Population PK/PD analysis for efgartigimod Phase 3 study in myasthenia gravis patients
Marostica E (1), Ahsman M (1), Van Bragt T (2), Noukens J (2), T’joen C (3), Ulrichts P (3), Vis P (1), Rossenu S (3), van Steeg T (1)
(1) LAP&P Consultants B.V., (2) Curare Consulting BV, (3) argenx BV
Introduction/Objectives: Efgartigimod (ARGX-113) is an antibody fragment and a neonatal Fc receptor (FcRn) antagonist that has been developed for the treatment of patients with severe autoimmune diseases mediated by pathogenic immunoglobulin G (IgG) autoantibodies. In patients with generalized myasthenia gravis (gMG), by blocking FcRn recycling efgartigimod lowered antibodies against the acetylcholine receptor (AChRAb). The objective of the analysis was to support the development of efgartigimod for gMG by means of modelling the efgartigimod PK as well as the effects of efgartigimod on total IgG and AChRAb reduction, which are eventually linked to the disease. The PK/total IgG/AChRAb model served as a basis for capturing the clinical responses in patients with gMG observed with efgartigimod treatment.
Methods: Data from the ADAPT Phase 3 study (ARGX-113-1704 [1]) in patients with gMG treated with four once-weekly efgartigimod IV 10 mg/kg infusions were analyzed. The existing PK model based on Phase 2 data, consisted of a three-compartmental model with linear clearance (CL) and the volume of the two peripheral compartments (V2 and V3) were assumed to be equal [2]. To reflect the mechanism of action, the existing Phase 2 total IgG model consisted of an indirect response turnover model, in which efgartigimod stimulated the degradation rate of total IgG (kout). An Emax model was implemented to capture the saturable effect of efgartigimod on kout [2]. Further, a PK/total IgG/AChRAb model was developed, in which the reduction of AChRAb is directly linked to the reduction of total IgG, under the assumption that AChRAb is part of the total IgG pool. The existing models for PK, total IgG and AChRAb were optimized using the Phase 3 data. Further, a covariate analysis was performed to identify covariates for the PK and total IgG. Finally, simulations were performed to assess the impact of these covariates on the PK/PD of efgartigimod in the gMG population.
Results:
The final models adequately described efgartigimod PK, total IgG and binding AChRAb concentrations and reduction in patients with gMG. Parameters were precisely estimated and similar to the obtained parameters in the Phase 2 analysis. The covariate analysis for the PK of efgartigimod in gMG patients showed that weight and eGFR influenced CL significantly. Further, weight was found to be a covariate for the volume of the central compartment (V1). Next to the covariates affecting PK, an effect of weight was found to be statistically significant on the potency (EC50).
When applying a body weight dependent dosing and a capped dose for patients weighing more than 120 kg as applied in the Phase 3 study, AUC0−168h ranged from -23% (90%CI: -27%, -19%) to +40% (90%CI: +34%, +46%), with respect to the reference subject, for a body weight of 53 kg (5th percentile) and 120 kg, respectively. These results suggested that the increase in exposure is driven mainly by the increase in dose and to a lesser extent by the effect of body weight on clearance. Comparison of the exposure in patients with normal renal function and patients with mild renal impairment (eGFR ≥ 60 mL/min/1.73m2 but < 90 mL/min/1.73m2) showed a relative AUC change of 1.28 (90%CI: 1.19, 1.37) in patients with mild renal impairment. An apparent increase in EC50 with increasing body weight was found, but simulations showed that the magnitude of this effect was small and did not modify the total IgG reduction in a clinically relevant manner. The power coefficient for the binding AChRAb was estimated to be 1.03, indicating that the reduction in AChRAb was proportional to the reduction in total IgG. Consequently, the assumption that AChRAb is part of the total IgG pool was confirmed.
Conclusions: In conclusion, the PK was successfully linked to total IgG and binding AChRAb. Covariates were identified for both PK and total IgG reduction and allowed for simulations on the impact of these covariates in gMG patients to support the development of efgartigimod. Further, the final model linking PK, total IgG and AChRAb served as a good basis for evaluation of the effects of efgartigimod on disease score.
References:
[1] argenx BV. Clinical Study Report ARGX-113-1704: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase 3 Trial to Evaluate the Efficacy, Safety and Tolerability of ARGX-113 in Patients with Myasthenia Gravis Having Generalized Muscle Weakness (ADAPT), 18 August 2020.
[2] J. Berkhout. Development and application of population PK/PD/disease model of ARGX-113 to support dose selection for phase III using data from a phase II study in myasthenia gravis patients. Technical report, LAP&P Consultants BV, Leiden, The Netherlands, 2018.
