Rozanolixizumab is a humanised IgG4 monoclonal antibody that decreases serum IgG concentration by inhibiting the binding of IgG to FcRn, a receptor that under physiological conditions protects IgG from intracellular degradation and recycles IgG back to the cell surface.
By the same mechanism, rozanolixizumab decreases the concentration of pathogenic IgG autoantibodies associated with gMG. Clinical data with rozanolixizumab have not identified any clinically relevant impact on levels of albumin, which binds at a different site on FcRn.
In a double-blind placebo-controlled study in gMG patients, weekly subcutaneous administration of rozanolixizumab at the recommended dose resulted in a rapid and sustained reduction in total IgG serum concentrations, with significant lowering of IgG of 45% compared to baseline within 1 week, and a maximum decrease of 73% at about 3 weeks. After stopping administration, IgG concentrations recovered towards baseline levels within approximately 8 weeks. Similar changes were observed during the subsequent cycles of the study.
The reduction in total IgG by rozanolixizumab in neutralising antibody-positive patients was not different from patients who were antidrug antibody-negative.
Following subcutaneous administration of rozanolixizumab, peak plasma levels are achieved after approximately 2 days. The absolute bioavailability of rozanolixizumab after subcutaneous administration was about 70% as estimated by population pharmacokinetic analysis.
The apparent volume of distribution of rozanolixizumab is approximately 7 l estimated by population pharmacokinetic analysis.
Rozanolixizumab is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG.
The apparent linear clearance for the free active substance is approximately 0.9 l/day. The half-life of rozanolixizumab is concentration-dependent and cannot be calculated. Rozanolixizumab plasma concentrations are undetectable within one week after dosing.
Rozanolixizumab exhibited nonlinear pharmacokinetics typical for a monoclonal antibody that undergoes target-mediated drug disposition. At steady-state, maximum plasma concentrations and area under the concentration time curve (AUC) were predicted to be 3-fold and 4-fold higher at weight-tiered doses of ≈10 mg/kg as compared to ≈7 mg/kg, respectively.
A population pharmacokinetic analysis did not reveal a clinically significant impact of age, sex or race on the pharmacokinetics of rozanolixizumab.
No dedicated studies have been conducted in patients with renal or hepatic impairment. However, renal or hepatic impairment is not expected to affect the pharmacokinetics of rozanolixizumab. Based on a population pharmacokinetic analysis, renal function (estimated glomerular filtration rate [eGFR] 38-161 ml/min/1.73 m²) or hepatic biochemical and function tests (alanine transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase and bilirubin) had no clinically significant effect on rozanolixizumab apparent linear clearance.
Development of neutralising antibodies was associated with a 24% decrease in overall plasma exposure of rozanolixizumab. There was no apparent impact of immunogenicity on efficacy and safety.
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity (including safety pharmacology and fertility endpoints) and toxicity to reproduction and development. Administration to cynomolgus and rhesus monkeys resulted in the expected reduction in IgG. Vaccination during the treatment phase elicited normal IgM levels and a low IgG response due to accelerated IgG degradation. However, boost vaccination after rozanolixizumab clearance resulted in normal IgM and IgG response.
The mutagenic potential of rozanolixizumab has not been evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.
Carcinogenicity studies have not been conducted with rozanolixizumab.
No treatment-related changes were noted in the male and female reproductive organs or male and female fertility parameters of sexually mature animals in 26-week repeated dose toxicity study. Rozanolixizumab had no effects on embryo-foetal and postnatal development. Offspring from treated dams had very low levels of IgG at birth, as expected from the pharmacology. IgG level recovered to control values or greater within 60 days. There was no impact on immune cell number, lymphoid organ architecture and immune function of the pups of treated mothers as assessed by a T-cell Dependent Antibody Response (TDAR) assay.
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