induration 33%, pain 31%, and erythema 26%). Fremanezumab reduced monthly migraine days (CM quarterly −7.2 days, CM monthly −8.0 days, EM quarterly −5.2 days, EM monthly −5.1 days) and headache days of at least moderate severity (CM quarterly −6.4 days, CM monthly −6.8 days, EM quarterly −4.4, EM monthly −4.2 days) from baseline to 12 months. Reductions in any acute headache medication use and headache-related disability were also maintained over 12 months.ConclusionsFremanezumab quarterly and fremanezumab monthly were well tolerated and demonstrated sustained improvements in monthly migraine days, headache days, and headache-related disability for up to 12 months in patients with migraine.ClinicalTrials.govNCT02638103.Classification of evidenceThis study provides Class IV evidence that long-term fremanezumab treatment is safe, well tolerated, and effective at sustaining reductions in monthly migraine and headache days.

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.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.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.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.

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 (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 )

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 P P 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.

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.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.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]; p0·0001) and with monthly fremanezumab (LSM change -4·1 [0·34]; LSM difference vs placebo -3·5 [-4·2 to -2·8]; p0·0001). 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.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.Teva Pharmaceuticals.

Recently, Gao et al. published an article titled “Monthly versus quarterly fremanezumab for the prevention of migraine: a systemic review and meta-analysis from randomized controlled trials” which concluded that monthly administration of fremanezumab led to significant reduction in monthly migraine days (MMD) when compared to quarterly fremanezumab. We have noted a critical flaw in Gao et al. meta-analysis wherein the authors have mistakenly utilized standard error values in place of standard deviation values in performing their pooled analyses. This error directly impacts the study results and conclusions. In this brief communication, we present revised analysis using correct methods. Using the correct SD values, our pooled analysis showed no significant difference in mean change from baseline in MMD between the two fremanezumab dosing regimens (P = 0.17). Furthermore, in the corrected subgroup analyses by type of migraine, there were no significant differences in mean change from baseline in MMD between monthly fremanezumab and quarterly fremanezumab (chronic migraine, P = 0.50; episodic migraine, P = 0.69). Overall, results from our corrected meta-analyses show that there is no significant difference in migraine prevention efficacy between monthly and quarterly fremanezumab dosing.

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

The FOCUS phase 3b study evaluated the long-term efficacy of fremanezumab in patients with chronic or episodic migraine (CM/EM) and prior documented inadequate response to 2-4 preventive treatment classes during 12-week double-blind period (DBP) and open-label extension (OLE).Following 28-day baseline period, patients were randomised (1:1:1) to quarterly or monthly fremanezumab or placebo for DBP. Patients completing DBP entered OLE, where all patients received treatment with monthly fremanezumab. Outcomes are summarised by DBP group.During DBP, least squares mean changes in monthly migraine days (MMD) in placebo, quarterly, and monthly fremanezumab groups, respectively, were –0.8, –3.9, and –4.5 for CM patients (n=509) and –0.6,–3.7, and –3.8 for EM patients (n=328; P–5.1, and –5.8 for CM patients (n=493) and –3.9, –5.1, and –5.1 for EM patients (n=313). Reductions were also observed for CM and EM patients in monthly headache days of at least moderate severity during DBP and increased during OLE. In placebo, quarterly, and monthly fremanezumab groups, respectively, for DBP, ≥50% reduction in MMD were 8%, 27%, and 29% for CM patients and 10%, 47%, and 43% for EM patients (PFremanezumab demonstrated long-term efficacy in CM and EM patients with prior inadequate response to multiple preventive classes.

BackgroundMonoclonal 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.FindingsThe 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 ConclusionsAs 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.

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 0.20 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.

Additional file 3. Mean (SD) Monthly Migraine Days and Headache Days of at Least Moderate Severity at Baseline.

Supplemental material, sj-pdf-1-cep-10.1177_03331024211007789 for 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 by Orit Cohen-Barak, Andrijana Radivojevic, Aksana Jones, Jill Fiedler-Kelly, Michael Gillespie, Michael Brennan, Dikla Gutman, Michele Rasamoelisolo, Hussein Hallak, Pippa Loupe, Yoel Kessler, Xiaoping Ning, Micha Levi, Andrew H Ahn and Laura Rabinovich-Guilatt in Cephalalgia

Additional file 5. Safety in Patients From Europe and the United States. Injection-site adverse events in patients from Europe and the United States by treatment group.

Additional file 1: Supplemental Methods. Description of outcomes and statistical analyses for secondary endpoints, prespecified evaluations, and safety analyses.

Additional file 4. Change in Patient-reported Outcomes 4 Weeks After the Third Dose of Study Drug. Change in 6-item Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) scores and Patient Global Impression of Change (PGIC) responder rates from baseline to 4 weeks after the third dose of study drug. PGIC responder was defined as a patient who reported a rating of 5 to 7 (moderately better, better, or a great deal better) on the PGIC.

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 P P 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.

ObjectiveTo evaluate adverse events (AEs) in a subgroup of migraine patients with baseline cardiovas- cular (CV) medication use in this pooled analysis of three phase 3 trials of fremanezumab.MethodsThis analysis included data from the HALO EM, HALO CM, and FOCUS studies, in which patients were randomized 1:1:1 to subcutaneous quarterly or monthly fremanezumab or matched placebo over 12 weeks. AEs were evaluated for patients with baseline CV medication use.ResultsOverall, 280 of 2,842 patients (9–11% across treatment groups) in this pooled population were receiving CV medications at baseline, most commonly agents acting on the renin-angiotensin system (3–4%) and beta-blockers (3–4%). In the placebo, quarterly fremanezumab, and monthly fremanezumab groups, respectively, 53%, 66%, and 64% of patients reported at least 1 AE, and the most common AEs were injection-site-related (pain [19%, 29%, and 20%], erythema [10%, 20%, and 13%], and induration [8%, 18%, and 24%]). Cardiovascular AEs (CVAEs) were infrequent; no individual CVAE was reported for >1 patient in any treatment group. No safety signals were identified.ConclusionIn this pooled analysis, fremanezumab treatment was well tolerated over 12 weeks, with low incidences of CVAEs, comparable to placebo, in patients with migraine using CV medications at baseline.JMarzella@cellohealth.com52

ObjectiveTo evaluate efficacy of fremanezumab in a subgroup of chronic migraine (CM) patients with inadequate response to ≥3 migraine preventive medication classes (CM ≥3 inadequate responses subgroup) from the double-blind, phase 3b FOCUS study.MethodsIn FOCUS, patients with inadequate response to 2–4 migraine preventive treatment classes were randomized (1:1:1) to quarterly fremanezumab, monthly fremanezumab, or placebo for 12 weeks. Changes in monthly migraine days (MMD), 6-item Headache Impact Test (HIT-6) score, and monthly days using acute headache medication and response rates (≥30% reduction in MMD), were evaluated in CM≥3 inadequate responses subgroup.ResultsOf 838 randomized patients, 293 were included in this analysis. Change from baseline in MMD over 12 weeks was significantly greater with fremanezumab (LSM[SE]: quarterly, −4.0[0.56]; monthly, −4.1[0.56]) versus placebo (−1.0[0.59]; PConclusionsIn CM patients with inadequate response to ≥3 migraine preventive medication classes, fremanezumab was well tolerated and effective.mknagge@cellohealth.com53

Objective Presentation of pooled analysis of safety data for fremanezumab in patients with chronic (CM) or episodic migraine (EM) from 4 placebo-controlled phase 2b and phase 3 studies. Background There is a need for an effective, safe, and well-tolerated preventive therapy that specifically targets the pathophysiology of migraine to reduce the frequency and severity of migraine attacks in patients with CM or EM who experience 4 or more migraine days per month. Fremanezumab is a fully humanized monoclonal antibody that targets calcitonin gene-related peptide, a neuropeptide involved in the pathophysiology of migraine. Design/methods The 4 placebo-controlled phases 2b and 3 studies included in this analysis were 16-week, multicenter, randomized, double-blind, placebo-controlled, and parallel-group studies consisting of a screening visit, a 28-day pretreatment baseline period, and a 12-week treatment period with a final evaluation 4 weeks after the final dose of the study drug. Safety endpoints included adverse events (AEs) and immunogenicity. Results A total of 2566 patients were randomized across all studies (fremanezumab, n = 1704; placebo, n = 862), and 2563 patients were treated. Common reasons for study discontinuation were withdrawal by patient (n = 78), patient lost to follow-up (n = 60), and AE (n = 50). The mean (standard deviation) duration of exposure was 83.8 (13.6) days for the patients who received fremanezumab, with a total exposure of 390.4 patient years and maximum exposure of 181 days. AEs were mostly mild to moderate in severity and were reported among 48-69% of patients in all treatment groups, and most were injection site reactions (pain, induration, and erythema). Two deaths occurred (chronic obstructive pulmonary disease and intentional overdose of diphenhydramine), both of which were deemed unrelated to study drug by the investigators and sponsor. Cardiovascular adverse events, abnormal liver function tests, and hypersensitivity were uncommon and occurred at similar rates between the placebo and fremanezumab groups. Conclusions Fremanezumab is a generally safe and well-tolerated preventive therapy for migraine in adults.