PWI-002 - A TRANSLATIONAL MODELING AND SIMULATION APPROACH TO INFORM FIRST-IN-HUMAN DOSE SELECTION FOR AN SIRNA TARGETING COMPLEMENT C3.

R. Crass, A. Carvalho, A. Park, F. Gauderault, E. Richardson, K. Prem; Apellis Pharmaceuticals.

Background: APL-3007 is an N-acetylgalactosamine (GalNAc) conjugated small interfering RNA (siRNA) targeting complement C3 messenger RNA (mRNA). Complement C3 is the convergence point of the three principal pathways of complement cascade activation, which is believed to play a key role in a broad range of diseases. The objective of this analysis was to develop translational pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) models to characterize the concentration-time profiles of APL-3007 and its target, C3, using data from non-human primates (NHPs) to inform first-in-human (FIH) dosing.

Methods: The analysis used data from one nonclinical study conducted in NHPs. Vehicle and APL-3007 0.3, 3, 10, and 30 mg/kg were administered as single subcutaneous (SC) doses to 3 male animals per group. Samples were collected and analyzed for APL-3007 in plasma and C3 protein in serum. PK and PK/PD non-linear mixed effects model development was performed using NONMEM with data processing in R. A likelihood-based method (M3, Beal SL 2001) was used to analyze all post-dose PK data including samples below the limit of quantification. A sequential approach was used in PK/PD modeling, where PK/PD parameters were conditioned upon empirical Bayesian estimates of PK parameters. Simulated human exposure and biomarker responses were generated using allometric scaling for PK parameters and target population specific parameters for biomarker turnover.

Results: A 2-compartment model with first-order absorption and parallel linear and non-linear elimination adequately characterized the observed PK data. Serum C3 response to APL-3007 was characterized using an indirect response model (IDRM) with an effect compartment to capture the delay between plasma drug concentration and biomarker response. Human simulations predict that a single 100 mg SC dose will induce at least 25% knockdown of serum C3 with single doses ≥900 mg needed to achieve >90% knockdown in serum.

Conclusion: A translational modeling and simulation approach was used to identify a target dose range for the FIH study of a novel GalNAc siRNA using data from NHPs without the requirement of intensive mechanistic modeling. A single-dose range of 100 mg to 1800 mg was identified for study in healthy subjects.