The US Food and Drug Administration (FDA) has approved fedratinib (Inrebic, Celgene) capsules for the treatment of adult patients with certain types of myelofibrosis. Fedratinib, a highly selective JAK2 inhibitor, is indicated for patients with intermediate-2 or high-risk primary or secondary (post–polycythemia vera or post–essential thrombocythemia) myelofibrosis. Currently, ruxolitinib (Jakafi, Jakavi, Incyte/Novartis) is the only drug that has been approved for myelofibrosis. It entered the marketplace in 2011. "Prior to today, there was one FDA-approved drug to treat patients with myelofibrosis, a rare bone marrow disorder. Our approval today provides another option for patients," said Richard Pazdur, MD, director of the FDA's Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research, in a statement. "The FDA is committed to encouraging the development of treatments for patients with rare diseases and providing alternative options, as not all patients respond in the same way." Today's approval was based on the results of the JAKARTA study, a pivotal phase 3, multicenter, randomized, double-blind, placebo-controlled trial that evaluated the efficacy of daily oral doses (400 mg or 500 mg) of fedratinib as compared to placebo in patients with intermediate-2 or high-risk primary myelofibrosis, post–polycythemia vera myelofibrosis, or post–essential thrombocythemia myelofibrosis with splenomegaly. The cohort included 289 patients in 94 sites in 24 countries. The primary endpoint of the study was spleen response rate, defined as the proportion of patients who demonstrated a reduction in spleen volume of ≥35% after six 1-month treatment cycles. Secondary endpoints included symptom response rate, defined as the proportion of patients with a ≥50% reduction in total symptom score after six 1-month treatment cycles, as measured by the modified Myelofibrosis Symptom Assessment Form v2.0 diary. The results showed that 35 of 96 patients treated with a daily dose of fedratinib 400 mg (the dose recommended in the approved label) experienced a significant therapeutic effect (measured by a ≥35% reduction from baseline in spleen volume at the end of cycle six (week 24), as assessed with an MRI or CT scan, with a follow-up scan 4 weeks later). In addition, 36 patients experienced a ≥50% reduction in myelofibrosis-related symptoms, including night sweats, itching, abdominal discomfort, feeling full sooner than normal, pain under the ribs on the left side, and bone or muscle pain. Fedratinib previously received orphan drug designation for the treatment of secondary and primary myelofibrosis and was granted priority review designation. Common adverse effects associated with this agent include diarrhea, nausea, vomiting, fatigue, and muscle spasms. Healthcare professionals are cautioned that patients may experience severe anemia and thrombocytopenia. In addition, patients should be monitored for gastrointestinal toxicity and for hepatic toxicity. A boxed warning is included in the prescribing information. It advises healthcare professionals and patients about the risk for serious and fatal encephalopathy, including Wernicke encephalopathy, a neurologic emergency related to a deficiency in thiamine. Healthcare professionals are advised to assess thiamine levels in all patients prior to beginning therapy, during treatment, and as clinically indicated. If encephalopathy is suspected, fedratinib should be immediately discontinued. "Patients with myelofibrosis, including the number who are ineligible for or failed existing therapy, continues to increase, representing a well-defined unmet medical need," said Jay Backstrom, MD, chief medical officer for Celgene, in a statement. "We believe fedratinib can play an important role in the treatment of myelofibrosis, and we look forward to working with the FDA as the review process advances." Source
