(W-094) Population Pharmacokinetic/Pharmacodynamic Analysis of Cemdisiran (ALN-CC5) in Healthy Subjects and Patients with Immunoglobulin A Nephropathy

Megan Melch, MS – Associate Director, Alnylam Pharmaceuticals; Jongtae Lee, MD – Director, Alnylam Pharmaceuticals; Prajakta Badri, PhD – Senior Director, Alnylam Pharmaceuticals; Ishir Bhan, MD – Senior Director, Alnylam Pharmaceuticals; Nitin Mehrotra, PhD – Senior Director, Alnylam Pharmaceuticals; Gabriel Robbie, PhD – Senior Vice President, Alnylam Pharmaceuticals

Objectives: Cemdisiran is a subcutaneously administered novel synthetic RNA interference (RNAi) therapeutic being evaluated for the treatment of immunoglobulin A nephropathy (IgAN). Cemdisiran acts by reducing complement component 5 (C5) concentrations. The purpose of this analysis was to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model to characterize changes in serum C5 concentrations, to evaluate the impact of covariates on PK/PD parameters and to simulate alternative dosing regimens.

Methods: A population PK/PD model was developed using nonlinear mixed-effects modeling approach using NONMEM 7.5. The effect of allometrically scaled cemdisiran liver concentrations on serum C5 was modeled as an inhibitory function through an intermediary RNA-induced silencing complex (RISC) effect compartment. Serum C5 concentration data from phase 1 in healthy subjects and phase 2 in patients with IgAN studies were analyzed. Categorical and continuous measures for demographics and other relevant factors were evaluated for their effect on serum C5 reduction. Standard model evaluation techniques were used to assess adequacy and robustness of the PK/PD model.

Results: An indirect response model adequately described serum C5 profiles following single and multiple subcutaneous administration across a wide dose range. The covariate effect of patients with IgAN (compared to healthy subjects) on IC₅₀ and body weight on RISC clearance (CL_RISC) were found to be statistically significant in the PK/PD model. Patients with IgAN had a 46% lower IC50 compared to healthy subjects. CL_RISC increased with increase in body weight. However, the range of C5 reductions greatly overlapped thus effects of these covariates were not considered clinically meaningful. Other covariates, age, sex, baseline C5 levels, race and estimated glomerular filtration rate (eGFR; range of 26.0~139 mL/min/1.73m²) were not found to be significant. Steady state C5 suppression of 99% is expected with a dosing regimen of 600 mg q4W.

Conclusions: The cemdisiran population PK/PD model provided adequate characterization of observed serum C5 concentrations in patients with IgAN. There were no clinically meaningful differences in serum C5 reduction across the covariates evaluated and hence no dose adjustment was deemed necessary.

Citations: NA