Safety and Tolerability of Fremanezumab for the Prevention of Migraine: A Pooled Analysis of Phases 2b and 3 Clinical Trials.

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.

A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects.

OBJECTIVES: The primary and secondary objectives of this phase 1 study were to evaluate the pharmacokinetic profile, safety, and immunogenicity of fremanezumab subcutaneous (sc) doses tested in phase 2 and 3 trials (225 mg, 675 mg and 900 mg) following single administration in Japanese (n = 32) and Caucasian (n = 32) healthy subjects. METHODS: Japanese and matched Caucasian healthy subjects were enrolled into one of four cohorts and were randomly assigned to one of four treatments: 225, 675, or 900 mg fremanezumab, or placebo. Pharmacokinetic and immunogenicity sampling, and safety and tolerability assessments occurred at one inpatient visit and 12 ambulatory visits during the 36-week study. RESULTS: Pharmacokinetic analyses included those randomized to fremanezumab (n = 24 for each ethnic group) and safety analyses included all subjects enrolled in the study (n = 32 for each ethnic group). Fremanezumab concentration-time profiles and pharmacokinetic parameters per dose were similar for Japanese and Caucasians at all dose levels. Geometric mean ratios (GMRs) for Cmax for Japanese to Caucasian subjects were 0.91, 1.04 and 1.14 for the 225 mg, 675 mg and 900 mg fremanezumab doses. GMRs for AUC0-inf were 0.96, 1.09, and 0.98, respectively. Median Tmax (range 5-11 days) and mean half-lives (range 31-39 days) were similar across doses for both ethnicities. Most frequently occurring adverse events were injection site reactions, abdominal pain, headache, upper respiratory tract infection, constipation and nasopharyngitis. There was no development of anti-drug-antibodies and no clinically meaningful changes in laboratory findings. CONCLUSION: The results of the pharmacokinetic exposure parameters and safety measures were similar for Japanese and Caucasians and support the once monthly and once quarterly sc injections of fremanezumab.

Phase 1b/2a Study Assessing the Safety and Efficacy of Felzartamab in Anti-Phospholipase A2 Receptor Autoantibody-Positive Primary Membranous Nephropathy.

Introduction: Primary membranous nephropathy (PMN) is most often caused by autoantibodies to phospholipase A2 receptor (PLA2R). M-PLACE (NCT04145440) is an open-label, phase 1b/2a study that assessed the safety and efficacy of the fully human anti-CD38 monoclonal antibody felzartamab in high-risk anti-PLA2R+ PMN. Methods: Patients with newly diagnosed or relapsed PMN (cohort 1 [C1]; n = 18) or PMN refractory to immunosuppressive therapy (IST) (cohort 2 [C2]; n = 13) received 9 infusions of felzartamab 16 mg/kg in the 24-week treatment period, followed by a 28-week follow-up. The primary end point was the incidence and severity of treatment-emergent adverse events (TEAEs). Results: A total of 31 patients were enrolled and received felzartamab. Twenty-seven patients (87.1%) had TEAEs, including infusion-related reactions (IRRs) (29.0%), hypogammaglobulinemia (25.8%), peripheral edema (19.4%), and nausea (16.1%). Five patients (16.1%) had serious TEAEs that all resolved. Immunologic response (anti-PLA2R titer reduction ≥50%) was achieved by 20 of 26 efficacy-evaluable patients (76.9%) (C1, 13/15 [86.7%]; C2, 7/11 [63.6%]). Anti-PLA2R titer reductions were rapid (week 1 response, 44.0%; response 7 months after last felzartamab dose [end of study, EOS], 53.8%). Partial proteinuria remission (urine protein-to-creatinine ratio [UPCR] reduction ≥50%, UPCR <3.0 g/g, and stable estimated glomerular filtration rate [eGFR]) was achieved by 9 of 26 patients (34.6%) (C1, 7/15 [46.7%]; C2, 2/11 [18.2%]) before or at EOS (median follow-up, 366 days). Serum albumin increased from baseline to EOS in 20 of 26 patients (76.9%) (C1, 12/15 [80.0%]; C2, 8/11 [72.7%]). Conclusion: In this population with high-risk anti-PLA2R+ PMN, felzartamab was tolerated and resulted in rapid partial and complete immunologic responses and partial improvements in proteinuria and serum albumin in some patients.