Fedratinib

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Fedratinib
Fedratinib.svg
Clinical data
Trade names Inrebic
Other namesSAR302503; TG101348
AHFS/Drugs.com Monograph
License data
Routes of
administration 		By mouth
Drug class Antineoplastic agent
ATC code
Legal status
Legal status
Identifiers
  • N-tert-Butyl-3-{5-methyl-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C27H36N6O3S
Molar mass 524.68 g·mol−1
3D model (JSmol)
Density 1.247 ± 0.06 g/cm3
  • CC1=CN=C(N=C1NC2=CC(=CC=C2)S(=O)(=O)NC(C)(C)C)NC3=CC=C(C=C3)OCCN4CCCC4
  • InChI=1S/C27H36N6O3S/c1-20-19-28-26(30-21-10-12-23(13-11-21)36-17-16-33-14-5-6-15-33)31-25(20)29-22-8-7-9-24(18-22)37(34,35)32-27(2,3)4/h7-13,18-19,32H,5-6,14-17H2,1-4H3,(H2,28,29,30,31)
  • Key:JOOXLOJCABQBSG-UHFFFAOYSA-N
 X mark.svgNYes check.svgY  (what is this?)

Fedratinib, sold under the brand name Inrebic, is an anti-cancer medication used to treat myeloproliferative diseases including myelofibrosis. [5] It is used in the form of fedratinib hydrochloride capsules that are taken by mouth. It is a semi-selective inhibitor of Janus kinase 2 (JAK-2). [5] [6] It was approved by the FDA on 16 August 2019. [5]

Contents

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. [7]

Medical uses

In the United States, fedratinib is indicated for the treatment of adults with intermediate-2 or high-risk primary or secondary (following polycythemia vera or essential thrombocythemia) myelofibrosis. [2]

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. [3]

Pharmacology

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). [8] 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 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. [9]

Fedratinib was approved for medical use in the United States in August 2019. [2] [5] [6]

The U.S. Food and Drug Administration (FDA) granted the application for fedratinib priority review and orphan drug designations. [5] The FDA granted the approval of Inrebic to Impact Biomedicines, Inc., a wholly owned subsidiary of Celgene Corporation. [5]

Related Research Articles

Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 and 2, but were ultimately published as "Janus kinase". The name is taken from the two-faced Roman god of beginnings, endings and duality, Janus, because the JAKs possess two near-identical phosphate-transferring domains. One domain exhibits the kinase activity, while the other negatively regulates the kinase activity of the first.

<span class="mw-page-title-main">Polycythemia vera</span> Medical condition

Polycythemia vera is an uncommon myeloproliferative neoplasm in which the bone marrow makes too many red blood cells.

<span class="mw-page-title-main">Polycythemia</span> Laboratory diagnosis of high hemoglobin content in blood

Polycythemia is a laboratory finding in which the hematocrit and/or hemoglobin concentration are increased in the blood. Polycythemia is sometimes called erythrocytosis, and there is significant overlap in the two findings, but the terms are not the same: polycythemia describes any increase in hematocrit and/or hemoglobin, while erythrocytosis describes an increase specifically in the number of red blood cells in the blood.

<span class="mw-page-title-main">Chronic myelogenous leukemia</span> Medical condition

Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulation of these cells in the blood. CML is a clonal bone marrow stem cell disorder in which a proliferation of mature granulocytes and their precursors is found. It is a type of myeloproliferative neoplasm associated with a characteristic chromosomal translocation called the Philadelphia chromosome.

<span class="mw-page-title-main">Thrombocythemia</span> Medical condition

Thrombocythemia is a condition of high platelet (thrombocyte) count in the blood. Normal count is in the range of 150x109 to 450x109 platelets per liter of blood, but investigation is typically only considered if the upper limit exceeds 750x109/L.

<span class="mw-page-title-main">Hydroxycarbamide</span> Medical drug

Hydroxycarbamide, also known as hydroxyurea, is a medication used in sickle-cell disease, essential thrombocythemia, chronic myelogenous leukemia, polycythemia vera, and cervical cancer. In sickle-cell disease it increases fetal hemoglobin and decreases the number of attacks. It is taken by mouth.

<span class="mw-page-title-main">Essential thrombocythemia</span> Medical condition

Essential thrombocythemia (ET) is a rare chronic blood cancer characterised by the overproduction of platelets (thrombocytes) by megakaryocytes in the bone marrow. It may, albeit rarely, develop into acute myeloid leukemia or myelofibrosis. It is one of the myeloproliferative neoplasm wherein the bone marrow produces too many white or red blood cells, or platelets.

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 the bone marrow. This is most often associated with a somatic mutation in the JAK2, CALR, or MPL genes. In PMF, the bony aspects of bone marrow are remodeled in a process called osteosclerosis; in addition, fibroblast secrete collagen and reticulin proteins that are collectively referred to as (fibrosis). These two pathological processes compomise the normal function of bone marrow resulting in decreased production of blood cells such as erythrocytes granulocytes and megakaryocytes, the latter cells responsible for the production of platelets.

<span class="mw-page-title-main">Myeloproliferative neoplasm</span> Medical condition

Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers in which excess red blood cells, white blood cells or platelets are produced in the bone marrow. Myelo refers to the bone marrow, proliferative describes the rapid growth of blood cells and neoplasm describes that growth as abnormal and uncontrolled.

<span class="mw-page-title-main">Celgene</span> American biopharmaceutical company

Celgene Corporation is a pharmaceutical company that makes cancer and immunology drugs. Its major product is Revlimid (lenalidomide), which is used in the treatment of multiple myeloma, and also in certain anemias. The company is incorporated in Delaware, headquartered in Summit, New Jersey, and a subsidiary of Bristol Myers Squibb (BMS).

<span class="mw-page-title-main">Thrombopoietin receptor</span> Protein-coding gene in the species Homo sapiens

The thrombopoietin receptor also known as the myeloproliferative leukemia protein or CD110 is a protein that in humans is encoded by the MPL oncogene.

<span class="mw-page-title-main">Lestaurtinib</span> Chemical compound

Lestaurtinib is a tyrosine kinase inhibitor structurally related to staurosporine. This semisynthetic derivative of the indolocarbazole K252a was investigated by Cephalon as a treatment for various types of cancer. It is an inhibitor of the kinases fms-like tyrosine kinase 3 (FLT3), Janus kinase 2 (JAK2), tropomyosin receptor kinase (trk) A (TrkA), TrkB and TrkC.

A Janus kinase inhibitor, also known as JAK inhibitor or jakinib, is a type of immune modulating medication, which inhibits the activity of one or more of the Janus kinase family of enzymes, thereby interfering with the JAK-STAT signaling pathway in lymphocytes.

Givinostat (INN) or gavinostat is a histone deacetylase inhibitor with potential anti-inflammatory, anti-angiogenic, and antineoplastic activities. It is a hydroxamate used in the form of its hydrochloride.

<span class="mw-page-title-main">Ruxolitinib</span> Medication

Ruxolitinib, sold under the brand name Jakafi among others, is a medication used for the treatment of intermediate or high-risk myelofibrosis, a type of myeloproliferative neoplasm that affects the bone marrow; polycythemia vera, when there has been an inadequate response to or intolerance of hydroxyurea; and steroid-refractory acute graft-versus-host disease. Ruxolitinib is a Janus kinase inhibitor. It was developed and marketed by Incyte Corp in the US under the brand name Jakafi, and by Novartis elsewhere in the world, under the brand name Jakavi.

<span class="mw-page-title-main">Momelotinib</span> Chemical compound

Momelotinib (INN, formerly GS-0387, CYT-387) is an inhibitor of Janus kinases JAK1 and JAK2, acting as an ATP competitor with IC50 values of 11 and 18 nM, respectively. The inhibitor is significantly less active towards other kinases, including JAK3 (IC50 = 0.16 μM).

<span class="mw-page-title-main">Baricitinib</span> Chemical compound

Baricitinib, sold under the brand name Olumiant among others, is an immunomodulatory medication used for the treatment of rheumatoid arthritis, alopecia areata, and COVID-19. It acts as an inhibitor of janus kinase (JAK), blocking the subtypes JAK1 and JAK2.

<span class="mw-page-title-main">Gandotinib</span> Chemical compound

Gandotinib (LY-2784544) is an experimental drug developed by Eli Lilly for treatment of cancer. It is a small molecule JAK2 inhibitor, with additional minor inhibition of STAT3.

Prefibrotic primary myelofibrosis (Pre-PMF) is a rare blood cancer, classified by the World Health Organization as a distinct type of myeloproliferative neoplasm in 2016. The disease is progressive to overt primary myelofibrosis, though the rate of progression is variable and not all patients progress. Symptoms and presentation can mimic essential thrombocythemia, with the main differentiator for pre-PMF being the presence of fibrosis in the bone marrow.

<span class="mw-page-title-main">Bomedemstat</span> Chemical compound

Bomedmestat is an investigational drug under development by Imago BioSciences for the treatment of myeloproliferative neoplasms including essential thrombocythemia, polycythemia vera and myelofibrosis.

References

  1. ↑ "Summary Basis of Decision (SBD) for Inrebic". Health Canada. 23 October 2014. Retrieved 29 May 2022.
  2. 1 2 3 "Inrebic- fedratinib hydrochloride capsule". DailyMed. Retrieved 3 March 2021.
  3. 1 2 "Inrebic EPAR". European Medicines Agency (EMA). 9 December 2020. Retrieved 3 March 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  4. ↑ "Inrebic Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  5. 1 2 3 4 5 6 "FDA approves treatment for patients with rare bone marrow disorder". U.S. Food and Drug Administration (FDA) (Press release). 16 August 2019. Archived from the original on 21 November 2019. Retrieved 16 August 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  6. 1 2 "Drug Trials Snapshots: Inrebic". U.S. Food and Drug Administration (FDA). 30 August 2019. Archived from the original on 21 November 2019. Retrieved 20 November 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  7. ↑ Pardanani A, Gotlib JR, Jamieson C, Cortes JE, Talpaz M, Stone RM, Silverman MH, Gilliland DG, Shorr J, Tefferi A (March 2011). "Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis". Journal of Clinical Oncology. 29 (7): 789–796. doi:10.1200/JCO.2010.32.8021. PMC   4979099 . PMID   21220608.
  8. ↑ Pardanani A, Hood J, Lasho T, Levine RL, Martin MB, Noronha G, Finke C, Mak CC, Mesa R, Zhu H, Soll R, Gilliland DG, Tefferi A (August 2007). "TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations". Leukemia. 21 (8): 1658–1668. doi: 10.1038/sj.leu.2404750 . PMID   17541402. S2CID   22723501.
  9. ↑ "Celgene to Acquire Impact Biomedicines, Adding Fedratinib to Its Pipeline of Novel Therapies for Hematologic Malignancies". Celgene (Press release). 7 January 2018. Retrieved 18 January 2018.


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