In a much-anticipated double milestone, the Food and Drug Administration has approved ruxolitinib for treatment of patients with myelofibrosis.
Ruxolitinib, an orphan drug to be marketed as Jakafi by Incyte Corp., becomes the first agent to be approved for the rare blood disease. The indication covers patients with intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF, according to a statement from Wilmington, Del.–based Incyte.
The FDA decision also makes ruxolitinib the first approved agent in a new class of drugs called JAK (Janus-associated kinase) inhibitors. Deregulation of signaling in the JAK pathway is believed to be associated with the enlarged spleen and other symptoms of myelofibrosis. Ruxolitinib inhibits the tyrosine kinases JAK1 and JAK2, which are suspected of being up-regulated in various inflammatory disorders and malignancies.
"Jakafi represents another example of an increasing trend in oncology where a detailed scientific understanding of the mechanisms of a disease allows a drug to be directed toward specific molecular pathways," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the agency’s announcement.
"The clinical trials leading to this approval focused on problems that patients with myelofibrosis commonly encounter, including enlarged spleens and pain," he noted.
In the pivotal phase III COMFORT-I and COMFORT-II trials, ruxolitinib produced substantial symptom relief in patients who were resistant or refractory to available myelofibrosis therapy or ineligible for allogeneic bone marrow transplantation. All 528 patients in these studies had enlarged spleens (splenomegaly) and other disease-related symptoms. They were assigned to treatment with ruxolitinib, placebo, or best available therapy (usually hydroxyurea or glucocorticoids).
More patients on ruxolitinib had a greater-than-35% reduction in spleen size, compared with those given the alternatives, the FDA noted. Similarly, patients on ruxolitinib were more likely to have a more-than-50% reduction in MF-related symptoms, such as abdominal discomfort, night sweats, itching, and bone or muscle pain, compared with placebo.
The Incyte announcement noted that 41.9% of patients who were treated with ruxolitinib in the COMFORT-I trial had a 35% or greater reduction in spleen volume at 24 weeks, compared with 0.7% of patients taking placebo (P less than 0.0001). The median time to response was less than 4 weeks.
In the COMFORT-II trial, 28.5% of patients who were treated with ruxolitinib had a 35% or greater reduction in spleen volume at 48 weeks, compared with none of the patients in the best available therapy arm, Incyte said. COMFORT-II was conducted by Novartis, which is collaborating with Incyte outside the United States.
Incyte said that the ruxolitinib dosage should be adjusted based on safety and efficacy. The recommended starting dose of ruxolitinib for most patients of 15 mg or 20 mg given orally twice daily based on the patient’s platelet count. A blood cell count must be performed before initiation of therapy, the company said, and complete blood counts should be monitored every 2-4 weeks until doses are stabilized.
Thrombocytopenia, anemia, fatigue, diarrhea, dyspnea, headache, dizziness, and nausea were the most common side effects, according to the FDA.