Objective:

To determine the optimal nipocalimab dose and dosing regimen using modeling and simulation for a pivotal Ph3 study in gMG patients.

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).

Design/Methods:

Mathematical models linking nipocalimab IV dosing with its pharmacokinetics (PK), FcRn occupancy, total IgG reduction and efficacy (ie. MG - Activities of Daily Living [MG-ADL]), were developed based on the data collected from nipocalimab Ph1 studies in healthy participants and a Ph2 study in gMG patients. 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. Ph2 gMG study dosing ranged from 5 mg/kg Q4W to 60 mg/kg Q2W. 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. 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.