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Introduction: Through 2018, three calcitonin gene-related peptide pathway–targeted monoclonal antibodies (CGRP mAbs) had received US Food and Drug Administration (FDA) approval for migraine prevention: erenumab, fremanezumab, and galcanezumab. Methods: This retrospective analysis evaluated adverse events (AEs) spontaneously reported to the FDA Adverse Event Reporting System (FAERS) safety surveillance database during the first 6 months post-approval of erenumab (May 2018 to November 2018), fremanezumab (September 2018 to March 2019), and galcanezumab (September 2018 to March 2019). Reporting rates (RR) per 1000 exposed patients were calculated from number of reported events (when product classified as "primary suspect") in each AE category and estimated number of treated patients based on de-identified prescription data (IQVIA database) and were ranked on the basis of frequency for each product. Results: RR per 1000 exposed patients for "migraine" (erenumab, 4.89; fremanezumab, 1.01; galcanezumab, 2.99), "headache" (3.32, 1.27, 3.07), and "drug ineffective" (3.68, 1.14, 1.69) were commonly reported for all three products, as were migraine-associated symptoms ("nausea": 2.94, 0.91, 1.09) and "injection-site" reactions ("pain": 2.94, 0.8, 4.9; "swelling": 0.56, 0.53, 1.25; "pruritus": 0.26, 0.63, 1.14; "erythema": 0.58, 0.71, 1.58). "Constipation" ranked second for erenumab (4.90) but did not make the top ten events for fremanezumab (0.46) or galcanezumab (0.76); cardiovascular events did not rank in the top ten AEs for any product. The frequency of serious outcomes was low, with ≤ 2% of AEs categorized as serious across the CGRP mAbs. Conclusion: These results aid in supporting the safety profile of CGRP mAbs in the real-world setting and may provide clinicians and patients with additional insight when considering migraine preventive treatments. [ABSTRACT FROM AUTHOR]

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]

Background: The efficacy and tolerability of fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP) and is approved for the preventive treatment of migraine in adults, have been demonstrated in randomized, double-blind, placebo-controlled trials. Real-world data can further support those clinical trial data and demonstrate the full clinical benefits of fremanezumab. This chart review assessed the effectiveness of fremanezumab for improving clinical outcomes in adult patients with migraine treated according to real-world clinical practice. Methods: This retrospective, panel-based, online physician chart review study used electronic case report forms with US physicians. Patient inclusion criteria were a physician diagnosis of migraine, fremanezumab treatment initiation at ≥ 18 years of age after US Food and Drug Administration approval, ≥ 1 dose of fremanezumab treatment, and ≥ 2 assessments of monthly migraine days (MMD; 1 within 30 days before treatment initiation and ≥ 1 after initiation). Changes from baseline in MMD, monthly headache days (MHD), and Migraine Disability Assessment (MIDAS) and 6-item Headache Impact Test (HIT-6) scores were assessed over 6 months. These endpoints were evaluated in the overall population and subgroups divided by dosing schedule and number of prior migraine preventive treatment failures. Results: This study included data from 421 clinicians and 1003 patients. Mean age at fremanezumab initiation was 39.7 years, and most patients were female (75.8%). In the overall population, mean baseline MMD and MHD were 12.7 and 14.0, respectively. Mean (percent) reductions from baseline in MMD and MHD, respectively, were − 4.6 (36.2%) and − 4.7 (33.6%) at Month 1, − 6.7 (52.8%) and − 6.8 (48.6%) at Month 3, and − 9.2 (72.4%) and − 9.8 (70.0%) at Month 6. Mean (percent) reductions from baseline in MIDAS and HIT-6 scores also increased over the 6-month study period, from − 6.2 (21.6%) and − 8.4 (14.0%) at Month 1 to − 18.1 (63.1%) and − 16.2 (27.0%) at Month 6, respectively. Improvements in these outcomes over 6 months were observed across all evaluated subgroups. Conclusions: This real-world study demonstrated effectiveness of fremanezumab treatment for up to 6 months, irrespective of dosing regimen or number of prior migraine preventive treatment failures, reflecting ongoing, clinically meaningful improvements in patient outcomes. [ABSTRACT FROM AUTHOR]

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: 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]

Background: Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway, including the fully humanized monoclonal antibody (IgG2Δa) fremanezumab, have demonstrated safety and efficacy for migraine prevention. Clinical trials include responders and nonresponders; efficacy outcomes describe mean values across both groups and thus provide little insight into the clinical benefit in responders. Clinicians and their patients want to understand the extent of clinical improvement in patients who respond. This post hoc analysis of fremanezumab treatment attempts to answer this question: what is the benefit in subjects who responded to treatment during the two, phase 3 HALO clinical trials? Methods: We included subjects with episodic migraine (EM) or chronic migraine (CM) who received fremanezumab quarterly (675 mg/placebo/placebo) or monthly (EM: 225 mg/225 mg/225 mg; CM: 675 mg/225 mg/225 mg) during the 12-week randomized, double-blind, placebo-controlled HALO EM and HALO CM clinical trials. EM and CM responders were defined as participants with a reduction of ≥ 2 or ≥ 4 monthly migraine days, respectively. Treatment benefits evaluated included reductions in monthly migraine days, acute headache medication use, and headache-related disability, and changes in health-related quality of life (HRQoL). Results: Overall, 857 participants from the HALO trials were identified as responders (EM: 429 [73.8%]; CM: 428 [56.7%]). Reductions in the monthly average number of migraine days were greater among EM (quarterly: 5.4 days; monthly: 5.5 days) and CM (quarterly: 8.7 days; monthly: 9.1 days) responders compared with the overall population. The proportion of participants achieving ≥ 50% reduction in the average monthly number of migraine days was also greater in responders (EM: quarterly, 59.8%; monthly, 63.7%; CM: quarterly, 52.8%; monthly, 59.0%) than in the overall population. Greater reductions in the average number of days of acute headache medication use, greater reductions in headache-related disability scores, and larger improvements in HRQoL were observed among EM and CM responders compared with the overall populations. Conclusions: Fremanezumab responders achieved clinically meaningful improvements in all outcomes. The magnitude of improvements with fremanezumab across efficacy outcomes was far greater in responders than in the overall trial population, providing insight into expected treatment benefits in participants who respond to fremanezumab in clinical practice. Trial registration: ClinicalTrials.gov identifiers: NCT02629861 (HALO EM) and NCT02621931 (HALO CM). [ABSTRACT FROM AUTHOR]

Background: We evaluated the efficacy of fremanezumab, a fully humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, in patients with chronic migraine (CM) with and without medication overuse (MO). Methods: In a 12-week, phase 3 trial, patients with CM were randomized to fremanezumab quarterly (675 mg/placebo/placebo), monthly (675 mg/225 mg/225 mg), or placebo. Post hoc analyses assessed the impact of fremanezumab in patients with and without MO (monthly use of acute headache medication ≥15 days, migraine-specific acute medication ≥10 days, or combination medication ≥10 days) on efficacy outcomes, including headache days of at least moderate severity (HDs), and six-item Headache Impact Test (HIT-6) and Migraine-Specific Quality of Life (MSQoL) questionnaire scores. Results: Of 1130 patients enrolled, 587 (51.9%) had baseline MO. Fremanezumab reduced placebo-adjusted least-squares mean (95% confidence interval) monthly HDs (− 2.2 [− 3.1 to − 1.2] and − 2.7 [− 3.7 to − 1.8]; P < 0.0001) in patients with MO and without MO (quarterly − 1.4 [− 2.3 to − 0.5], P = 0.0026; monthly − 1.4 [− 2.3 to − 0.6], P = 0.0017). Significantly more fremanezumab-treated patients had ≥ 50% reduction in HDs versus placebo, regardless of baseline MO (with: quarterly 70/201 [34.8%], monthly 78/198 [39.4%] vs placebo 26/188 [13.8%]; without: quarterly 71/174 [40.8%], monthly 75/177 [42.4%] vs placebo 41/183 [22.4%]). Fremanezumab improved HIT-6 and MSQoL scores. Significantly more fremanezumab-treated patients reverted to no MO (quarterly 111/201 [55.2%], monthly 120/198 [60.6%]) versus placebo (87/188 [46.3%]). Conclusions: Fremanezumab is effective for prevention of migraine in patients with CM, regardless of MO, and demonstrated a benefit over placebo in reducing MO. Trial registration: ClinicalTrials.gov NCT02621931 (HALO CM), registered December 12, 2012. [ABSTRACT FROM AUTHOR]

Background: Adherence to a therapy, though a key factor for successful treatment, is low among patients with chronic conditions such as migraine. Dose frequency plays a major role in adherence. This study evaluated the impact of having flexible dosing options on acceptance of and adherence to a new migraine preventive therapy class among adults with migraine. Methods: In this observational study, two 20-min online surveys were completed: one by physicians currently treating adult patients with migraine and the other by adults with migraine. Both surveys presented the participants with three scenarios: 1) only monthly, 2) only quarterly, and 3) both dosing options of the new medication are available. Physicians estimated the proportion of their migraine patients who would receive the new medication in each scenario. Patients were asked about their dosing preference when either or both options are available. Respondents were asked to rate the likelihood of their acceptance of and adherence to the therapy. Results: 400 physicians and 417 US adults with migraine completed the surveys. The availability of both dosing options yielded a significant increase in the proportion of patients expected to receive the new medication. The overall proportion of patients favoring monthly dosing (35%) was similar to the proportion favoring quarterly dosing (40%). Among those who preferred monthly dosing (n = 147), a greater proportion indicated they are more likely to fill the prescription (77% vs 56%, P < 0.05) and remain adherent (80% vs 57%, P < 0.05) when only monthly is available versus when only quarterly is available. Similarly, among those who preferred quarterly dosing (n = 166), a greater proportion indicated they are likely to fill (63% vs 55%, P < 0.05) and remain adherent (62% vs 54%, P < 0.05) when only quarterly is available compared with when only monthly is available. Conclusions: Physicians anticipated that the proportion of patients to receive the new medication would increase when both dosing options are available. Patients stated that they are more likely to fill the prescription and adhere to the new therapy when their preferred dosing regimen is available. [ABSTRACT FROM AUTHOR]