Treating patients who have anemia due to myelofibrosis (MF) with zilurgisertib, a selective, oral ALK2 inhibitor, appears safe and well tolerated, according to a study presented at the 2023 American Society of Clinical Oncology Annual Meeting.
“Elevated levels of the iron regulator hepcidin can cause functional iron deficiency anemia; hepcidin dysregulation is central to anemia of chronic inflammation observed in several malignancies such as MF. ALK2 (ie, ACVR1) contributes to MF-associated anemia via hepcidin upregulation. We evaluated the safety and activity of zilurgisertib, a selective, oral ALK2 inhibitor, in [patients] with anemia due to MF,” the researchers wrote.
In this ongoing, open-label, multicenter, phase 1/2 dose-escalation/expansion analysis, lead researcher Prithviraj Bose and colleagues assessed zilurgisertib alone (treatment group A [TGA]) in 31 patients or with ruxolitinib (treatment group B [TGB]) in 11 patients. Patients in the population of interest were ≥18 years old with primary/secondary MF of intermediate (Int)-1 (TGB only) or Int-2/high-risk (TGA and TGB) and were transfusion-dependent or had symptomatic anemia. The primary outcome was safety and tolerability. Secondary outcomes included efficacy (per anemia response parameters), pharmacokinetics, and pharmacodynamics.
The investigators noted that at the time of analysis, dose escalation was ongoing in both treatment groups. Thus far, no dose-limiting toxicities (DLTs) or study drug-related serious adverse events (AEs) have been observed in either treatment arm. The maximum tolerated dose had not been reached at the time of analysis. Notably, the researchers observed a reduction in hepcidin following zilurgisertib dosing in both TGA and TGB, with maximal hepcidin reduction at 6 hours post-dose.
“Treatment with zilurgisertib monotherapy or in combination with ruxolitinib in this patient population was generally well tolerated, with predominantly grade 1/2 [treatment-emergent] AEs and no DLTs. Reduced hepcidin levels were observed with both monotherapy and in combination with [ruxolitinib], and preliminary improvements in anemia were observed, which suggests potential for therapeutic activity,” the researchers concluded.
Source: Bose P, Mohan S, Oh S, et al. Phase 1/2 study of the actin receptor-like kinase (ALK)-2 inhibitor zilurgisertib (INCB0000928, LIMBER-104) as monotherapy or with ruxolitinib (RUX) in patients with anemia due to myelofibrosis (MF). Abstract #7017. Published for the 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, Illinois.