Martine Neyens 1, Yaowei Zhu 2, Nolan Campbell 3, John J. Sheehan, Ruben Faelens 1
1 Johnson & Johnson (Beerse, Belgium), 2 Johnson & Johnson (Spring House, USA), 3 Johnson & Johnson (Horsham, USA), 4 Johnson & Johnson (Titusville, USA)
Introduction: Neonatal Fc Receptor (FcRn), which mediates immunoglobulin G (IgG) recycling, is a promising target for treatment of auto-immune diseases. By blocking FcRn, total serum IgG and pathogenic IgG decreases, thereby leading to clinical improvement. For generalized Myasthenia Gravis (gMG), an auto-immune disease where antibodies attack the neuromuscular junction, several FcRn blockers are currently approved. Efgartigimod (ArgenX, Belgium) is given intravenously every week for 4 weeks, after which treatment typically restarts after a 4 week off period. Nipocalimab (Johnson & Johnson, USA) is given intravenously every two weeks without any off period. A head-to-head clinical trial (EPIC, NCT07217587) is planned to assess how well nipocalimab works when compared to efgartigimod in participants with generalized myasthenia gravis.
Objective: To inform the upcoming clinical trial and clinical practice when switching FcRn-blockers in gMG, we simulated total serum IgG reductions when switching from efgartigimod to nipocalimab.
Methods: Nipocalimab pharmacokinetics and FcRn receptor occupancy was modeled [1] using a quasi-steady state approximation of the target-mediated disposition model with parallel linear and target-mediated clearance. IgG turnover was described using a synthesis rate, intrinsic catabolic rate and FcRn-mediated recycling rate. Recycling was inhibited based on the amount of FcRn bound to nipocalimab.
Efgartigimod pharmacokinetics [2] was described by a three-compartment model with linear clearance. A similar indirect response turnover model was used to describe IgG dynamics, where an Emax model was used to capture the saturable induction of IgG degradation rate.
Efgartigimod IgG model was reparametrized to align with the nipocalimab IgG model. Natural IgG turnover rate (with FcRn recycling active) was 20% higher in the efgartigimod model, which was a result of efgartigimod model parsimony in light of the linear clearance of the drug. All other systemic IgG parameters (baseline IgG, maximal %IgG reduction, time until maximal reduction, IgG recycling rate and IgG synthesis rate) were equivalent in both models. After implementing a lower limit cut-off for the efgartigimod inhibitory effect at lower concentrations (see [3] for mechanistic basis), the combined model using all nipocalimab IgG systemic parameters also fit IgG data from efgartigimod ADAPT trial.
Simulations for nipocalimab and efgartigimod were performed using sampled bodyweight and eGFR, based on the distributions reported in the original publication [2].
Results: De novo initiation of nipocalimab IV 30mg/kg loading dose + 15mg/kg every-2-weeks resulted in a rapid initial IgG reduction of 72% at Week(W)2 and subsequently alternated between 80% (odd weeks) and 66% (prior to next dose).
Efgartigimod cycles (4W on/4W off) yielded IgG reductions of 65% at W4 and 24% at W8. Switching to nipocalimab after an 8W efgartigimod therapy resulted in robust (>70%) IgG reduction within 1W after switching and reduction of 74% at W2, suggesting no additional reduction in IgG vs de novo initiation.
If switching is delayed, for example when IgG levels returned to baseline at 12W after efgartigimod cycle start, the IgG profile post-switching matched that predicted after de novo initiation; robust IgG reduction occurred within 1W after switching.
Conclusion: These modeling results support switching to nipocalimab after completing 8W efgartigimod IV cycle.
References:
[1] Valenzuela, Belén, et al. “Nipocalimab Dose Selection in Generalized Myasthenia Gravis.” CPT: Pharmacometrics & Systems Pharmacology 14.12 (2025): 2074-2085.
[2] Marostica et al, “Population PK/PD analysis for efgartigimod Phase 3 study in myasthenia gravis patients” PAGE 31 (2023) Abstr 10382 [www.page-meeting.org/?abstract=10382]
[3] Hoefman, Sven, et al. “Translational population target binding model for the anti-FcRn fragment antibody efgartigimod.” Journal of Pharmacokinetics and Pharmacodynamics 52.1 (2025): 2.
Reference: PAGE 34 (2026) Abstr 11867 [www.page-meeting.org/?abstract=11867]
Poster: Drug/Disease Modelling - CNS