Exposure-response assessment for NMOSD attack
The Kaplan-Meier plot of AC-determined NMOSD attacks during the RCP in placebo and inebilizumab-treated subjects with low (first-tertile), medium (second tertile) and high (third tertile) AUC0-14d is shown in Figure 4. Subjects with low and medium AUC0-14d shown higher probability on attack-free period compared to subjects with high AUC0-14d and placebo. The AUC following the first dose was selected for the exposure-response (E‑R) assessment since the steady-state PK data were unavailable. Per protocol, subjects experiencing NMOSD attack exited the RCP and had the option to enroll into the OLP to initiate or continue to receive inebilizumab treatment, resulting in incomplete PK profiles following the 2nd dose in those who discontinued treatment in the RCP. There was no apparent relationship between the hazard ratio for the primary endpoint with AUC0-14d. There was no apparent relationship between the hazard ratio of NMOSD attack for inebilizumab relative to placebo during the RCP with the first dose AUC of inebilizumab.
Although body weight was identified as a PK covariate from the population modeling, with the 300 mg dose residing on the efficacy plateau, there were no clear trends in efficacy across the different quartiles of body weight (Figure 5). Based on the analysis of the primary efficacy endpoint, the adjustment of inebilizumab fixed dose (300 mg) by body weight is not warranted. The presence of ADA was detected in 25 subjects (8 of 56 placebo, 17 of 174 inebilizumab treatment groups) at baseline or during the RCP. From population modeling, the development of ADA had no significant effect on the PK of inebilizumab. No apparent effect of the presence of ADA on B cell depletion by inebilizumab treatment in the RCP or the primary efficacy endpoint was observed.