Sutimlimab Pharmacokinetics and Pharmacodynamics in Patients with Cold Agglutinin Disease.

Abstract

Sutimlimab, a humanized monoclonal antibody targeting the classical complement pathway, is approved in the US, Japan, and EU for the treatment of hemolytic anemia in adults with cold agglutinin disease. The objectives of this study were to support dose selection for Phase 3 studies, assess dose recommendations, and establish the relationship between sutimlimab exposure and clinical outcome (hemoglobin [Hb] levels). Clinically meaningful biomarkers were graphically analyzed and the exposure-response relationship was proposed. The pharmacokinetic (PK) characteristics of sutimlimab were best described by a two-compartment model with parallel linear and non-linear clearance terms. Body weight was a significant covariate for the volume of distribution in the central compartment (Vc) and total body clearance of sutimlimab. Ethnicity (Japanese, non-Japanese) was a covariate on Vc and maximal non-linear clearance. There were no PK differences between healthy participants and patients. Following graphical exposure-response analysis for biomarkers, a pharmacokinetic-pharmacodynamic model was developed by integrating an indirect response/turnover model for Hb with a maximum effect (Emax) model, relating the Hb-elevating effect of sutimlimab to plasma exposure. Renal function and occurrence of blood transfusion were identified as covariates on Hb change from baseline. Simulations showed that Emax was attained with the approved dosing (6.5 g in patients <75 kg, and 7.5 g in patients {greater than or equal to}75 kg), independent of covariate characteristics, and provided adequate sutimlimab exposure to maximize effects on Hb, bilirubin, and total complement component C4 levels. A change in Hb from baseline at steady state of 2.2 g/dL was projected, consistent with Phase 3 study observations. Significance Statement The final validated population PK and PK/PD models confirm that the approved dosing regimen for sutimlimab (6.5 g in patients <75 kg, and 7.5 g in patients ≥75 kg) is sufficient, without the need for further dose adjustments in populations of patients with cold agglutinin disease.