Abstract CT243: Clinical trial simulation to inform dose selection of zilurgisertib, an ALK2 inhibitor, in patients with anemia due to myelofibrosis (MF)

Abstract Disease-associated anemia is reported in over one-third of patients at MF diagnosis and can be exacerbated by currently available MF therapies. Further, anemia is associated with poor prognosis in MF. Activation of activin receptor-like kinase (ALK)-2 (also known as ACVR1) may contribute to MF-associated anemia via up-regulated levels of hepcidin. Zilurgisertib (INCB000928) is a potent and selective ALK2 inhibitor that has demonstrated dose-dependent improvement in hemoglobin levels in a cancer-induced anemia mouse model, in which maximum hemoglobin increase was observed when zilurgisertib trough concentration covered pSMAD IC50 for at least half of the dosing interval. Zilurgisertib is being evaluated as monotherapy or in combination with ruxolitinib in a phase 1/2 dose-escalation and -expansion study in patients with anemia due to MF (NCT04455841). The objective of the current study is to use modeling and simulation, which integrate both preclinical and clinical data, to inform dose finding for the ongoing phase 1/2 trial in MF patients. Population (Pop) PK analyses were conducted using a total of 3089 zilurgisertib plasma concentrations from 161 healthy subjects in 3 completed phase 1 studies: a single ascending dose study (64 subjects, 10-500 mg), a multiple ascending dose study (59 subjects, 50-400 mg QD and 300 mg BID), and a drug-drug interaction study (38 subjects, 100 mg single dose of zilurgisertib alone). A nonlinear mixed-effects modeling approach in Monolix software was used for the analyses. Zilurgisertib PK were well-characterized by a 3-compartment model with nonlinear clearance and inter-occasion variability on absorption rate constant and bioavailability. The diagnostic plots and visual predictive check demonstrated that the model appropriately characterized the zilurgisertib plasma concentrations. Because zilurgisertib PK are similar between MF patients and healthy subjects, as suggested by available PK data in MF patients receiving doses up to 200 mg, the pop PK model developed with data from healthy subjects was used to simulate steady-state exposures in MF patients receiving 200 to 600 mg daily dose. Simulation results showed that daily doses of ≥600 mg would result in >90% of patients achieving exposure similar to the observed exposure associated with maximum efficacy in the mouse model. The conclusions from this clinical trial simulation support the decision to continue dose escalation in MF patients receiving zilurgisertib monotherapy. Citation Format: Yan-ou Yang, Hong Yang, Betty Lamothe, Matthew Stubbs, Amanda McBride, Francis Seguy, Kevin Rockich, Jay Getsy, Phillip Wang, Xiang Liu, Jeff Jackson, Ekaterine Asatiani, Xuejun Chen. Clinical trial simulation to inform dose selection of zilurgisertib, an ALK2 inhibitor, in patients with anemia due to myelofibrosis (MF) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT243.