Fedratinib

Fedratinib
Clinical data
Trade names	Inrebic
Other names	SAR302503; TG101348
AHFS/Drugs.com	Monograph
License data	US DailyMed: Inrebic;
Routes of; administration	By mouth
Drug class	Antineoplastic agent
ATC code	L01EJ02 (WHO) ;
Legal status
Legal status	CA: ℞-only; US: ℞-only; EU: Rx-only;
Identifiers
	IUPAC name N-tert-Butyl-3-{5-methyl-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide;
CAS Number	936091-26-8 ;
PubChem CID	16722836;
DrugBank	DB12500;
ChemSpider	17626393;
UNII	6L1XP550I6;
KEGG	D10630;
ChEBI	CHEBI:91408;
ChEMBL	ChEMBL1287853;
CompTox Dashboard (EPA)	DTXSID90239483 ;
Chemical and physical data
Formula	C27H36N6O3S
Molar mass	524.68 g·mol−1
3D model (JSmol)	Interactive image;
Density	1.247 ± 0.06 g/cm3
	SMILES CC1=CN=C(N=C1NC2=CC(=CC=C2)S(=O)(=O)NC(C)(C)C)NC3=CC=C(C=C3)OCCN4CCCC4;
	InChI 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;
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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]

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]

References

^ "Summary Basis of Decision (SBD) for Inrebic". Health Canada. 23 October 2014. Retrieved 29 May 2022.
^ ^a ^b ^c "Inrebic- fedratinib hydrochloride capsule". DailyMed. Retrieved 3 March 2021.
^ ^a ^b "Inrebic EPAR". European Medicines Agency (EMA). 9 December 2020. Retrieved 3 March 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ "Inrebic Product information". Union Register of medicinal products. Retrieved 3 March 2023.
^ ^a ^b ^c ^d ^e ^f "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. This article incorporates text from this source, which is in the public domain.
^ ^a ^b "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. This article incorporates text from this source, which is in the public domain.
^ 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.
^ 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.
^ "Celgene to Acquire Impact Biomedicines, Adding Fedratinib to Its Pipeline of Novel Therapies for Hematologic Malignancies". Celgene (Press release). 7 January 2018. Archived from the original on 31 October 2021. Retrieved 18 January 2018.

External links

Clinical trial number NCT01437787 for "Phase III Study of SAR302503 in Intermediate-2 and High Risk Patients With Myelofibrosis (JAKARTA)" at ClinicalTrials.gov

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[1] "Summary Basis of Decision (SBD) for Inrebic". Health Canada. 23 October 2014. Retrieved 29 May 2022.

[Inrebic_FDA_label-2] "Inrebic- fedratinib hydrochloride capsule". DailyMed. Retrieved 3 March 2021.

[Inrebic_EPAR-3] "Inrebic EPAR". European Medicines Agency (EMA). 9 December 2020. Retrieved 3 March 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

[4] "Inrebic Product information". Union Register of medicinal products. Retrieved 3 March 2023.

[FDA_PR-5] ^ ^a ^b ^c ^d ^e ^f "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. This article incorporates text from this source, which is in the public domain.

[FDA_Snapshot-6] "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. 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. Archived from the original on 31 October 2021. Retrieved 18 January 2018.

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