Discussion and Conclusions (1,500 words limit)
Inebilizumab is an affinity-optimized, afucosylated, CD19-directed
cytolytic antibody for the treatment of NMOSD, a rare autoimmune
disease. Following cell surface binding to B lymphocytes, inebilizumab
results in antibody-dependent cellular cytolysis. In a Phase 2/3 study
N-MOmentum, 300 mg inebilizumab intravenously administered two weeks
apart resulted in profound and persistent peripheral CD20+ B cell
depletion and significant reduction in NMOSD attack during the 28-week
RCP.
The pharmacokinetics of intravenously administered inebilizumab were
adequately described by a 2-compartment model with parallel first-order
and time-dependent nonlinear elimination pathways (Yan L et al,
submitted). As for other therapeutic monoclonal antibodies, the CL and
Vd of inebilizumab increased with body weight: subjects
with large body weight tended to have lower PK exposure following fix
dose administration. This analysis focused on the evaluation of
pharmacodynamics of inebilizumab using a population modeling approach,
and exposure-response assessments to evaluate the impact of PK exposure,
body weight and the presence of ADA on efficacy endpoints for the
treatment of NMOSD.
The pooled CD20+ B cell data from two dose-ranging
Phase 1 studies of inebilizumab in subjects with scleroderma and
Multiple Sclerosis were initially utilized for exploration of various PD
models. Then the B cell data from the pivotal NMOSD study were included
for the development of the base model. Further assessments were
performed to identify and evaluate demographic covariate effects on B
cell response to inebilizumab treatment.
Compared to CD20, CD19 is expressed on a wider lineage of B cells, from
pro-B to plasmablasts and some plasma cells. A mechanistic hematopoietic
transit model was developed to describe the depletion of peripheral B
cell count in adults following inebilizumab treatment. In this model,
inebilizumab depletes CD20+ B cells in each aging
compartment as well as pro-B in blood. Given the high potency of
inebilizumab, EC50 (inebilizumab concentration
corresponding to half-maximal B cell depletion) could not be reliably
estimated. Instead, the pharmacodynamic effect of inebilizumab was
described using a log-linear model (Equation 5), which approximates an
asymptotic exposure-response relationship when the PK exposure exceeds
EC50.
The estimated kCD19 was 0.0751 d-1,
corresponding to a 13-day residence time of CD19+ pro-B cells before
maturation to CD20+ B cells in the circulation. On the other hand,
mature CD20+ B cell has a rather long lifespan, with an estimated
typical value of 391 days in humans. However, there was a large
interindividual variability of CD20+ B cell lifespan across subjects.
Although Systemic Sclerosis subjects in a Phase 1 study (Study CP200)
tended to have lower estimate of B cell depletion slope than Multiple
Sclerosis and NMOSD subjects, from population analysis the difference
was not statistically significant. On the other hand, the effect of
inebilizumab on slope increased with baseline CD20+ B
cell count: the effect of inebilizumab was greater in subjects with
higher CD20+ B cell count at baseline. ADA, age and
other demographic covariates had no impact on PD of inebilizumab.
The goodness-of-fit and visual predictive check plots were used to
evaluate the appropriateness of the model structure in predicting the
clinical data. Due to the small sample size of each dose group of Phase
1 studies (Studies CP200 and 1102), the prediction bands although
captured the depletion and recovering trends of CD20+B cell response, in some regions deviated from the observations (Figure
3). Nevertheless, when the sample size is adequate (N-MOmentum), the B
response in adult subjects with NMOSD was well described by the PD
model.
There was no apparent relationship of PK exposure
(AUC0‑14d) to inebilizumab and the outcome of the
primary or key secondary efficacy endpoints (Figures 4-5, S2-S4).
Results of the exposure-response analyses confirmed that the fixed dose
of 300 mg inebilizumab resides at the efficacy plateau for the treatment
of NMOSD. In fact, the efficacy was slightly lower in subjects with high
AUC0-14d, likely due to random variability across
subgroups (Figures 4-5). The relationship of
AUCcumulative and time to onset of NMOSD attack during
the RCP was skewed since subjects experiencing NMOSD attack exited the
RCP and had the option to enter an OLP to receive active inebilizumab
treatment per protocol (Figure 5). The early withdrawal from the RCP led
to a lower AUCcumulative in subjects that experienced
NMOSD attack. In addition, subjects with slow, medium and fast CL of
inebilizumab had nearly identical outcomes, confirming that the 300 mg
fixed dose of inebilizumab resides at the efficacy plateau (Figure 5).
Although body weight has an impact on PK based on the population PK
analysis, it did not affect the inebilizumab efficacy. The 300 mg dose,
residing at the efficacy plateau, minimized the impact of PK variability
on efficacy outcome. As such, dose-adjustment by body weight is not
warranted.
Consistent with the absence of significant impact of ADA on inebilizumab
PK, from population modeling and exposure-response assessment, the
presence of ADA had no impact on PD (B cell depletion) or efficacy
endpoints in subject with NMOSD. However, this conclusion should be
taken with caution due to the small number of subjects who tested
positive for ADA during the RCP.
The population PD modeling and results of the exposure-response analysis
of the primary and key secondary endpoints demonstrate that the 300 mg
fixed dose of inebilizumab is an adequate dose to achieve an effective B
cell depletion and reduced risk for AC-determined NMOSD attack.