Nipocalimab Dose Selection for A Phase 3 Study in Adult Patients with Generalized Myasthenia Gravis
Juan-José Pérez-Ruixo, Yaowei Zhu, Martine Neyens, Marie-Helene Jouvin, Sindhu Ramchandren, Yan Xu, Jocelyn H. Leu, Anne-Gaëlle Dosne, Yuan Xiong, Belén Valenzuela, Leona Ling, Partha Nandy, Hong Sun
Janssen Research & Development
Background: Nipocalimab (JNJ-80202135) is a fully human IgG1λ monoclonal antibody that blocks neonatal Fc receptors (FcRn) inhibiting IgG recycling and lowering systemic IgG, including pathogenic IgG autoantibodies. Potential for nipocalimab efficacy in autoimmune diseases was demonstrated in a Phase 2 (Ph2) study in patients with generalized myasthenia gravis (gMG).
Objectives: To determine the optimal nipocalimab dose and dosing regimen using modeling and simulation for a pivotal Ph3 study in gMG patients.
Methods: Mathematical models linking nipocalimab IV dosing with its pharmacokinetics (PK) and FcRn occupancy through the quasi-steady-state approach of the target mediated drig disposition model was developed. In addition, FcRn occupancy was driving the turnoever of the total IgG reduction through an indirect response model. The total IgG reduction was related tothe gMG efficacy endpoint (ie. MG - Activities of Daily Living [MG-ADL]) through an effect compartment model. Also, the indirect response models were used to characterize the increase in serum albumin, total cholesterol and LDL increase. All these models were developed based on the data collected from nipocalimab Ph1 studies in healthy participants and a Ph2 study in gMG patients (1-3). Ph2 gMG study dosing ranged from 5 mg/kg Q4W to 60 mg/kg Q2W. Model-based simulations were conducted to identify the optimal nipocalimab dose, schedule and loading dose for a Ph3 gMG study.
Results: Nipocalimab exhibited nonlinear FcRn-mediated disposition and rapid, dose-dependent IgG lowering in Ph1 and Ph2 studies. Dose-dependent improvements in MG- ADL associated with a 70% IgG reduction accounted for ~90% of the maximum MG-ADL reduction. Model-based simulation indicated a 15 mg/kg Q2W maintenance dose that achieved >70% target IgG lowering with minimal gains at higher doses (i.e. 30 mg/kg). For a given dose, the fluctuation of IgG lowering and MG-ADL reduction is less pronounced with Q2W than Q4W schedule. A 30 mg/kg loading dose was incorporated to lower IgG and MG-ADL scores by 2 weeks. The proposed dosing regimen is predicted to have an average steady-state albumin lowering of 12%, and total cholesterol and LDL increase of 6% and 8%, respectively, which are expected to have limited clinical impact.
Conclusions: A 30 mg/kg loading dose followed by 15 mg/kg Q2W maintenance dose was identified as optimal for the Ph3 gMG study. The predicted exposure in patients with gMG is well below the exposure from 60 mg/kg q2w dosing regimen in Ph2, which was generally safe and well-tolerated.
References:
[1] Ling LE, Hillson JL, Tiessen RG, Bosje T, Lersel MP, Nix DJ, Markowitz L, Cilfone NA, Duffner J, Streisand JB, Manning AM, Arroyo S. M281, an Anti-FcRn Antibody: Pharmacodynamics, Pharmacokinetics, and Safety Across the Full Range of IgG Reduction in a First-in-Human Study. Clin Pharmacol Ther. 2019 Apr; 105(4) : 1031-1039.
[2] Ramchandren S. Presented at: American Academy of Neurology; April 2-7, 2022; Virtual.
[3] Ramchandren S, et al. MGFA 2022. Poster 90.