Xia LI1, Juan-José Pérez-Ruixo1, Jocelyn Leu2, John Sheehan3, Ruben Faelens1
1Clinical Pharmacology and Pharmacometrics, Janssen Research & Development LLC, a Johnson & Johnson Company, 2Clinical Pharmacology and Pharmacometrics, Janssen Research & Development LLC, a Johnson & Johnson Company, 3Global Medical Affairs, Janssen Global Services
Background and Objectives: Nipocalimab, a fully human IgG1 monoclonal antibody, binds selectively and with high affinity to FcRn, which inhibits FcRn-mediated IgG recycling. This inhibition results in a decreased half-life and rapid reduction of circulating IgG levels. This reduction encompasses pathogenic autoantibodies that target proteins at the neuromuscular junction in generalized Myasthenia Gravis (gMG) including: AChR (IgG1 and IgG3), MuSK (IgG4), and LRP (IgG1 and IgG2) autoantibodies. Clinical studies (Phase 2 and 3) [1-2] demonstrate that nipocalimab can reduce total serum IgG in a dose-dependent manner, resulting in favorable efficacy and safety profile in patients with gMG. We aim to characterize the nipocalimab effect on IgG subclasses (IgG1, IgG2, IgG3, IgG4) and anti-AChR autoantibody concentrations to understand the effects of nipocalimab on the range of underlying pathogenic autoantibodies causing the disease. Methods: Clinical studies. This analysis used data from the Phase 2 study (N=68) and pivotal Phase 3 study (N=166) in gMG patients. Nipocalimab IV dose regimens evaluated in the Phase 2 study (5 mg/kg Q4W, 30 mg/kg Q4W, 60 mg/kg single dose, and 60 mg/kg Q2W) and the pivotal phase 3 study (30 mg/kg for the loading dose and 15 mg/kg Q2W for the maintenance dose) in patients with gMG [1-2] were pooled to develop a longitudinal mechanistic population PK/ FcRn occupancy (RO) / IgG subclass – anti-AChR antibody model, using a sequential modeling approach, where the population PK/RO model parameters were fixed to the previously estimated values [3]. The time course of IgG subclass or pathogenic anti-AChR antibody concentrations were modelled through an indirect-response model that assumed a zero-order production process, first-order elimination and first-order recycling, which was linearly related to the fraction of free FcRn receptor available for nipocalimab binding. The model described was used to estimate the model parameters separately for each IgG subclass or pathogenic anti-AChR antibody concentrations using NONMEM 7.4.3. We simulated 1000 virtual patients with gMG receiving nipocalimab 30 mg/kg for the loading dose and 15 mg/kg Q2W for the maintenance dose over 14 weeks. The predicted reductions in IgG subclass or pathogenic AChR autoantibody concentrations over time were graphically depicted to illustrate the nipocalimab effect and compared to IgG subclass profiles observed in phase 2 study with efgartigimod [4]. Results and discussions: The indirect-response model, accounting for FcRn-induced IgG recycling, suitably described the time course of each serum IgG subclass and pathogenic AChR autoantibody concentrations and their variability after nipocalimab administration. The baseline serum IgG subclasses were precisely estimated as concentration of IgG1 at 38.2 µmol/l (64.2%), IgG2 at 17.9 µmol/l (29.9%), IgG3 at 1.43 µmol/l (2.40%), IgG4 at 2.13 µmol/l (3.53%), and anti-AChR at 0.00806 µmol/l (0.0135%), which closely matched the observed values of 63.6%, 30.0%, 2.43%, and 3.98%. IgG3 had the deepest nadir among IgG subclasses. When FcRn was fully blocked by nipocalimab, IgG3 degraded the fastest with a degradation rate of 0.847 d-1, reaching a nadir of an 87.3% decrease from baseline. Upon unblocking FcRn, IgG3 exhibited the quickest recovery, increasing to a pre-dose level corresponding to a 54.9% decrease from the baseline level. IgG4 degraded the slowest, with a degradation rate of 0.257 d-1, reaching a nadir of 74.7% decrease, with the slowest recovery, increasing to a pre-dose level corresponding to a 56.6% decrease. The IgG1 and IgG2 nadirs were 82.2% and 79.6%, with pre-dose levels of 65.6% and 68.1%, respectively. Overall, total IgG reached a nadir of an 82.5% decrease and increased to a pre-dose level of 68.6% decrease from baseline. Anti-AChR degraded at a rate of 0.558 d-1, close to the median degradation rate of IgG1 and IgG3. Anti-AChR reached a nadir of 88.3% decrease from baseline, closely aligned with IgG3, and later recovered to a pre dose reduction of 66.2% from baseline. Model-based simulations comparing nipocalimab with efgartigimod 10 mg/kg QW showed faster, deeper and more sustained IgG lowering across IgG subclasses and anti-AChR autoantibodies with nipocalimab. Conclusion: Nipocalimab inhibits FcRn-mediated IgG recycling and rapidly decreases all IgG subclasses (IgG1, IgG2, IgG3, IgG4) and pathogenic anti-AChR autoantibodies in patients with gMG to larger extend than efgartigimod. This result highlights the potential of nipocalimab to gMG.
1. Antozzi C, Guptill J, Bril V, et al. Safety and Efficacy of Nipocalimab in Patients With Generalized Myasthenia Gravis: Results From the Randomized Phase 2 Vivacity-MG Study. Neurology. 2024;102(2):e207937. doi:10.1212/WNL.0000000000207937 2. Antozzi C, Vu T, Ramchandren S, et al. Safety and efficacy of nipocalimab in adults with generalised myasthenia gravis (Vivacity-MG3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2025;24(2):105-116. doi:10.1016/S1474-4422(24)00498-8 3. Belén V, Martine N, Yaowei Z, et al. Nipocalimab Dose Selection in Myasthenia Gravis (to be submitted). 4. James H., Tim H. Phase 2 Study of Efgartigimod in Patients with Generalized Myasthenia Gravis. American Academy of Neurology, LA, April 24, 2018
Reference: PAGE 33 (2025) Abstr 11537 [www.page-meeting.org/?abstract=11537]
Poster: Clinical Applications