Extended Data Fig. 2: Pepinemab is detected in CSF at expected level for target engagement.
a. Drug concentration in CSF of subjects treated with pepinemab. Mean+SEM is shown; dotted lines indicate target concentration (~100-300 ng/ml). b. Concentration of soluble SEMA4D (sSEMA4D) in CSF, mean+SEM are shown for each treatment group (n = 26 PEPI, n = 28 PBO). *** indicates statistical significance, p = 0.000000001855. As seen in previous trials18,19, levels of total soluble SEMA4D (including complex of drug bound to target) increased 1.7-fold upon dosing due to the increased half-life of the pepinemab/SEMA4D complex in subjects treated with pepinemab compared to those treated with placebo (average of 5.9 vs 3.5 ng/ml respectively, p < 0.001), demonstrating evidence of target engagement in CSF. The mean (SD) observed maximum serum concentration (Cmax) after all infusions post visit 12 in Cohort B overall was 218 (115) µg/mL and the AUCtau over the dosing interval was 68,900 (14,447) µg*hr/mL. Based on the empirical Bayesian estimates of the pharmacokinetic parameters, the terminal elimination half-lives for Cohorts B1 and B2 were calculated to be approximately 25 and 23 days, respectively. In general, the clearance of pepinemab was low and the volume of distribution small, which is common to other therapeutic monoclonal antibodies and similar to observations in previously completed studies with pepinemab18,19.
