Ruxolitinib Explained

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;[1] [2] polycythemia vera, when there has been an inadequate response to or intolerance of hydroxyurea;[3] [4] 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.[5]

It was approved for medical use in the United States in 2011, and in the European Union in 2012. Ruxolitinib is the first FDA-approved pharmacologic treatment to address repigmentation in vitiligo patients.[6]

Medical uses

In the United States and the European Union, ruxolitinib is indicated for the treatment of disease-related splenomegaly or symptoms in adults with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythaemia-vera myelofibrosis, or post-essential thrombocythaemia myelofibrosis. It is also indicated for the treatment of adults with polycythaemia vera who are resistant to or intolerant of hydroxyurea. Ruxolitinib is also indicated for the treatment of steroid-refractory acute graft-versus-host disease in people who are twelve years of age and older, and for the treatment of chronic graft-versus-host disease (cGVHD) after failure of one or two lines of systemic therapy in people twelve years of age and older.[7] [8] It is commonly given as an oral tablet.

In the United States, ruxolitinib cream is indicated for the topical treatment of mild to moderate atopic dermatitis and vitiligo. In the European Union, ruxolitinib cream is indicated for the treatment of non-segmental vitiligo with facial involvement in adults and adolescents from 12 years of age.

Side effects

In myelofibrosis, the most common side effects include thrombocytopenia (low blood platelet counts), anaemia (low red blood cell counts), neutropenia (low levels of neutrophils), urinary tract infections (infection of the kidney, renal pelvis, ureter, bladder or urethra), bleeding, bruising, weight gain, hypercholesterolaemia (high blood cholesterol levels), dizziness, headache and raised liver enzyme levels.[9]

In polycythaemia vera, the most common side effects include anemia (low red blood cell counts) and thrombocytopenia (low blood platelet count), bleeding, bruising, hypercholesterolaemia (high blood cholesterol levels), hypertriglyceridemia (high blood fat levels), dizziness, raised liver enzyme levels and high blood pressure.

In acute graft-versus-host disease, the most common hematologic adverse reactions include anemia, thrombocytopenia, and neutropenia. The most common nonhematologic adverse reactions include infections and edema.

Immunologic side effects have included herpes zoster (shingles) and case reports of opportunistic infections.[10] Metabolic side effects have included weight gain. Laboratory abnormalities have included alanine transaminase (ALT) abnormalities, aspartate transaminase (AST) abnormalities, and mildly elevated cholesterol levels.[3]

Mechanism of action

Ruxolitinib is a Janus kinase inhibitor (JAK inhibitor) with selectivity for subtypes JAK1 and JAK2.[11] [12] Ruxolitinib inhibits dysregulated JAK signaling associated with myelofibrosis. JAK1 and JAK2 recruit signal transducers and activators of transcription (STATs) to cytokine receptors leading to modulation of gene expression.

History

In March 2012, the phase III Controlled Myelofibrosis Study with Oral JAK Inhibitor-I (COMFORT-I) and COMFORT-II trials showed significant benefits by reducing spleen size and relieving debilitating symptoms.[13] [14] [15] [16]

Society and culture

Legal status

In November 2011, ruxolitinib was approved by the U.S. Food and Drug Administration (FDA)[17] for the treatment of intermediate or high-risk myelofibrosis based on results of the COMFORT-I and COMFORT-II Trials.[18]

In 2014, it was approved in polycythemia vera when there has been an inadequate response to or intolerance of hydroxyurea, based on the RESPONSE trial.[19] [4]

In May 2019, the indication for ruxolitinib was expanded in the US to include steroid-refractory acute graft-versus-host disease.[20] The indication was further expanded in the US in September 2021, for the treatment of chronic graft-versus-host disease (cGVHD) after failure of one or two lines of systemic therapy in people 12 years of age and older.[21]

In September 2021, ruxolitinib cream (sold under the brand name Opzelura) was approved for medical use in the United States[22] for the treatment of mild to moderate atopic dermatitis (AD).[23] It is the first topical Janus kinase inhibitor approved in the United States.

In July 2022, ruxolitinib cream (sold under the brand name Opzelura) was approved for medical use in the United States for the treatment of vitiligo.[24]

On 23 February 2023, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Opzelura, intended for the treatment of non-segmental vitiligo. The applicant for this medicinal product is Incyte Biosciences Distribution B.V.[25]

Research

It is being investigated for plaque psoriasis,[11] alopecia areata,[26] relapsed diffuse large B-cell lymphoma, and peripheral T-cell lymphoma.

In February 2016, a phase III trial for pancreatic cancer was terminated due to insufficient efficacy.[27]

Eight weeks-treatment with ruxolitinib blunted senescent cell-mediated inhibition of adipogenesis and increased insulin sensitivity in 22-month-old mice.[28]

As of September 2019, a clinical trial is in progress to evaluate "Treatment Free Remission After Combination Therapy With Ruxolitinib Plus Tyrosine Kinase Inhibitors".

Notes and References

  1. Mesa RA, Yasothan U, Kirkpatrick P . Ruxolitinib . Nature Reviews. Drug Discovery . 11 . 2 . 103–4 . February 2012 . 22293561 . 10.1038/nrd3652 . 233195859 .
  2. Harrison C, Mesa R, Ross D, Mead A, Keohane C, Gotlib J, Verstovsek S . Practical management of patients with myelofibrosis receiving ruxolitinib . Expert Review of Hematology . 6 . 5 . 511–23 . October 2013 . 24083419 . 10.1586/17474086.2013.827413 . 5470231 . 8201600 .
  3. Web site: Jakafi- ruxolitinib tablet . DailyMed . 26 February 2020 . 16 November 2020 . 3 November 2020 . https://web.archive.org/web/20201103114348/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f1c82580-87ae-11e0-bc84-0002a5d5c51b . live .
  4. Vannucchi AM, Kiladjian JJ, Griesshammer M, Masszi T, Durrant S, Passamonti F, Harrison CN, Pane F, Zachee P, Mesa R, He S, Jones MM, Garrett W, Li J, Pirron U, Habr D, Verstovsek S . 6 . Ruxolitinib versus standard therapy for the treatment of polycythemia vera . The New England Journal of Medicine . 372 . 5 . 426–35 . January 2015 . 25629741 . 4358820 . 10.1056/NEJMoa1409002 .
  5. Web site: FDA Approves Jakafi® (Ruxolitinib) for the Treatment of Patients with Uncontrolled Polycythemia Vera . 4 December 2014 . 8 March 2023 . 8 March 2023 . https://web.archive.org/web/20230308063507/https://www.businesswire.com/multimedia/home/20141204005888/en/ . live .
  6. FDA approves topical treatment . U.S. Food and Drug Administration (FDA) . 19 July 2022 . 20 December 2022 . 20 December 2022 . https://web.archive.org/web/20221220073908/https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-topical-treatment-addressing-repigmentation-vitiligo-patients-aged-12-and-older . live .
  7. Web site: FDA approves ruxolitinib for chronic graft-versus-host disease . U.S. Food and Drug Administration (FDA) . 22 September 2021 . 22 September 2021 . 23 September 2021 . https://web.archive.org/web/20210923041936/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ruxolitinib-chronic-graft-versus-host-disease . live .
  8. EU Commission Approval . Novartis . 5 May 2022 . 5 July 2022 . 6 July 2022 . https://web.archive.org/web/20220706053649/https://www.novartis.com/news/media-releases/novartis-receives-european-commission-approval-jakavi-be-first-post-steroid-treatment-acute-and-chronic-graft-versus-host-disease . live .
  9. Web site: Jakavi EPAR . European Medicines Agency (EMA) . 17 September 2018 . 16 November 2020 . 12 November 2020 . https://web.archive.org/web/20201112034205/https://www.ema.europa.eu/en/medicines/human/EPAR/jakavi . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  10. Wysham NG, Sullivan DR, Allada G . An opportunistic infection associated with ruxolitinib, a novel janus kinase 1,2 inhibitor . Chest . 143 . 5 . 1478–1479 . May 2013 . 23648912 . 5991580 . 10.1378/chest.12-1604 .
  11. Mesa RA . Ruxolitinib, a selective JAK1 and JAK2 inhibitor for the treatment of myeloproliferative neoplasms and psoriasis . IDrugs . 13 . 6 . 394–403 . June 2010 . 20506062 .
  12. Pardanani A, Tefferi A . Targeting myeloproliferative neoplasms with JAK inhibitors . Current Opinion in Hematology . 18 . 2 . 105–10 . March 2011 . 21245760 . 10.1097/MOH.0b013e3283439964 . 2059415 .
  13. Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, McQuitty M, Hunter DS, Levy R, Knoops L, Cervantes F, Vannucchi AM, Barbui T, Barosi G . 6 . JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis . The New England Journal of Medicine . 366 . 9 . 787–98 . March 2012 . 22375970 . 10.1056/NEJMoa1110556 . 2158/605459 . free .
  14. Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, Catalano JV, Deininger M, Miller C, Silver RT, Talpaz M, Winton EF, Harvey JH, Arcasoy MO, Hexner E, Lyons RM, Paquette R, Raza A, Vaddi K, Erickson-Viitanen S, Koumenis IL, Sun W, Sandor V, Kantarjian HM . 6 . A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis . The New England Journal of Medicine . 366 . 9 . 799–807 . March 2012 . 22375971 . 4822164 . 10.1056/NEJMoa1110557 .
  15. Tefferi A . Challenges facing JAK inhibitor therapy for myeloproliferative neoplasms . The New England Journal of Medicine . 366 . 9 . 844–6 . March 2012 . 22375977 . 10.1056/NEJMe1115119 .
  16. ASCO Annual Meeting 2011: JAK Inhibitor Ruxolitinib Demonstrates Significant Clinical Benefit in Myelofibrosis
  17. Web site: Drug Approval Package: Jakafi (ruxolitinib) Tablets NDA # 202192 . 20 December 2022 . 20 December 2022 . https://web.archive.org/web/20221220080133/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202192Orig1s000TOC.cfm . live .
  18. FDA Approves Incyte's Jakafi (ruxolitinib) for Patients with Myelofibrosis . Incyte . 2 January 2012 . 24 June 2017 . https://web.archive.org/web/20170624001633/http://investor.incyte.com/phoenix.zhtml?c=69764&p=irol-newsArticle&ID=1631201&highlight= . live .
  19. Web site: Edvardas . Kaminskas . vanc . Supplemental FDA approval letter for Jakafi (ruxolitinib) tablets . U.S. Food and Drug Administration . 4 December 2014 . 1 May 2016 . 11 April 2021 . https://web.archive.org/web/20210411105725/https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/202192Orig1s008ltr.pdf . live .
  20. Web site: FDA approves ruxolitinib for acute graft-versus-host disease . U.S. Food and Drug Administration . 24 May 2019 . 20 December 2022 . 20 December 2022 . https://web.archive.org/web/20221220074057/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ruxolitinib-acute-graft-versus-host-disease . live .
  21. Web site: FDA approves ruxolitinib for chronic graft-versus-host disease . U.S. Food and Drug Administration . 31 January 2022 . 20 December 2022 . 23 September 2021 . https://web.archive.org/web/20210923041936/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ruxolitinib-chronic-graft-versus-host-disease . live .
  22. Web site: Drug Approval Package: OPZELURA . 20 December 2022 . 20 December 2022 . https://web.archive.org/web/20221220074630/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215309Orig1s000TOC.cfm . live .
  23. Web site: Incyte Announces U.S. FDA Approval of Opzelura (ruxolitinib) Cream, a Topical JAK Inhibitor, for the Treatment of Atopic Dermatitis (AD) . Incyte . Business Wire . 21 September 2021 . 21 September 2021 . 22 September 2021 . https://web.archive.org/web/20210922212303/https://www.businesswire.com/news/home/20210921006072/en/ . live .
  24. Web site: Incyte Announces U.S. FDA Approval of Opzelura (ruxolitinib) Cream for the Treatment of Vitiligo . Incyte . Business Wire . 19 July 2022 . 19 July 2022 . 19 July 2022 . https://web.archive.org/web/20220719011431/http://www.businesswire.com/news/home/20220718005819/en/Incyte-Announces-U.S.-FDA-Approval-of-Opzelura%E2%84%A2-ruxolitinib-Cream-for-the-Treatment-of-Vitiligo/ . live .
  25. Web site: Opzelura: Pending EC decision . European Medicines Agency (EMA) . 24 February 2023 . 24 February 2023 . 24 February 2023 . https://web.archive.org/web/20230224165613/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/opzelura . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  26. Falto-Aizpurua L, Choudhary S, Tosti A . Emerging treatments in alopecia . Expert Opinion on Emerging Drugs . 19 . 4 . 545–56 . December 2014 . 25330928 . 10.1517/14728214.2014.974550 . 21604470 .
  27. Web site: Douglas W. . House . vanc . Incyte bags late-stage development of Jakafi for solid tumors; shares down 10% premarket. . February 2016 . Seeking Alpha . 11 February 2016 . 10 October 2016 . https://web.archive.org/web/20161010090813/http://seekingalpha.com/news/3100076-incyte-bags-late-stage-development-jakafi-solid-tumors-shares-10-percent-premarket . live .
  28. Xu M, Palmer AK, Ding H, Weivoda MM, Pirtskhalava T, White TA, Sepe A, Johnson KO, Stout MB, Giorgadze N, Jensen MD, LeBrasseur NK, Tchkonia T, Kirkland JL . 6 . Targeting senescent cells enhances adipogenesis and metabolic function in old age . eLife . 4 . e12997 . December 2015 . 26687007 . 4758946 . 10.7554/eLife.12997 . free .

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