nuvisertib + momelotinib

Nuvisertib + momelotinib is an investigational oral combination therapy being studied for the treatment of myelofibrosis, particularly in patients with resistance or suboptimal response to existing JAK inhibitor therapy. **Nuvisertib** (TP-3654) is a selective, small molecule inhibitor of the serine/threonine-protein kinase PIM1, a kinase downstream of the JAK/STAT pathway, promoting cell survival and proliferation. In myelofibrosis, PIM1 dysregulation is implicated in disease progression and resistance to JAK inhibitors. **Momelotinib** is an approved small molecule inhibitor of Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), and activin receptor type 1 (ACVR1), indicated for the treatment of myelofibrosis and effective at reducing splenomegaly, symptom burden, and anemia. The combination is being evaluated in phase 1/2 clinical trials for its safety, efficacy, and ability to overcome resistance seen with JAK inhibitor monotherapies in intermediate/high-risk myelofibrosis. Preclinical and early clinical data suggest that combination of PIM1 and JAK inhibition may provide synergistic effects in reducing disease burden and symptomatology by targeting complementary pathways[1][3][5][6][7].