Eculizumab as a Key Comparator for the Evaluation of Complement Targeted Novel Therapeutic Strategies with a QSP Model

Authors: Clemens L, Kenz Z, Sandefur CI, Shoda LKM
Conference: ACoP
Keywords: COMPLEMENTsym, Eculizumab (ECU), Paroxysmal Nocturnal Hemoglobinuria (PNH), QSP (quantitative systems pharmacology), QSP model
Software: COMPLEMENTsym, Monolix®
Division: Quantitative Systems Pharmacology (QSP)

Objective

  • 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 model 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 NHVs, single dose data in RA patients, and repeat dose data in PNH patients
  • The PK model then predicted RA patient exposure from alternate protocols
  • ECU was modeled as reducing free C5. ECU activity was optimized to free C5 levels in PNH patients, with functional impact of reduced C5 on hemolysis in PNH patients8 and in RA patients
  • 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 data.

Conclusion

  • Simulated ECU exposure and activity were consistent with optimization and validation data
  • The QSP model, COMPLEMENTsym, was qualified using available clinical data
  • This work demonstrated successful association of a fluid phase analyte with a clinically relevant endpoint (i.e., hemolysis)
  • Successful representation of eculizumab provides a comparator compound against which novel complement therapies could be evaluated in head-to-head comparisons or as combination therapies

By Lara Clemens, Zackary R. Kenz, Conner Sandefur, Lisl KM Shoda

Fifteenth American Conference of Pharmacometrics (ACoP15), November 10-13, 2024, Phoenix, Arizona