A phase III trial investigating ruxolitinib found the oral drug effective at reducing spleen swelling in patients with myelofibrosis, a rare hematologic cancer. Ruxolitinib is an inhibitor of Janus kinases (JAKs) 1 and 2 and interleukin (IL)-6 signaling. Incyte Corporation and Novartis are collaborating on development of ruxolitinib and have announced plans to apply for regulatory approval in the United States and Europe within the next few months based on data from this and another pivotal phase III trial.
Nearly half of myelofibrosis patients have a JAK2V617F mutation or other mutations along the JAK pathway that disrupts its normal signaling activity. Studies have shown that patients with myelofibrosis who do not have the JAK2V617F mutation also typically have activated JAK signaling. A phase I-II study of ruxolitinib by Verstovsek and colleagues, published in the September 19, 2010, issue of the New England Journal of Medicine, found similar response rates in patients with and without the mutation.
In the phase III COMFORT-II (Controlled Myelofibrosis Study with Oral JAK Inhibitor Therapy) trial, 219 patients were randomized 2 to 1 to receive ruxolitinib or the best available approved treatment. According to Incyte's press release, after 48 weeks of treatment, more patients in the ruxolitinib group had experienced a decrease in spleen size 35% or greater. The company said "meaningful reductions" were also observed in constitutional symptoms, such as primary and post-essential thrombocythemia/polycythemia vera. Treatment-related adverse effects were described as manageable, and investigators plan to present data at an upcoming oncology meeting.
In the earlier phase I/II study, more than 150 patients were treated with ruxolitinib for >1 year. Less than 10% of patients experienced nonhematologic toxic effects, and common hematologic toxic effects included anemia and thrombocytopenia (grade 3/4). Investigators for that trial, which sought to establish the maximum tolerated dose, reported that ruxolitinib was absorbed rapidly, reaching peak plasma concentrations 1 to 3 hours after dosing then rapidly declining, with a terminal half-life of 2 to 3 hours. Toxicities were managed in the phase I/II study with dose reduction or treatment interruption.
Aberrant JAK signaling is also associated with inflammatory conditions such as psoriasis and rheumatoid arthritis, and studies are investigating ruxolitinib in patients with these disorders. The US Food and Drug Administration has already granted ruxolitinib orphan drug status for myelofibrosis.