Momelotinib (JAK1/JAK2/ACVR1 inhibitor): mechanism of action, clinical trial reports, and therapeutic prospects beyond myelofibrosis

Abstract

Janus kinase 2 inhibitors (JAKi) are now part of the therapeutic armamentarium for primary and secondary myelofibrosis (MF). Patients with MF endure shortened survival and poor quality of life (QoL). Allogeneic stem cell transplant is currently the only treatment modality in MF with the potential to cure the disease or prolong survival. By contrast, current drug therapy in MF targets QoL and does not modify the natural history of the disease. The discovery of JAK2 and other JAK-STAT activating mutations (i.e., CALR and MPL) in myeloproliferative neoplasms, including MF, has facilitated the development of several JAKi that are not necessarily specific to the oncogenic mutations themselves but proved effective in countering JAK-STAT signaling, resulting in suppression of inflammatory cytokines and myeloproliferation. This non-specific activity resulted in clinically favorable effects on constitutional symptoms and splenomegaly and, consequently, FDA approval of three small molecule JAKi: ruxolitinib, fedratinib, and pacritinib. A fourth JAKi, momelotinib, is poised for FDA approval soon and has been shown to provide additional benefit in alleviating transfusiondependent anemia in MF. The salutary effect of momelotinib on anemia has been attributed to inhibition of activin A receptor, type 1 (ACVR1) and recent information suggests similar effect from pacritinib. ACRV1 mediates SMAD2/3 signalling that contributes to upregulation of hepcidin production and iron-restricted erythropoiesis. Therapeutic targeting of ACRV1 raises therapeutic prospects in other myeloid neoplasms associated with ineffective erythropoiesis, such as myelodysplastic syndromes with ring sideroblasts or SF3B1 mutation, especially those with co-expression of JAK2 mutation and thrombocytosis.