The Discovery and Development of Ruxolitinib for the Treatment of Myelofibrosis

Ruxolitinib, a Janus kinase (JAK) 1 and JAK2 inhibitor, is the first FDA-approved therapy for intermediate or high-risk myelofibrosis (MF), the most serious of a group of haematological disorders known as myeloproliferative neoplasms. The idea of targeting JAKs for the treatment of cancer was first conceived in 2002, based on the biological premise that inhibition of STAT transcription factors would block tumour growth and proliferation. In 2004, discovery of a gain-of-function mutation in JAK2 known as JAK2 V617F in MPNs steered the development of ruxolitinib toward MF. MF is characterised by bone marrow fibrosis, progressive splenomegaly, debilitating constitutional symptoms, cytopenias and shortened survival. JAK2 V617F is present only in ∼50% of MF patients, while JAK dysregulation is present in all MF patients, indicating multiple mechanisms are involved in JAK dysregulation. Treatment of MF patients with ruxolitinib resulted in rapid and sustained reduction in splenomegaly and improvements in measured MF symptoms, shown first in a Phase I/II trial and later confirmed in two Phase III randomised trials, which supported its approval. Clinical benefits were observed regardless of JAK2 V617F status. Additional applications of ruxolitinib in MF and other diseases, including polycythemia vera, pancreatic cancer and other cancers, are under investigation.