Efgartigimod alfa is a human IgG1 antibody fragment engineered for increased affinity to the neonatal Fc Receptor (FcRn). Efgartigimod alfa binds to FcRn, resulting in a reduction in the levels of circulating IgG including pathogenic IgG autoantibodies. Efgartigimod alfa does not affect the levels of other immunoglobulins (IgA, IgD, IgE or IgM), or those of albumin.
IgG autoantibodies are the underlying cause of the pathogenesis of MG. They impair neuromuscular transmission by binding to acetylcholine receptors (AChR), muscle-specific tyrosine kinase (MuSK) or low-density lipoprotein receptor-related protein 4 (LRP4).
In a double-blind placebo-controlled study in gMG patients, efgartigimod alfa decreased serum IgG levels and AChR autoantibody levels at the recommended dose and schedule. Maximum mean percentage decrease in total IgG levels compared to baseline reached 61% one week after the last infusion of the initial treatment cycle and returned to baseline levels 9 weeks after the last infusion. Similar effects were also observed for all subtypes of IgG. Decrease in AChR autoantibody levels followed a similar time course with maximum mean percentage decrease of 58% one week after the last infusion and return to baseline levels 7 weeks after the last infusion. Similar changes were observed during the second cycle of the study.
Based upon patient population PK data analysis the volume of distribution is 13 L.
Efgartigimod alfa is expected to be degraded by proteolytic enzymes into small peptides and amino acids.
The terminal half-life is 80 to 120 hours (3 to 5 days). Based upon patient population PK data analysis, the clearance is 0.108 L/h. The molecular weight of efgartigimod alfa is approximately 54 kDa, which is at the boundary of molecules that are renally filtered.
The pharmacokinetics profile of efgartigimod alfa is linear, independent of dose or time, with negligible accumulation. The geometric mean accumulation ratio based on observed peak concentrations was 1.12.
The pharmacokinetics of efgartigimod alfa were not affected by age (19-78 years), gender and race.
A population pharmacokinetic analysis showed that the effect of bodyweight on efgartigimod alfa exposure was limited at a dose of 10 mg/kg in patients up to 120 kg as well as in patients of 120 kg and above who received a capped dose of 1 200 mg/infusion. There was no effect of bodyweight on the extent of IgG reduction. In the double-blind placebo-controlled study, 5 (3%) patients were over 120 kg. The median bodyweight of patients on efgartigimod alfa in the study was 76.5 kg (min 49; max 229).
No dedicated pharmacokinetic studies have been performed in patients with renal impairment.
The effect of renal function marker estimated glomerular filtration rate [eGFR] as a covariate in a population pharmacokinetic analysis showed a reduced clearance resulting in a limited increase in exposure in patients with mild renal impairment (eGFR 60-89 mL/min/1.73 m²). No specific dose adjustment is recommended in patients with mild renal impairment.
There is insufficient data on the impact of moderate renal impairment (eGFR 30-59 mL/min/1.73 m²) on efgartigimod alfa pharmacokinetic parameters. There is no data on the impact of severe renal impairment (eGFR <30 mL/min/1.73 m²) on pharmacokinetic parameters of efgartigimod alfa.
No dedicated pharmacokinetic study has been performed in patients with hepatic impairment.
The effect of hepatic function markers as covariates in a population pharmacokinetic analysis did not show any impact on the pharmacokinetics of efgartigimod alfa.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity.
In reproduction studies in rats and rabbits, intravenous administration of efgartigimod alfa did not result in adverse effects on fertility and pregnancy nor were teratogenic effects observed up to dose levels corresponding to 11-fold (rats) and 56-fold (rabbits) to the exposure (AUC) at the maximum recommended therapeutic dose.
No studies have been conducted to assess the carcinogenic and genotoxic potential of efgartigimod alfa.
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