JAK1/2 and pan-deacetylase inhibitor combination therapy yields improved efficacy in preclinical mouse models of JAK2V617F-driven disease

JAK inhibitors have demonstrated rapid and durable reductions in splenomegaly, as well as improvement in symptoms and quality of life in patients with myelofibrosis. However, the impact on the mutant allele burden and bone marrow fibrosis has been modest, indicating that combinations with other agents may further improve outcomes. Histone deacetylase inhibition has emerged as a promising combination modality based on in vitro studies using JAK2V617F mutant models that suggested a synergistic effect upon combination with a JAK2 inhibitor, and encouraging single-agent activity of the pan-deacetylase inhibitor panobinostat in phase I/II myelofibrosis trials. Here, we investigated the combination of the JAK1/2 inhibitor ruxolitinib and panobinostat in mouse models of JAK2V617F-driven disease. The combination was found to have a more profound effect on efficacy readouts as compared to either agent alone, and the analysis of pharmacodynamic readouts demonstrated that ruxolitinib and panobinostat have non-overlapping and complementary effects on biological pathways

JAK1/2 and pan-deacetylase inhibitor combination therapy yields improved efficacy in preclinical mouse models of JAK2V617F-driven disease

JAK inhibitors have demonstrated rapid and durable reductions in splenomegaly, as well as improvement in symptoms and quality of life in patients with myelofibrosis. However, the impact on the mutant allele burden and bone marrow fibrosis has been modest, indicating that combinations with other agents may further improve outcomes. Histone deacetylase inhibition has emerged as a promising combination modality based on in vitro studies using JAK2V617F mutant models that suggested a synergistic effect upon combination with a JAK2 inhibitor, and encouraging single-agent activity of the pan-deacetylase inhibitor panobinostat in phase I/II myelofibrosis trials. Here, we investigated the combination of the JAK1/2 inhibitor ruxolitinib and panobinostat in mouse models of JAK2V617F-driven disease. The combination was found to have a more profound effect on efficacy readouts as compared to either agent alone, and the analysis of pharmacodynamic readouts demonstrated that ruxolitinib and panobinostat have non-overlapping and complementary effects on biological pathways

JAK1/2 and pan-deacetylase inhibitor combination therapy yields improved efficacy in preclinical mouse models of JAK2V617F-driven disease”

JAK inhibitors have demonstrated rapid and durable reductions in splenomegaly, as well as improvement in symptoms and quality of life in patients with myelofibrosis. However, the impact on the mutant allele burden and bone marrow fibrosis has been modest, indicating that combinations with other agents may further improve outcomes. Histone deacetylase inhibition has emerged as a promising combination modality based on in vitro studies using JAK2V617F mutant models that suggested a synergistic effect upon combination with a JAK2 inhibitor, and encouraging single-agent activity of the pan-deacetylase inhibitor panobinostat in phase I/II myelofibrosis trials. Here, we investigated the combination of the JAK1/2 inhibitor ruxolitinib and panobinostat in mouse models of JAK2V617F-driven disease. The combination was found to have a more profound effect on efficacy readouts as compared to either agent alone, and the analysis of pharmacodynamic readouts demonstrated that ruxolitinib and panobinostat have non-overlapping and complementary effects on biological pathways

NVP-CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms

Summary Although clinically tested JAK inhibitors offer significant benefit to myeloproliferative neoplasm (MPN) patients, they do not induce molecular remissions. We previously demonstrated that MPN cells become persistent to type I JAK inhibitors which bind the active conformation of JAK2 and enable JAK2 transactivation. We investigated if NVP-CHZ868, a novel type II JAK inhibitor, would demonstrate activity in JAK inhibitor persistent cells and in murine MPN models. JAK2/MPL-mutant cell lines were sensitive to NVP-CHZ868, including type I JAK inhibitor-persistent cells. CHZ868 showed significant activity in murine MPN models and induced reductions in mutant allele burden not observed with type I JAK inhibitors. These data demonstrate that type II JAK inhibition should be pursued as a therapeutic approach for MPN patients. Significance Although clinically tested JAK inhibitors reduce splenomegaly and systemic symptoms, they cannot significantly reduce the MPN clone. We previously demonstrated that MPN cells can acquire persistence to type I JAK inhibitors, which bind the active conformation of JAK2 and enable activation of JAK2 in trans by other JAK family members. We show that engaging JAK2 in the inactive conformation with the novel type II inhibitor CHZ868 retains efficacy in type I JAK inhibitor persistent cells, and shows increased efficacy in murine models of polycythemia vera and myelofibrosis, including significant reductions in disease burden not observed with first-generation JAK inhibitors. These data demonstrate that type II JAK inhibitors improve the targeting of aberrant JAK2 signaling, offering increased therapeutic efficacy