Srdan Verstovsek, MD, PhD, Medical Oncologist and Professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center, discusses the mechanism of action of momelotinib, a JAK-inhibitor being investigated as a treatment for myelofibrosis.
Myelofibrosis is a rare cancer characterized by extensive scarring of the bone marrow and the disruption of normal blood cells production. This leads to severe anemia that can cause weakness and fatigue. Bone marrow scarring can also lead to low platelet levels, which increases the risk of bleeding. Additionally, myelofibrosis often causes an enlarged spleen.
As Dr. Verstovsek explains, momelotinib is a potent inhibitor of Janus kinase 1 (JAK1), Janus kinase 2 (JAK2) and Activin A receptor, type I (ACVR1). This unique profile results in clinical activity against each of the three hallmark features of myelofibrosis – anemia, constitutional symptoms and splenomegaly. 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 myelofibrosis 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. This is significant as other JAK-inhibitors used to manage myelofibrosis actually worsen patients’ anemia.
Recently, positive top line data were announced from the pivotal phase 3 MOMENTUM trial—a global, randomized, double-blind clinical trial evaluating momelotinib in myelofibrosis patients who are symptomatic and anemic. The trial met all of its primary and key secondary endpoints.
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