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.