Population Pharmacokinetic/Pharmacodynamic Modeling and Simulation of a Flat Quarterly Riliprubart Dosing Regimen for Patients With Cold Agglutinin Disease

Abstract ID 92096 Poster Board 029 Introduction: Riliprubart is a humanized immunoglobulin G4 monoclonal antibody that inhibits the active form of C1s, preventing activation of the classical complement pathway (CP), whilst leaving the lectin and the alternative pathways functionally intact. Riliprubart is currently in development for the treatment of complement-mediated diseases, including cold agglutinin disease (CAD). Aim: To determine a dosing regimen for patients with CAD using population pharmacokinetic/pharmacodynamic (popPK/PD) modeling and simulations. Methods: The PKs of riliprubart in healthy subjects was characterized by a two-compartment model with linear elimination and first order absorption. Typical clearance was 2.12 mL/h, and body weight was the primary source of PK variability on peripheral volume of distribution. The riliprubart PK/PD relationship with Wieslab® CP or 50% hemolytic component (CH50) in healthy subjects was adequately described by a direct non-linear effect model. Based on the popPK/PD model developed using data from healthy subjects, riliprubart PK and PD were evaluated in patients with CAD after a single intravenous (IV) dose of 30 or 15 mg/kg. Using a Bayesian approach with pre-defined quality criteria, the PK characteristics of riliprubart in CAD patients was consistent with healthy subjects. Hemoglobin (Hb) response to riliprubart exposure in patients with CAD was adequately described by an indirect PK/PD model, including a zero-order rate constant for Hb production, and a first-order constant for Hb elimination, which is inhibited by riliprubart in the central compartment. The popPK and popPK/PD models were used to simulate a virtual population of 1,000 patients dosed with a quarterly IV regimen, with an additional dose on Day 29, at 3 dose levels: 30 mg/kg, 50 mg/kg and 3.5 g. Evaluation criteria included safety margins and efficacy (as informed by reduction of CH50 values to complement deficient states and >2 g/dL Hb increase from baseline). Results: A quarterly IV regimen with an additional dose on Day 29 for both 50 mg/kg and 3.5 g were projected to achieve the CH50 and Hb efficacy targets for >90% of the population, including patients with extreme low and high body weights. For the flat dose approach, there was a trend in area under the curve at steady state (AUCss) decreasing from extreme low body weights (35–54 kg) to extreme high body weights (130–200 kg); this decrease was ∼2.8-fold. For the body weight-based dose regimen, there was an increase in AUCss with increasing body weight over the same range; this increase was ∼1.2-fold. For 65–105 kg, the exposure between flat and weight-based approaches were comparable. The greatest difference was observed for the low (35–54 kg) and high (130–200 kg) body weights; however, the exposure difference between flat and weight-based approaches were 90% of patients were predicted to have Ctrough,ss above 300 μg/mL, achieving complement deficient states (based on CH50) leading to improvements of Hb in patients with CAD. Conclusion: Using a popPK/PD modeling and simulation approach to examine the relationship between clinical and PD efficacy markers for riliprubart, a flat quarterly dose of 3.5 g IV with an additional Day 29 dose was proposed to maximize the likelihood of therapeutic benefits for patients with CAD. Funding: This study was funded by Sanofi.