AimFremanezumab is approved for migraine prevention in Europe, the United States (US), Japan, South Korea, and several other countries; however, there are no data available on fremanezumab as a migraine preventive treatment in a Chinese population. This study evaluated the efficacy and safety of fremanezumab in Chinese adults with migraine.MethodsThis randomized, multicenter, Phase 3 trial consisted of a 4-week screening period, a 12-week double-blind period (DBP), and a 12-week open-label extension (OLE). Chinese adults with episodic and chronic migraine were randomized 1:1:2 to receive fremanezumab monthly (225 mg), fremanezumab quarterly (675 mg), or matched monthly placebo during the DBP. During the OLE, all participants received fremanezumab monthly (225 mg). The primary endpoint was mean change from baseline in monthly migraine days (MMD) during the DBP. Secondary endpoints included mean change from baseline in migraine days during the first 4 weeks of treatment and in monthly number of days with acute headache medication use during the DBP. Similar endpoints were assessed during the OLE. Safety assessments included, but were not limited to, adverse event (AE) reporting.ResultsIn total, 365/454 screened participants were randomized to fremanezumab (n = 182 [monthly, n = 91; quarterly, n = 91]) or placebo (n = 183). Significantly greater changes from baseline in MMD were observed with fremanezumab versus placebo during the DBP (-4.6 vs -2.8; p < 0.0001) and in mean migraine days during the first 4 weeks of treatment (-4.5 vs -2.2; p < 0.0001). The mean change from baseline in days of acute headache medication use during the DBP was -3.0 with fremanezumab and -1.1 for placebo (p < 0.0001). During the OLE, the mean change from baseline in MMD was -6.8 and -7.2 for those assigned to fremanezumab and placebo, respectively, during the DBP. The percentage of participants with any AE was similar between fremanezumab and placebo groups during the DBP (47% vs 43%); serious AEs were infrequent (fremanezumab, 1%; placebo, <1%). Similar trends in AEs were observed during the OLE.ConclusionIn this study, fremanezumab demonstrated significant improvements over placebo with respect to reductions in MMD and days with acute headache medication use, with these reductions being maintained over the OLE. Fremanezumab demonstrated a favorable safety profile, with no safety signals. These results are comparable to pivotal adult trials in Europe and the US, supporting the use of fremanezumab in Chinese adults living with migraine.Clinical trial pre-registrationClinicalTrials.gov identifier: NCT05458011; submitted: 11 July 2022; first participant enrolled: 30 September 2022; available at: https://clinicaltrials.gov/study/NCT05458011; first submitted: 11 July 2022).

BACKGROUND:Fremanezumab, a humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, is approved for the prevention of migraine in adults. Evidence from randomized, controlled trials in children and adolescents is needed. METHODS:We randomly assigned participants 6 to 17 years of age with a diagnosis of episodic migraine (defined as migraine for ≥6 months and a history of ≤14 headache days per month) to receive monthly subcutaneous injections of fremanezumab (120 mg for participants with a body weight of <45 kg and 225 mg for those with a body weight of ≥45 kg) or matched placebo for 3 months. Participants were allowed to use migraine-specific medications to treat acute headaches. The primary end point was the change from baseline in the average number of migraine days per month. Key secondary end points included the change in the number of days per month with headache of at least moderate severity and a reduction of 50% or more in the number of migraine days per month. RESULTS:Of 237 participants who underwent randomization, 234 were included in the full analysis population: 123 in the fremanezumab group (36 received the 120-mg dose and 87 received the 225-mg dose) and 111 in the placebo group. Fremanezumab reduced the number of migraine days per month by 2.5 as compared with 1.4 with placebo (difference, 1.1; P = 0.02) and the number of days per month with headache of at least moderate severity by 2.6 as compared with 1.5 with placebo (difference, 1.1; P = 0.02). The percentage of participants who had a reduction of 50% or more in the number of migraine days per month was 47.2% with fremanezumab and 27.0% with placebo (P = 0.002). Injection-site erythema was the most common adverse event with fremanezumab (9.8% of participants, vs. 5.4% with placebo). CONCLUSIONS:Among children and adolescents with episodic migraine, fremanezumab resulted in greater reductions in the number of migraine days and headache days than placebo. Injection-site erythema was the most common adverse event with fremanezumab. Longer follow-up is required to further understand the efficacy and safety of the drug in this population. (Funded by Teva Pharmaceuticals; ClinicalTrials.gov number, NCT04458857.).

This pooled analysis of data from 3 randomized, double-blind, placebo-controlled phase 3 trials (HALO chronic migraine [CM], HALO episodic migraine [EM], and FOCUS) evaluated timing and location of injection-site adverse events (AEs).

Calcitonin gene-related peptide (CGRP) pathway-targeted treatments have been shown to be efficacious in the prevention of episodic and chronic migraine. Currently approved therapies include monoclonal antibodies (mAbs) that target CGRP (eptinezumab, fremanezumab, and galcanezumab) and the CGRP receptor (erenumab), and small molecule CGRP receptor antagonists (atogepant and rimegepant). While CGRP pathway–targeted treatments are generally well-tolerated, in a review article by Holzer and Holzer-Petsche published in the January 2022 issue of Frontiers in Physiology the authors discussed the role of the CGRP pathway in gastrointestinal physiology, with a specific focus on constipation associated with the use of CGRP pathway–targeted treatments. The authors state that real-world surveys have shown constipation to be a “major adverse event” reported in “more than 50% of patients treated with erenumab, fremanezumab or galcanezumab.” As described in the current commentary, the limited data from the cited references in the review article by Holzer and Holzer-Petsche do not support that statement.

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. 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. 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

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

This analysis used data pooled from phase 3 studies (HALO EM/CM/LTS and FOCUS double-blind period [DBP]/open-label extension [OLE]) to evaluate 6-month safety and efficacy of quarterly fremanezumab (QTY) and monthly fremanezumab (MLY).

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.

Fremanezumab (AJOVY; Teva Pharmaceutical Industries Ltd, Netanya, Israel), approved for the preventive treatment of migraine, is available as a subcutaneous injection either once a month or once every 3 months using an autoinjector or a prefilled syringe. The present study evaluated the pharmacokinetic (PK) bioequivalence of a single subcutaneous injection of fremanezumab 225 mg administered using an autoinjector compared to a prefilled syringe in healthy volunteers. Blood samples for PK and antidrug antibodies were collected before and after dosing. Safety and tolerability assessments included physical examinations, adverse event reporting, laboratory evaluations, and immunogenicity. Following single-dose administration, the mean concentration-time profiles for the 2 treatment groups (autoinjector, n = 106; and prefilled syringe, n = 110) were similar. The point estimates for the back-transformed ratio (autoinjector/prefilled syringe) of geometric least squares means of maximum plasma concentration, area under the plasma concentration-time curve from time 0 to the time of the last measurable drug concentration, and area under the plasma concentration-time curve from time 0 extrapolated to infinity were 1.03, 1.04, and 1.05, respectively, with the 90% confidence intervals entirely contained within bioequivalence margins of 0.8 to 1.25. For both groups, median time to maximum observed concentration was 5 days and mean terminal elimination half-life was approximately 29 days. Treatment-related adverse events were reported by 39 (36%) subjects in the autoinjector group and 26 (24%) in the prefilled syringe group, and the majority were nonserious injection site reactions. The incidence of treatment-emergent antidrug antibody response was low and evenly distributed between the autoinjector (n = 3; 3%) and prefilled syringe (n = 4; 4%) groups. These results indicate that the fremanezumab autoinjector presentation provides an easy-to-use bioequivalent PK profile with a similar safety and tolerability profile to that of the prefilled syringe.

To the Editor, We read with interest the article by Noseda et. al. titled Safety profile of erenumab, galcanezumab and fremanezumab in pregnancy and lactation: Analysis of the WHO pharmacovigilance database (1). In their analysis of fetal malformations that occurred while the mother was taking a monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) pathway, the authors discuss a case of renal agenesis that occurred concurrent withmaternal use of fremanezumab. The authors list the concomitant medications used by the mother, including the anti-migraine preparation acetylsalicylic acid/caffeine/paracetamol, and state that none of these medications are known tobe associatedwith an increased risk of birth defects. In support of this assertion, they reference a 2012 publication byHernandez et al. (2). Since the time of that publication, however, a significant amount of data associating non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin with fetal renal toxicity has come to light (3,4). In fact, several NSAIDs already include a labeled warning against use in pregnancy due to risk of renal toxicity (5,6). Furthermore, in October 2020, the USFood andDrugAdministration issued a requirement to update the labels of all NSAID-containing medications with the risk of severe fetal renal disease with maternal use after 20 weeks’ gestation (3). In light of these data, we feel that if the event discussed in the article was indeed due to an adverse drug reaction, the aspirin-based preparation cannot be ruled out as a causal agent. Throughout pre-clinical and clinical studies with fremanezumab, no safety signals have been detected with regard to pregnancy or offspring (7). Teva and other CGRP pathway-targeting antibody manufacturers are conducting post-marketing studies to further evaluate this aspect of the safety profile. In the meantime, the prescribing information for fremanezumab has a section dedicated to pregnancy and lactation that summarizes what is currently known and not known. We hereby provide the above clarifications to the editor for consideration in reviewing and commenting on articles on this topic.

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.