|Other names||Fedratinib hydrochloride, SAR302503; TG101348|
|Drug class||Antineoplastic agent (inhibitor of Janus kinase 2 (JAK-2) and FLT-3)|
|Side effects||Diarrhea, nausea, low red blood cells, low platelets|
|Typical dose||400 mg OD|
|Chemical and physical data|
|Molar mass||524.68 g·mol−1|
|3D model (JSmol)|
|Density||1.247 ± 0.06 g/cm3|
Fedratinib, sold under the brand name Inrebic, is a medication used to treat myelofibrosis. This includes primary myelofibrosis, post-polycythaemia vera myelofibrosis, and post-essential thrombocythaemia myelofibrosis. It is used when there is an enlarged spleen or other symptoms. It is taken by mouth.
Fedratinib was approved for medical use in the United States in 2019 and Europe in 2021. In the United Kingdom a month of medication costs the NHS about £6,100 as of 2021. This amount in the United States costs about 21,300 USD.
This includes disease-related splenomegaly or symptoms in adults with primary myelofibrosis, following polycythaemia vera or essential thrombocythaemia, who are Janus kinase (JAK) inhibitor naïve or have been treated with ruxolitinib.
Myelofibrosis is a myeloid cancer associated with anemia, splenomegaly, and constitutional symptoms. Patients with myelofibrosis frequently harbor mutations which activate the JAK-STAT signaling pathway and which are sensitive to fedratinib. Phase I trial results focused on safety and efficacy of fedratinib in patients with high- or intermediate-risk primary or post–polycythemia vera/essential thrombocythemia myelofibrosis have been published in 2011.
It is generally taken at a dose of 400 mg once per day.
Mechanism of action
Fedratinib acts as a competitive inhibitor of protein kinase JAK-2 with IC50=6 nM; related kinases FLT3 and RET are also sensitive, with IC50=25 nM and IC50=17 nM, respectively. Significantly less activity was observed against other tyrosine kinases including JAK3 (IC50=169 nM). In treated cells the inhibitor blocks downstream cellular signalling (JAK-STAT) leading to suppression of proliferation and induction of apoptosis.
Fedratinib was originally discovered at TargeGen. In 2010, Sanofi-Aventis acquired TargeGen and continued development of fedratinib until 2013. In 2016, Impact Biomedicines acquired the rights to fedratinib from Sanofi and continued its development for the treatment of myelofibrosis and polycythemia vera. In January 2018, the drug's rights were transferred to Celgene with their purchase of Impact Biomedicines.
The U.S. Food and Drug Administration (FDA) granted the application for fedratinib priority review and orphan drug designations. The FDA granted the approval of Inrebic to Impact Biomedicines, Inc., a wholly owned subsidiary of Celgene Corporation.
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