Skip to main content

Fedratinib: First Approval

Abstract

Fedratinib (INREBIC®) is a JAK2-selective inhibitor that has been developed as an oral treatment for myelofibrosis. In August 2019, fedratinib received its first global approval in the USA for the treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis. Phase III clinical development for myelofibrosis is ongoing worldwide. This article summarizes the milestones in the development of fedratinib leading to this first approval for myelofibrosis.

This is a preview of subscription content, access via your institution.

References

  1. Pozdnyakova O, Wu K, Patki A, et al. High concordance in grading reticulin fibrosis and cellularity in patients with myeloproliferative neoplasms. Mod Pathol. 2014;27(11):1447–54.

    CAS  Article  Google Scholar 

  2. Pardanani A, Vannucchi AM, Passamonti F, et al. JAK inhibitor therapy for myelofibrosis: critical assessment of value and limitations. Leukemia. 2011;25(2):218–25.

    CAS  Article  Google Scholar 

  3. Keohane C, Kordasti S, Seidl T, et al. JAK inhibition induces silencing of T helper cytokine secretion and a profound reduction in T regulatory cells. Br J Haematol. 2015;171(1):60–73.

    CAS  Article  Google Scholar 

  4. Celgene Corporation. INREBIC® (fedratinib) capsules, for oral use: US prescribing information. 2019. http://www.fda.gov/. Accessed 16 Aug 2019.

  5. Celgene Corporation. U.S. FDA approves INREBIC® (fedratinib) as first new treatment in nearly a decade for patients with myelofibrosis [media release]; 16 Aug 2019. http://ir.celgene.com.

  6. US FDA. FDA approves fedratinib for myelofibrosis. 2019. http://www.fda.gov. Accessed 27 Aug 2019.

  7. TargeGen Inc. Sanofi-Aventis to acquire TargeGen, Inc [media release]; 1 July 2010. http://www.targegen.com.

  8. Impact Biomedicines. Startup Impact Biomedicines raises $22M to bring fedratinib to myelofibrosis patients [media release]; 16 Oct 2017. http://www.impactbiomedicines.com.

  9. Impact Biomedicines. Impact Biomedicines closes $90 million financing with Oberland Capital to fund fedratinib program advancement [media release]; 27 Oct 2017. http://www.impactbiomedicines.com.

  10. Celgene Corporation, Impact Biomedicines. Celgene to acquire Impact Biomedicines, adding fedratinib to its pipeline of novel therapies for hematologic malignancies [media release]; 8 Jan 2018. http://www.celgene.com.

  11. Zhou T, Georgeon S, Moser R, et al. Specificity and mechanism-of-action of the JAK2 tyrosine kinase inhibitors ruxolitinib and SAR302503 (TG101348). Leukemia. 2014;28(2):404–7.

    CAS  Article  Google Scholar 

  12. Wernig G, Kharas MG, Okabe R, et al. Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell. 2008;13(4):311–20.

    CAS  Article  Google Scholar 

  13. Hood J, Cao J, Chow C, et al. Development of TG101348 for the treatment of JAK2-driven malignancies [abstract no. 7083]. J Clin Oncol. 2008;26(Suppl 15):7083.

    Article  Google Scholar 

  14. Kittur J, Lasho TL, Butterfield JH, et al. TG101348, an orally bioavailable JAK2-selective inhibitor, potently inhibits KITD816V and FIP1L1-PDGFRA in vitro [abstract no. 2807]. Blood. 2008;112(11):2807.

    Google Scholar 

  15. Olnes MJ, Poon A, Tucker Z, et al. JAK2 inhibition with TG101348 inhibits monosomy 7 myelodysplastic syndromes (MDS) bone marrow cells in vitro: a potential targeted therapy for monosomy 7 MDS [abstract no. 973]. Blood. 2010;116(21):973.

    Google Scholar 

  16. Zhang Q, Zhang Y, Diamond S, et al. The Janus kinase 2 inhibitor fedratinib inhibits thiamine uptake: a putative mechanism for the onset of Wernicke’s encephalopathy. Drug Metab Dispos. 2014;42(10):1656–62.

    Article  Google Scholar 

  17. Hood J, Hazell A. Fedratinib does not inhibit thiamine uptake or induce experimental Wernicke’s encephalopathy in nonclinical studies [abstract no. 4993]. Blood. 2017;130(Suppl 1):4993.

    Google Scholar 

  18. Greco R, Hurley R, Sun F, et al. SAR302503: a Jak2 inhibitor with antitumor activity in solid tumor models [abstract no. 1796]. Cancer Res. 2012;72(8 Suppl 1):1796.

    Google Scholar 

  19. Gotlib J, Pardanani A, Jamieson C, et al. Long-term follow up of a phase 1/2 study of SAR302503, an oral JAK2 selective inhibitor, in patients with myelofibrosis (MF) [abstract no. 0361]. Haematologica. 2012;97(Suppl 1):0361.

    Google Scholar 

  20. Pardanani A, Gotlib JR, Jamieson C, et al. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol. 2011;29(7):789–96.

    CAS  Article  Google Scholar 

  21. Pardanani A, Tefferi A, Jamieson C, et al. A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis. Blood Cancer J. 2015;5:e335.

    CAS  Article  Google Scholar 

  22. Jamieson C, Hasserjian R, Gotlib J, et al. Effect of treatment with a JAK2-selective inhibitor, fedratinib, on bone marrow fibrosis in patients with myelofibrosis. J Transl Med. 2015;13:294.

    Article  Google Scholar 

  23. Zhang M, Xu CR, Shamiyeh E, et al. A randomized, placebo-controlled study of the pharmacokinetics, pharmacodynamics, and tolerability of the oral JAK2 inhibitor fedratinib (SAR302503) in healthy volunteers. J Clin Pharmacol. 2014;54(4):415–21.

    Article  Google Scholar 

  24. Zhang M, Xu C, Ma L, et al. Effect of food on the bioavailability and tolerability of the JAK2-selective inhibitor fedratinib (SAR302503): results from two phase I studies in healthy volunteers. Clin Pharmacol Drug Dev. 2015;4(4):315–21.

    CAS  Article  Google Scholar 

  25. Xu C, Shamiyeh E, Kanamaluru V, et al. A gastric PH modifier pantoprazole did not significantly affect the on pharmacokinetics of fedratinib in healthy male subjects [abstract no. PI-085]. Clin Pharmacol Ther. 2015;97(Suppl 1):PI-085.

    Google Scholar 

  26. Pardanani A, Harrison C, Cortes JE, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol. 2015;1(5):643–51.

    Article  Google Scholar 

  27. Mesa RA, Cortes JE, Cervantes F, et al. Symptom burden and health-related quality of life (HRQoL) in patients with myelofibrosis (MF) treated with fedratinib (SAR302503) in a phase III study (JAKARTA) [abstract no. 4061]. Blood. 2013;122(21):4061.

    Article  Google Scholar 

  28. Harrison CN, Schaap N, Vannucchi AM, et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol. 2017;4(7):e317–24.

    Article  Google Scholar 

  29. Harrison C, Schaap N, Vannucchi A, et al. Fedratinib in patients with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) previously treated with ruxolitinib (RUX): a reanalysis of the phase 2 JAKARTA-2 study [abstract no. PS1459 plus poster]. In: 24th Annual Congress of the European Hematology Association. 2019.

    Article  Google Scholar 

  30. Sanofi. Sanofi discontinues clinical development of investigational JAK2 agent fedratinib (SAR302503) [media release]; 18 Nov 2013. http://en.sanofi.com.

  31. Verstovsek S, Harrison CN, Barosi G, et al. FREEDOM: a phase 3b efficacy and safety study of fedratinib in intermediate- or high-risk myelofibrosis patients previously treated with ruxolitinib [abstract no. TPS7072]. J Clin Oncol. 2019;37(Suppl 15):TPS7072.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hannah A. Blair.

Ethics declarations

Funding

The preparation of this review was not supported by any external funding.

Conflicts of interest

During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the author on the basis of scientific completeness and accuracy. Hannah A. Blair is a salaried employee of Adis International Ltd/Springer Nature, is responsible for the article content and declares no relevant conflicts of interest.

Additional information

Enhanced material for this AdisInsight Report can be found at https://doi.org/10.6084/m9.figshare.9883325.

This profile has been extracted and modified from the AdisInsight database. AdisInsight tracks drug development worldwide through the entire development process, from discovery, through pre-clinical and clinical studies to market launch and beyond.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Blair, H.A. Fedratinib: First Approval. Drugs 79, 1719–1725 (2019). https://doi.org/10.1007/s40265-019-01205-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-019-01205-x