FEATURES
Beyond Ruxolitinib
Exploring the JAK Inhibitors Landscape
In 2011 , the U . S . Food and Drug Administration ( FDA ) approved ruxolitinib as the first therapy to treat myelofibrosis ( MF ), one of the group of bone marrow ( BM ) disorders known as myeloproliferative neoplasms ( MPNs ). Ruxolitinib has since become a standard of care for the treatment of intermediate- and high-risk primary MF , post – polycythemia vera ( PV ) MF , and post – essential thrombocythemia MF . In December 2014 , the FDA extended the approval of ruxolitinib to a second type of MPN , for the treatment of patients with PV who have had an inadequate response to or are intolerant of hydroxyurea .
The drug was also the first Janus-associated kinase ( JAK ) inhibitor to receive regulatory approval . This class of drugs inhibits the activity of one or more of the JAK family of enzymes , interfering with the activation of the JAK-STAT ( signal transducer and activator of transcription ) pathway . 1 Tofacitinib was the second JAK inhibitor approved by the FDA for rheumatoid arthritis in 2012 . Recurrent activating mutations in JAK2 activating JAK-STAT signaling were simultaneously discovered by four research groups in 2005 . 2-5
“ The development of JAK inhibitors for MPN came out of research to find out what makes these diseases tick ,” explained Aaron Gerds , MD , MS , an assistant professor of medicine at the Taussig Cancer Institute of the Cleveland Clinic , who specializes in the treatment of myeloid malignancies . “ What we [ learned in 2005 ] was that activation of the JAK-STAT pathway is a hallmark of this group of diseases . That opened up a whole new world of treatment possibilities because , at the time [ of that discovery ], there were no approved therapies for MPNs .”
ASH Clinical News spoke with experts in MPN treatment about the role of ruxolitinib , as well as several investigational agents under development .
A Mainstay of Treatment The FDA ’ s decision to approve ruxolitinib for MPN was based on two phase III clinical trials – COMFORT-I and COMFORT-II – in which treatment with the oral JAK1 / 2 inhibitor significantly reduced symptom burden and was associated with an improvement from other therapies with respect to the number of patients with reduced spleen volume of at least 35 percent from baseline . 6 , 7
Based on these results , ruxolitinib quickly became a standard treatment for this patient group with limited treatment options . “ In my practice , I would use ruxolitinib for most patients with MF who have symptoms of the disease ,” said Claire Harrison , DM , professor of MPNs and clinical director at the Guy ’ s and St . Thomas ’ Hospital in London , who was the
8 Focus on Myeloid Malignancies