Fedratinib, sold under the brand name Inrebic, is an anti-cancer medication used to treat myeloproliferative diseases including

myelofibrosis Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is activation and growth of mutated cells in ...

. It is used in the form of fedratinib

hydrochloride In chemistry, a hydrochloride is an acid salt resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base (e.g. an amine). An alternative name is chlorhydrate, which comes from French. An archaic alternati ...

capsules that are taken by mouth. It is a semi-selective inhibitor of Janus kinase 2 (JAK-2). It was approved by the FDA on 16 August 2019. Myelofibrosis is a

myeloid Myeloid tissue, in the bone marrow sense of the word '' myeloid'' ('' myelo-'' + '' -oid''), is tissue of bone marrow, of bone marrow cell lineage, or resembling bone marrow, and myelogenous tissue (''myelo-'' + '' -genous'') is any tissue ...

cancer associated with

anemia Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availabl ...

splenomegaly Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant (LUQ) of the human abdomen. Splenomegaly is one of the four cardinal signs of ''hypersplenism'' which include: some reduction in number of circulat ...

, 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.

Medical uses

In the United States, fedratinib is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

for the treatment of adults with intermediate-2 or high-risk primary or secondary (following

polycythemia vera In oncology, polycythemia vera (PV) is an uncommon myeloproliferative neoplasm in which the bone marrow makes too many red blood cells. Approximately 98% of PV patients have a JAK2 gene mutation in their blood-forming cells (compared with 0.1-0 ...

essential thrombocythemia In hematology, essential thrombocythemia (ET) is a rare chronic blood cancer (myeloproliferative neoplasm) characterised by the overproduction of platelets (thrombocytes) by megakaryocytes in the bone marrow. It may, albeit rarely, develop into a ...

) myelofibrosis. In the European Union, fedratinib is indicated for the treatment of 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 Ruxolitinib (sold under the brand names Jakafi and Jakavi among others, and as Opzelura in cream form) is a medication used for the treatment of intermediate or high-risk myelofibrosis, a type of myeloproliferative neoplasm that affects the b ...

Pharmacology

Mechanism of action

Fedratinib acts as a competitive inhibitor of

protein kinase A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them ( phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a f ...

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.

History

Fedratinib was originally discovered at TargeGen. In 2010,

Sanofi-Aventis Sanofi S.A. is a French multinational pharmaceutical and healthcare company headquartered in Paris, France. The corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 2004, Sanofi-Synthélabo merg ...

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 Celgene Corporation, headquartered in Summit, New Jersey, was a pharmaceutical company that produced cancer and immunology drugs. Its primary products were Revlimid (lenalidomide), which is used in the treatment of multiple myeloma (63% of 2018 r ...

with their purchase of Impact Biomedicines. Fedratinib was approved for medical use in the United States in August 2019. The U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) granted the application for fedratinib

priority review Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program ...

and

orphan drug An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...

designations. The FDA granted the approval of Inrebic to Impact Biomedicines, Inc., a wholly owned subsidiary of Celgene Corporation.

References

External links

* Aminopyrimidines Drugs developed by Bristol Myers Squibb Cancer treatments Orphan drugs Protein kinase inhibitors Sulfonamides Tert-butyl compounds Pyrimidines Anilines Ethanolamines 1-Pyrrolidinyl compounds {{antineoplastic-drug-stub