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

• Published in: Haematologica (Roma) 2023-11, Vol.108 (11), p.2919-2932
• Main Authors: Tefferi, Ayalew, Pardanani, Animesh, Gangat, Naseema
• Format: Article
• Language: English
• Subjects: Activin Receptors, Type I - therapeutic use; Anemia - drug therapy; Humans; Janus Kinase 2 - metabolism; Janus Kinase Inhibitors - therapeutic use; Myeloproliferative Disorders - drug therapy; Neoplasms - drug therapy; Nitriles - therapeutic use; Primary Myelofibrosis - diagnosis; Primary Myelofibrosis - drug therapy; Primary Myelofibrosis - genetics; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Quality of Life; Spotlight Review
• ISSN: 0390-6078; 1592-8721; 1592-8721
• DOI: 10.3324/haematol.2022.282612

Janus kinase (JAK) 2 inhibitors are now part of the therapeutic armamentarium for primary and secondary myelofibrosis (MF). Patients with MF endure shortened survival and poor quality of life. Allogeneic stem cell transplantation (ASCT) 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 quality of life 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 JAK inhibitors that are not necessarily specific to the oncogenic mutations themselves but have proven 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, approval by the Food and Drug Administration (FDA) of three small molecule JAK inhibitors: ruxolitinib, fedratinib, and pacritinib. A fourth JAK inhibitor, momelotinib, is poised for FDA approval soon and has been shown to provide additional benefit in alleviating transfusion-dependent 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 a similar effect from pacritinib. ACRV1 mediates SMAD2/3 signaling which contributes to upregulation of hepcidin production and iron-restricted erythropoiesis. Targeting 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 a JAK2 mutation and thrombocytosis.