Phase 1/2 study of the activin receptor-like kinase (ALK)-2 inhibitor zilurgisertib (INCB000928, LIMBER-104) as monotherapy or with ruxolitinib (RUX) in patients (pts) with anemia due to myelofibrosis (MF).
Authors: Bose Prithviraj , Mohan Sanjay , Oh Stephen , Gotlib Jason R. , Ritchie Ellen K. , Shimomura Taizo , Ali Haris , Boyer Francoise , Guglielmelli Paola , Hunter Anthony , Lamothe Betty , Cui Yi , Seguy Francis , McBride Amanda , Palandri Francesca , Takeuchi Masahiro , Kiladjian Jean-Jacques 
Published: June 2023

7017 Background: 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 pts with anemia due to MF. Methods: The ongoing open-label, multicenter, phase 1/2 dose-escalation/expansion INCB 00928-104 study (NCT04455841) is evaluating zilurgisertib alone (treatment group A [TGA]) or with RUX (treatment group B [TGB]). Eligible pts are ≥18 years old with primary/secondary MF of intermediate (Int)-1 (TGB only) or Int-2/high-risk (TGA and TGB) per the Dynamic International Prognostic Scoring System (DIPSS) and are transfusion-dependent or have symptomatic anemia. The primary endpoint is safety and tolerability. Secondary endpoints include efficacy (per anemia response parameters), pharmacokinetics, and pharmacodynamics (eg, hepcidin and iron metabolism parameters). Results: 31 pts were enrolled by data cutoff (30Nov2022), with 20 in TGA (50 mg once daily [qd], n = 4; 100 mg qd, n = 4; 200 mg qd, n = 6; 400 mg qd, n = 6) and 11 in TGB (100 mg qd, n = 4; 200 mg qd, n = 5; 400 mg qd, n = 2). Median (range) age was 73 (5384) y for TGA and 77 (6485) y for TGB. 65% of TGA pts had received prior RUX therapy. Overall, 90% of pts had Int-2 risk DIPSS, and the remainder had high-risk DIPSS (1 pt in TGA, 2 in TGB). 60% of pts in TGA and 27% in TGB were transfusion-dependent at the time of enrollment. Median baseline (BL) hemoglobin (Hb) was 7.7 (range, 710) g/dL in TGA and 8.5 (range, 89) g/dL in TGB. BL hepcidin was high in both cohorts (median [range]: TGA, 171 [18535] ng/mL; TGB, 123 [7250] ng/mL; normal range, 050 ng/mL). At the time of analysis, dose escalation was ongoing in both treatment groups. No dose-limiting toxicities (DLTs) or study drugrelated serious adverse events (AEs) occurred in either treatment group. Maximum tolerated dose had not been reached at the time of analysis. Treatment-emergent AEs (TEAEs) were mainly low grade. Grade ≥3 TEAEs occurred in 7 pts, with thrombocytopenia the most common (n = 4). Reduction in hepcidin following zilurgisertib dosing was observed in TGA and TGB, with maximal hepcidin reduction at 6 h postdose. Hb increase of > 1.5 g/dL from BL occurred in 3 pts (27%) in TGB and 1 pt (5%) in TGA. Conclusions: Treatment with zilurgisertib monotherapy or in combination with RUX in this patient population was generally well tolerated, with predominantly grade 1/2 TEAEs and no DLTs. Reduced hepcidin levels were observed with both monotherapy and in combination with RUX, and preliminary improvements in anemia were observed, which suggest potential for therapeutic activity. Clinical trial information: NCT04455841 .