PII-210 - A BIOMARKER-FOCUSED QSP MODEL OF COMPLEMENT ALTERNATIVE AND TERMINAL PATHWAYS TO EVALUATE POTENTIAL TARGETS FOR THERAPEUTIC IMPACT IN COMPLEMENT-ASSOCIATED DISEASES: PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) AS A CASE STUDY.

L. Clemens, Z. Kenz, C. Vallejo, C. Sandefur, S. Siler, L. Shoda; Simulations Plus, Inc..

Background: Complement overactivity has been implicated in multiple diseases, but therapeutic targeting of complement is complicated by feedback loops, redundant functions, and availability of druggable targets. These challenges are well-suited to mechanistic modeling. Here, a QSP model focused on alternative and terminal pathway complement analytes in circulation is described, including simulated populations (SimPops®) of normal healthy volunteers (NHVs) and PNH patients and exemplar treatments. This work aimed to evaluate the impact of exemplar treatments to validate the model for predictive use.

Methods: The QSP model leveraged published models (1–3) and publicly available data informing complement pathways and kinetics. The NHV SimPops (N>5000) was developed based on publicly available data supporting known variability in key parameters, qualified against clinical data ranges for 13 analytes. The PNH SimPops (N>1000) incorporates NHV variability in addition to disease specific modifications, qualified against data for 4 analytes. Exemplars were optimized (and validated where possible) against published complement analyte or hemolysis data.

Results: The PNH SimPops has baseline elevated complement activity compared to the NHV SimPops (3.5x increase in sC5b-9). Simulated eculizumab treatment of a complement-treatment naïve PNH SimPops was optimized to reproduce published free C5 and AP activity reductions. Simulated pegcetacoplan treatment in naïve and eculizumab-treated PNH SimPops recapitulated published C3 elevations without optimization. Simulated iptacopan in naïve PNH SimPops was optimized to reproduce published reductions in Bb. Simulated iptacopan in eculizumab-treated PNH SimPops recapitulated published Bb reductions without further optimization.

Conclusion: The SimPops demonstrate consistency with complement analytes in health and disease. The disease representation is strengthened by reproducing clinical data from PNH patients treated with eculizumab, pegcetacoplan, and iptacopan. This work establishes a model and framework to evaluate novel targets and compounds for complement-associated diseases.

1. Bakshi. Bull Math Biol. 82(2):33. (2020)
2. Bansal. Front Pharmacol. 13:855743. (2022)
3. Caruso. PLoS Comput Biol. 16(10):e1008139. (2020)