zilurgisertib (INCB00928)

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.

P1/2, N=22, Active, not recruiting, Incyte Corporation | Recruiting --> Active, not recruiting | N=80 --> 22

Treatment with zilurgisertib monotherapy or in combination with RUX in this pt population was generally well tolerated, with predominantly grade 1/2 TEAEs. Reduced hepcidin levels were observed at all dose levels with both monotherapy and in combination with RUX, with greater control of hepcidin over time observed at higher zilurgisertib doses. Preliminary improvements in anemia were observed in non–transfusion-dependent pts during dose escalation, suggesting potential for therapeutic activity.

Taken together, the potent and selective on-target activity of zilurgisertib suggests that ALK2 inhibition could reduce hepcidin and improve anemia, and that the combination of zilurgisertib with ruxolitinib is a rational and attractive approach to mitigate anemia in patients with MF. The combination of ruxolitinib and zilurgisertib is currently being evaluated in a phase 1 clinical trial in patients with anemia due to myeloproliferative disorders (NCT04455841).

To our knowledge, panniculitis has not been reported as a cutaneous adverse event in association with luspatercept or INCB000928. Ultimately, these lesions were interpreted to represent primary involvement by his myeloid neoplasm. This case highlights the utility of IDH1 R132H immunohistochemistry to quickly confirm cutaneous involvement by myeloid neoplasia harboring this specific mutation.

Other key inclusion criteria include ineligibility for or lack of response to standard anemia treatments including erythropoietin-stimulating agents for patients with MDS; failure of standard MM treatments including alkylating agents, glucocorticoids, immunomodulators (lenalidomide, pomalidomide, or thalidomide), proteasome inhibitors, and daratumumab; Eastern Cooperative Oncology Group performance status ≤1 (dose escalation) or ≤2 (dose expansion); and life expectancy >6 months. Key exclusion criteria include presence of MDS with ring sideroblasts or with atypical chronic myeloid leukemia, juvenile myelomonocytic leukemia, or MDS/MPN overlap syndromes with ring sideroblasts and thrombocytosis; MDS requiring cytoreductive treatment other than hydroxyurea; MDS with bone marrow and peripheral blood myeloblast count ≥10%; platelet count <50×10 9 /L; or is a candidate for or has had prior allogeneic stem cell transplantation...Patients will receive treatment for up to 6 months and may continue if deriving clinical benefit and no progression occurs. Sites are open in the United States, France, and Italy.

Other key inclusion criteria are: ineligibility for or lack of response to standard anemia treatments including ESAs; failure of standard MM treatments including alkylating agents, glucocorticoids, immunomodulators, proteasome inhibitors, daratumumab; ECOG PS ≤1 (dose-escalation) or ≤2 (dose-expansion); and life expectancy >6 months. Key exclusion criteria are: presence of MDS with ring sideroblasts or with atypical chronic myeloid leukemia, juvenile myelomonocytic leukemia, or MDS/MPN overlap syndromes with ring sideroblasts and thrombocytosis; MDS requiring cytoreductive treatment other than hydroxyurea; MDS with bone marrow and peripheral blood myeloblast count ≥10%; platelet count <50 × 109/L; or prior allogeneic stem cell transplantation...Sites are opening in the United States, France, and Italy. Results Not applicable Conclusion Not applicable