Fedratinib

Fedratinib
Names
Trade namesInrebic
Other namesFedratinib hydrochloride, SAR302503; TG101348
IUPAC name
  • N-tert-Butyl-3-{5-methyl-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide
Clinical data
Drug classAntineoplastic agent (inhibitor of Janus kinase 2 (JAK-2) and FLT-3)[1]
Main usesMyelofibrosis[1]
Side effectsDiarrhea, nausea, low red blood cells, low platelets[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Routes of
use		By mouth
Typical dose400 mg OD[1]
External links
AHFS/Drugs.comMonograph
Legal
License data
Legal status
Chemical and physical data
FormulaC27H36N6O3S
Molar mass524.68 g·mol−1
3D model (JSmol)
Density1.247 ± 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

Fedratinib, sold under the brand name Inrebic, is a medication used to treat myelofibrosis.[1] This includes primary myelofibrosis, post-polycythaemia vera myelofibrosis, and post-essential thrombocythaemia myelofibrosis.[2] It is used when there is an enlarged spleen or other symptoms.[2] It is taken by mouth.[1]

Common side effects include diarrhea, nausea, low red blood cells, and low platelets.[2] Other side effects may include encephalopathy.[1] It is an inhibitor of Janus kinase 2 (JAK-2) and FLT-3.[1]

Fedratinib was approved for medical use in the United States in 2019 and Europe in 2021.[1][2] In the United Kingdom a month of medication costs the NHS about £6,100 as of 2021.[4] This amount in the United States costs about 21,300 USD.[5]

Medical uses

It is used for the treatment of adults with intermediate-2 or high-risk primary or secondary (following polycythemia vera or essential thrombocythemia) myelofibrosis.[3]

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.[2]

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.[6]

Dosage

It is generally taken at a dose of 400 mg once per day.[1]

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).[7] 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.[8]

Fedratinib was approved for medical use in the United States in August 2019.[3][9][10]

The U.S. Food and Drug Administration (FDA) granted the application for fedratinib priority review and orphan drug designations.[9] The FDA granted the approval of Inrebic to Impact Biomedicines, Inc., a wholly owned subsidiary of Celgene Corporation.[9]

References

  1. 1 2 3 4 5 6 7 8 9 "Fedratinib Monograph for Professionals". Drugs.com. Retrieved 10 December 2021.
  2. 1 2 3 4 5 6 7 "Inrebic EPAR". European Medicines Agency (EMA). 9 December 2020. Archived from the original on 7 March 2021. Retrieved 3 March 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  3. 1 2 3 "Inrebic- fedratinib hydrochloride capsule". DailyMed. Archived from the original on 6 April 2021. Retrieved 3 March 2021.
  4. ↑ "Fedratinib". SPS - Specialist Pharmacy Service. 19 March 2018. Archived from the original on 11 December 2021. Retrieved 10 December 2021.
  5. ↑ "Fedratinib Prices, Coupons & Savings Tips - GoodRx". GoodRx. Retrieved 10 December 2021.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ "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.
  9. 1 2 3 "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.Public Domain This article incorporates text from this source, which is in the public domain.
  10. ↑ "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.Public Domain This article incorporates text from this source, which is in the public domain.
External sites:
Identifiers:
  • 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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