zilurgisertib (INCB00928)

P1/2, N=22, Terminated, Incyte Corporation | Completed --> Terminated; Strategic Business Decision

P2, N=98, Recruiting, Incyte Corporation | Trial primary completion date: Jul 2025 --> Feb 2025

P1/2, N=84, Active, not recruiting, Incyte Corporation | Trial completion date: Oct 2025 --> Nov 2027

P1/2, N=84, Active, not recruiting, Incyte Corporation | Trial completion date: Jun 2026 --> Oct 2025 | Trial primary completion date: Nov 2025 --> Apr 2025

P2, N=98, Recruiting, Incyte Corporation | N=60 --> 98 | Trial completion date: Apr 2028 --> Dec 2032

These include TGF-β ligand traps (luspatercept, elritercept), activin A receptor type 1 (ACVR1)/activin receptor-like kinase 2 (ALK2) inhibitors (momelotinib, zilurgisertib), and anti-hemojuvelin antibody-based therapies (DISC-0974). Luspatercept and momelotinib are approved for anemia related to lower-risk MDS and MF, respectively, and represent an important addition to the treatment armamentarium, along with imetelstat, a telomerase inhibitor, recently ratified for anemia in lower-risk MDS. A promising strategy to overcome the limitations of existing anemia-directed therapies includes the use of drug combinations with complementary mechanisms (luspatercept + erythropoiesis stimulating agents, luspatercept + momelotinib, DISC-0974 + momelotinib), and harnessing the erythropoietic potential of sodium-glucose co-transporter-2 inhibitors (SGLT-2I). Future research should address the complex pathophysiology of anemia, standardize definitions for anemia with gender-specified cutoffs, implement uniform erythroid response criteria, and consider early therapeutic intervention in clinical trials for anemia-directed therapies.

P1/2, N=84, Active, not recruiting, Incyte Corporation | Recruiting --> Active, not recruiting | N=206 --> 84

Zilurgisertib exhibited a favorable pharmacokinetic profile amenable to once-daily dosing that can be administered without regard to food. Study results support further clinical development of zilurgisertib in patients.

P1/2, N=22, Completed, Incyte Corporation | Active, not recruiting --> Completed

P1/2, N=206, Recruiting, Incyte Corporation | N=100 --> 206 | Trial completion date: Apr 2024 --> Jun 2026 | Trial primary completion date: Apr 2024 --> Nov 2025

P2, N=60, Recruiting, Incyte Corporation | Trial completion date: Dec 2024 --> Apr 2028 | Trial primary completion date: Dec 2023 --> Apr 2025

Among the approved JAK inhibitors (ruxolitinib, fedratinib, momelotinib, and pacritinib) for MF, momelotinib and pacritinib are preferably used in cytopenic patients; both agents are potent ACVR1 inhibitors that suppress hepcidin expression via the BMP6/ACVR1/SMAD pathway and restore iron homeostasis/erythropoiesis...Zilurgisertib (ACVR1 inhibitor) and DISC-0974 (anti-hemojuvelin monoclonal antibody) are evaluated in early phase clinical trials in patients with MF and anemia. Luspatercept (ACVR2B ligand trap) is assessed in transfusion-dependent MF patients in a registrational phase 3 trial. Approved ACVR1 inhibitors and novel agents in development are poised to improve the outcomes of anemic MF patients.