Fremanezumab selectively binds the calcitonin gene-related peptide (CGRP) ligand and blocks both CGRP isoforms (α- and β-CGRP) from binding to the CGRP receptor. While the precise mechanism of action by which fremanezumab prevents migraine attacks is unknown, it is believed that prevention of migraine is obtained by its effect modulating the trigeminal system. CGRP levels have been shown to increase significantly during migraine and return to normal with headache relief.
Fremanezumab is a humanised IgG2Δa/kappa monoclonal antibody derived from a murine precursor.
Fremanezumab is highly specific for CGRP and does not bind to closely related family members (e.g., amylin, calcitonin, intermedin and adrenomedullin).
After single subcutaneous administrations of 225 mg and 675 mg fremanezumab, median time to maximum concentrations (tmax) in healthy subjects was 5 to 7 days. The absolute bioavailability of fremanezumab after subcutaneous administration of 225 mg and 900 mg in healthy subjects was 55% (±SD of 23%) to 66% (±SD of 26%). Dose proportionality, based on population pharmacokinetics, was observed between 225 mg to 675 mg. Steady state was achieved by approximately 168 days (about 6 months) following 225 mg monthly and 675 mg quarterly dosing regimens. Median accumulation ratio, based on once monthly and once quarterly dosing regimens, is approximately 2.4 and 1.2, respectively.
Assuming the model-derived estimated bioavailability of 66% (±SD of 26%) holds for the patient population, the volume of distribution for a typical patient was 3.6 L (35.1% CV) following subcutaneous administration of 225 mg, 675 mg and 900 mg of fremanezumab.
Similar to other monoclonal antibodies, fremanezumab is expected to be degraded by enzymatic proteolysis into small peptides and amino acids.
Assuming the model-derived estimated bioavailability of 66% (±SD of 26%) holds for the patient population, central clearance for a typical patient was 0.09 L/day (23.4% CV) following subcutaneous administration of 225 mg, 675 mg and 900 mg of fremanezumab. The formed small peptides and amino acids may be re-used in the body for de novo synthesis of proteins or are excreted by the kidney. Fremanezumab has an estimated half-life of 30 days.
A population pharmacokinetic analysis looking at age, race, gender, and weight was conducted on data from 2,546 subjects. Approximately twice as much exposure is expected in the lowest body weight quartile (43.5 to 60.5 kg) compared to the highest body weight quartile (84.4 to131.8 kg). However, body weight did not have an observed effect on the clinical efficacy based on the exposure-response analyses in episodic and chronic migraine patients. No dose adjustments are required for fremanezumab. No data on exposure-efficacy relationship in subjects with body weight >132 kg is available.
Since monoclonal antibodies are not known to be eliminated via renal pathways or metabolised in the liver, renal and hepatic impairment are not expected to impact the pharmacokinetics of fremanezumab. Patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) have not been studied. Population pharmacokinetic analysis of integrated data from the fremanezumab clinical studies did not reveal a difference in the pharmacokinetics of fremanezumab in patients with mild to moderate renal impairment or hepatic impairment relative to those with normal renal or hepatic function.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, toxicity to reproduction and development.
As fremanezumab is a monoclonal antibody, no genotoxicity or carcinogenicity studies have been conducted.
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