Word Count (max 4000):
Abstract: 242/250 max
Introduction: 352/500 max
Methods: 1616/no max
Discussion and Conclusions: 876/1500 max
References: 9/60 max
Title: 130/160 characters max
Running Title: 70/70 characters max
Keywords: 7/7 max
Tables and Figures (in-text): 8/10 max (4 supplementary figures are also
included)
Keywords (max 7):
Inebilizumab, pharmacodynamics, exposure-response, population modeling,
B cell, CD19, NMOSD
ABSTRACT (250 word limit)
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.
Bullet point summary: (Each bullet point should have a maximum
of 15 words)
What is already known –
Inebilizumab binds to CD19 and depletes peripheral B cells in NMOSD
subjects
What this study adds –
300 mg efficacy plateau dose minimizes the impact of PK variability on
inebilizumab efficacy
Clinical significance –
300 mg inebilizumab was determined to be the optimal dosage for the
treatment of NMOSD