Eculizumab as a Key Comparator for the Evaluation of Complement Targeted Novel Therapeutic Strategies with a QSP Model
Authors: Clemens Lara , Kenz Zackary , Sandefur Conner , Shoda Lisl 
Published: February 2025

Objectives: Paroxysmal nocturnal hemoglobinuria (PNH) is one of multiple diseases in which complement dysregulation, leading to overactivity (i.e., complement‑mediated inflammation and/or cell lysis), has been implicated as a causal mechanism of disease. Eculizumab (ECU), a monoclonal antibody targeting complement protein C5, was FDA‑approved for the treatment of PNH in 2007, providing proof‑of‑concept that inhibiting complement activity could deliver therapeutic benefit. To facilitate the development of novel complement‑targeted therapies, ECU was represented as a comparator drug in a quantitative systems pharmacology (QSP) model of complement.Methods: COMPLEMENTsym™ is a QSP model1 of fluid-phase complement (patho-)physiology based on publicly available literature. The model includes simulated populations (SimPops®) representing normal healthy volunteers (NHV), as well as rheumatoid arthritis (RA) and PNH disease states. ECU exposure was modeled using a two-compartment pharmacokinetic (PK) model (MonolixSuite™) to reproduce single dose data in NHVs2,3, single dose data in RA patients4, and repeat dose data in PNH patients5. The PK model then predicted RA patient exposure from alternate protocols4,6. ECU was modeled as reducing free C5. ECU activity was optimized to free C5 levels in PNH patients7, with functional impact of reduced C5 on hemolysis in PNH patients8 and in RA patients4. The ECU representation was validated by combining the predicted exposures for three alternate repeat dosing protocols with the optimized parameter values for C5 reduction and hemolysis effect, and then comparing the resultant predictions with published data6.Results: By design, simulated ECU exposure reproduced NHV single dose, RA single dose, and PNH repeat dose data. The PK model was validated by simulation of an alternate single dose and comparison of PK metrics (Cmax, AUC, CL, Vd, t½) all falling within two-fold of experimentally‑derived data. By design, simulated ECU using validated PK in COMPLEMENTsym reproduced reported free C5 levels, reproduced dose-dependent hemolysis inhibition in RA patients, and reproduced hemolysis inhibition in PNH patients. The validation exercise demonstrated that the representation accurately captures exposure‑related differences in timing and magnitude of hemolysis inhibition, consistent with published data6.Conclusions: Simulated ECU exposure and activity were consistent with optimization and validation data. ECU inclusion in COMPLEMENTsym supported multiple goals: (1) qualifying a QSP model using available clinical data, (2) demonstrating successful association of a fluid‑phase analyte with a clinically‑relevant endpoint (i.e., hemolysis), and (3) providing comparator compounds against which novel complement therapies could be evaluated in head‑to‑head comparisons or as combination therapies.Citations: [1] Clemens. ASCPT Ann Mtg 2024[2] Chow 2020[3] Lee 2022[4] FDA 125166, Clin Pharm & Biopharmaceutics Review[5] Peffault de Latour 2020[6] Kivitz. ACR Ann Mtg 2001[7] Lee 2019[8] Harder 2019