Imlifidase

Imlifidase is a cysteine protease derived from the immunoglobulin G (IgG)-degrading enzyme of Streptococcus pyogenes that cleaves the heavy chains of all human IgG subclasses but no other immunoglobulins. The cleavage of IgG leads to elimination of Fc-dependent effector functions, including CDC and antibody-dependent cell-mediated cytotoxicity (ADCC). By cleaving all IgG, imlifidase reduces the level of DSA, thus enabling transplantation.

Pharmacodynamic effects

Clinical studies have demonstrated that IgG was cleaved within a few hours after administration of imlifidase 0.25 mg/kg. No early increase in plasma IgG due to reflux of uncleaved IgG from the extravascular compartment has been observed, indicating that imlifidase cleaves not only the plasma IgG but the entire IgG pool, including the extravascular IgG. The return of endogenous IgG starts 1-2 weeks after imlifidase administration and continues over the next weeks.

It should be noted that turbidimetry/nephelometry methods, commonly used at hospitals for total IgG measurements, do not discriminate between different IgG fragments generated after imlifidase treatment, and can therefore not be used to evaluate treatment effect.

The pharmacokinetics of imlifidase were comparable in healthy subjects and patients with ESRD. The exposure to imlifidase increased proportionally after a single intravenous 15-minute infusion of 0.12 to 0.50 mg/kg body weight.

The maximum concentration (C_max) of imlifidase was observed at or soon after the end of the infusion, with a mean of 5.8 (4.2-8.9) µg/mL after a dose of 0.25 mg/kg. The elimination of imlifidase was characterised by an initial distribution phase with a mean half-life of 1.8 (0.6-3.6) hours and a slower elimination phase with a mean half-life of 89 (60-238) hours. The mean clearance (CL) was 1.8 (0.6-7.9) mL/h/kg and the distribution volume (V_z) was 0.20 (0.06-0.55) L/kg during the elimination phase.

Non-clinical data reveal no special hazard for humans based on repeat-dose toxicity studies in rabbits and dogs, and an embryo-fetal development study in rabbits. Due to the rapid and extensive development of anti-imlifidase antibodies and associated toxicity after repeated administrations, a study on fertility and early embryonic development has not been feasible. No toxicity to the reproductive organs was observed in repeat-dose toxicity studies but the potential effect of imlifidase on male and female reproductive organs has not been fully addressed. No studies on pre- or postnatal toxicity have been conducted. No genotoxicity studies were performed since the active substance is a protein and is unlikely to interact directly with DNA or other chromosomal material.