Assessing the Relationship Between Immunoglobulin G Level and Efficacy of Nipocalimab Measured Using Myasthenia Gravis-activities of Daily Living scale
Zabeen Mahuwala1, Ruben Faelens2, Belen Valenzuela3, Martine Neyens2, Yaowei Zhu4, Jocelyn H. Leu4, Marie Fitzgibbon5, Sindhu Ramchandren6, Juan-Jose Perez Ruixo2
1Department of Neurology, University of Kentucky, Lexington, KY, USA, 2Johnson & Johnson, Beerse, Belgium, 3Johnson & Johnson, Madrid, Spain, 4Johnson & Johnson, Spring House, PA, USA, 5Johnson & Johnson, Raritan, NJ, USA, 6Johnson & Johnson, Titusville, NJ, USA
Objective:
To explore the longitudinal relationship between immunoglobulin G (IgG) level and Myasthenia Gravis-Activities of Daily Living (MG-ADL) score using semi-mechanistic pharmacometrics modeling with data from clinical studies of nipocalimab in generalized myasthenia gravis (gMG) and healthy volunteers.
Background:
In gMG, IgG-based autoantibodies attack the neuromuscular junction, causing muscle weakness. Nipocalimab, a neonatal fragment crystallizable receptor (FcRn) blocker, prevents IgG recycling and thus lowers levels of circulating IgG antibodies, including pathogenic autoantibodies, thereby improving symptoms of gMG.
Design/Methods:
Data from five phase-1, one phase-2, and one phase-3 (Vivacity-MG3) clinical studies were analyzed to characterize pharmacokinetics ([PK]; 3,429 serum nipocalimab concentrations [n=277]), pharmacodynamics ([PD]; 4,441 serum IgG concentrations [n=421] and 1,247 FcRn receptor occupancy data [n=78]). To establish the longitudinal relationship between IgG and MG-ADL, 2,317 absolute change from baseline (CFB) MG-ADL scores were analyzed in seropositive (anti-acetylcholine receptor, anti-muscle-specific receptor tyrosine kinase, anti-lipoprotein receptor-related protein-4) participants with gMG (n=220). A previously developed nonlinear mixed-effects model was used. The effects of baseline demographics and clinical characteristics on PK, PD, and MG-ADL parameters were investigated.
Results:
The previous model captured serum nipocalimab and total serum IgG concentrations of the Phase3 data well. MG-ADL CFB drug effect was linearly related to IgG %CFB at 0.28 points per 10% IgG %CFB. In the patient population, this resulted in approximately 2-points MG-ADL reduction for the nipocalimab-induced 70% IgG reduction. The slope of the regression line was dependent on baseline MG-ADL score. Age, body weight, race, ethnicity, sex, autoantibody status, gMG background therapy and gMG duration did not have a clinically relevant impact.
Conclusions:
The model confirmed IgG %CFB drives nipocalimab effect on MG-ADL. These results support that total serum IgG reduction is a good predictor for efficacy in gMG, allowing for comparison of clinical effect across FcRn inhibitors.
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