JAK Pathway Yielding Results

Ben Leach
Published: Wednesday, Jun 13, 2012
JAK2 Protein Though researchers have been aware of the Janus kinase (JAK) signaling pathway and its role in cellular processes for several decades, it was not until 2005 that mutations in the JAK gene were linked directly to the development of cancers. JAK plays an important role in the formation and development of blood cells, and defects in the gene have been identified in myeloproliferative neoplasms.

As a result, JAK inhibitors for the treatment of hematologic malignancies have been an intense research focus, with one drug receiving approval in 2011 and several more in various stages of clinical development.

In November, the FDA approved ruxolitinib (Jakafi; Incyte) for the treatment of intermediate or high-risk myelofibrosis, in which dysregulation of the JAK1 and JAK2 pathways results in a depletion of healthy bone marrow that burdens the liver and spleen.

In the phase III COMFORT-I study, 41.9% of patients receiving ruxolitinib had at least a 35% reduction in spleen size, and 45.9% of patients on the drug reported a reduction in symptoms.

Other JAK inhibitors are being assessed in clinical trials. These include:

  • Ruxolitinib: Incyte is continuing to develop the drug for several hematologic malignancies. A phase III trial is ongoing in polycythemia vera, a phase II study is under way in essential thrombocythemia vera, and phase I/II evaluations are continuing in advanced leukemias and other hematologic malignancies.
  • CYT387 (YM BioSciences): Two ongoing phase II trials are evaluating dosing, safety, and tolerability of the oral JAK1 and JAK2 inhibitor as monotherapy for patients with myelofibrosis. Results presented at the American Society of Hematology (ASH) Meeting in 2011 indicated significant durable response in anemia, splenomegaly, and constitutional symptoms, particularly at the 300- mg once-daily dose level.
  • SAR302503 (TG101348, Sanofi): A highly selective oral JAK2 inhibitor, SAR302503 is being tested in a phase III clinical trial that is currently enrolling patients with myelofibrosis. In an interim phase I/II analysis presented at ASH 2011, spleen responses were usually seen within the first three cycles, with 54.4% of patients achieving ≥ 50% spleen reduction after six months and 66.7% of patients achieving the same endpoint after 12 months.
  • LY2784544 (Eli Lilly): In the results of a phase I trial that were presented at ASH 2011, spleen reduction of at least 35% was observed in 13 of 17 evaluable patients (76%) with myeloproliferative neoplasm subtypes. A questionnaire found that 59% of patients reported symptom improvement ≥ 50%.

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