MECHANISM

Momelotinib is a potent inhibitor of Janus kinase1 (JAK1), Janus kinase2 (JAK2) and, uniquely amongst the JAK-inhibitor class, Activin A receptor, type I (ACVR1 or ALK2.

This unique profile results in demonstrable clinical activity against each of the three hallmark features of myelofibrosis (MF) – anemia, constitutional symptoms and splenomegaly – across the continuum of intermediate/high risk patients including JAKi-naïve and previously JAKi-treated subjects.

Momelotinib’s anemia benefit is primarily achieved through direct inhibition of ACVR1 leading to a decrease in circulating hepcidin. Hepcidin is often markedly elevated in MF and contributes to an iron restricted anemia. By lowering hepcidin, a corresponding increase in serum iron occurs with consequent clinically relevant increases in hemoglobin and red blood cells due to increased iron availability for erythropoiesis. Momelotinib has also been shown to stabilize, and in some cases ameliorate, thrombocytopenia.


In addition to its differentiated anemia benefit, momelotinib therapy elicits significant improvements in constitutional symptoms and splenomegaly by variously decreasing aberrant inflammatory cytokine signaling, mutant hematopoietic stem cell proliferation and red blood cell sequestration, consistent with potent inhibition of JAK1, JAK2 and the downstream JAK-STAT pathway.