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