To conduct population modeling of B cell response following inebilizumab treatment in adult subjects with neuromyelitis optica spectrum disorders (NMOSD), and to assess the impact of drug exposure to outcome.

NMOSD is an autoantibody-mediated, B cell-driven disease. Inebilizumab is a humanized, affinity-optimized, afucosylated IgG1κ monoclonal antibody that binds to CD19 resulting in effective depletion of B cells.

In a double-blind, placebo-controlled study (NCT02200770), adult NMOSD patients were randomized in a 3:1 ratio to receive intravenous (IV) infusions of either inebilizumab (300 mg) or placebo on Days 1 and 15 of a randomized-controlled period and every 6 months thereafter during the open label period. A hematopoietic transit model was developed to describe the depletion of circulating CD20+ B cell by inebilizumab. Furthermore, the relationships between inebilizumab pharmacokinetic (PK) exposure and the primary efficacy endpoint (Adjudication Committee (AC)-determined NMOSD attack) and key secondary efficacy endpoints were evaluated.

Treatment with inebilizumab led to rapid, profound, and sustained depletion of circulating B cells in NMOSD patients. The pharmacodynamic effect of inebilizumab was exerted by joint effects of reducing influx from pro-B cells and accelerating CD20+ B cell depletion in the blood. At the 300 mg dose, there was no apparent relationship between efficacy (reduction in disease attack risk, worsening from baseline in Expanded Disability Status Scale, cumulative total active MRI lesions, and number of NMOSD-related in-patient hospitalizations) with PK exposure. Subjects with low, medium and high PK exposure had a similar hazard ratio of AC-determined NMOSD attack.

The pharmacodynamic modeling and exposure-response analyses of primary and key secondary endpoints confirmed effective depletion of B cells is achieved with 300 mg IV dose administered on Day 1 and Day 15 and every 6 months thereafter. The PK variability between patients had no apparent effect on the hazard ratio for NMOSD attack.