Pharmacodynamic modeling and exposure-response assessment of
inebilizumab in subjects with neuromyelitis optica spectrum disorders
Abstract
BACKGROUND AND PURPOSE: Neuromyelitis optica spectrum disorders (NMOSD)
is an autoantibody-mediated, B cell-driven disease. Inebilizumab is a
humanized, affinity-optimized, afucosylated IgG1 kappa monoclonal
antibody that binds to the B cell specific surface antigen CD19,
resulting in rapid, profound, and sustained depletion of circulating
peripheral B cells in NMOSD subjects (pivotal study). The objective of
this study was to conduct population modeling of B cell response
following inebilizumab treatment in adult subjects with NMOSD, and to
assess the impact of drug exposure to outcome. EXPERIMENTAL APPROACH: A
hematopoietic transit model was developed to describe the joint effects
of reducing influx from pro-B cells and accelerating CD20+ B cell
depletion in the blood by inebilizumab. Furthermore, the relationships
between inebilizumab pharmacokinetic (PK) exposure and the primary
efficacy endpoint and key secondary efficacy endpoints were evaluated.
KEY RESULTS: At the 300 mg dose, there was no apparent relationship
between efficacy (reduction in disease attack risk, risk of worsening
from baseline in Expanded Disability Status Scale, cumulative total
active MRI lesions, and the number of NMOSD-related in-patient
hospitalizations) and PK exposure. Subjects with low, medium, and high
PK exposure had a similar hazard ratio of NMOSD attack vs Placebo group.
CONCLUSION AND IMPLICATIONS: The pharmacodynamic modeling confirmed
effective depletion of B cells is achieved with a 300 mg intravenous
dose of inebilizumab administered on Day 1 and Day 15 and every 6 months
thereafter. The PK variability between patients had no apparent effect
on clinical efficacy.