Ruxolitinib

Ruxolitinib, sold under the brand names Jakafi and Jakavi, is a medication approved in the US in 2011 for the treatment of intermediate or high-risk myelofibrosis,[1] a type of myeloproliferative disorder that affects the bone marrow;[5][6] polycythemia vera (PCV), when there has been an inadequate response to or intolerance of hydroxyurea;[1][7] and steroid-refractory acute graft-versus-host disease.[1] 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.[1]

Ruxolitinib
Clinical data
Trade namesJakafi, Jakavi, Opzelura
Other namesINCB018424, INC424
AHFS/Drugs.comMonograph
MedlinePlusa612006
License data
Pregnancy
category
  • AU: C
Routes of
administration		By mouth, topical
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability95%[4]
Protein binding97%[4]
MetabolismLiver (mainly CYP3A4-mediated)[4]
Elimination half-life2.8-3 hours[4]
ExcretionUrine (74%), faeces (22%)[4]
Identifiers
IUPAC name
  • (3R)-3-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC17H18N6
Molar mass306.373 g·mol−1
3D model (JSmol)
SMILES
  • N#CCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
InChI
  • InChI=1S/C17H18N6/c18-7-5-15(12-3-1-2-4-12)23-10-13(9-22-23)16-14-6-8-19-17(14)21-11-20-16/h6,8-12,15H,1-5H2,(H,19,20,21)/t15-/m1/s1 Y
  • Key:HFNKQEVNSGCOJV-OAHLLOKOSA-N Y
 NY (what is this?)  (verify)

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.[3] It is also indicated for the treatment of adults with polycythaemia vera who are resistant to or intolerant of hydroxyurea.[3] 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,[1] 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.[1][3][8][9]

In the United States, ruxolitinib cream is indicated for the topical treatment of mild to moderate atopic dermatitis and vitiligo.[2]

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 structures that carry urine), bleeding, bruising, weight gain, hypercholesterolaemia (high blood cholesterol levels), dizziness, headache and raised liver enzyme levels.[3]

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.[3]

In acute graft-versus-host disease, the most common hematologic adverse reactions include anemia, thrombocytopenia, and neutropenia.[1] The most common nonhematologic adverse reactions include infections and edema.[1]

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.[1]

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.[1]

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]

In September 2021, ruxolitinib cream (sold under the brand name Opzelura) was approved for medical use in the United States for the treatment of mild to moderate atopic dermatitis (AD).[17] It is the first topical janus kinase inhibitor approved in the United States.[17]

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.[18]

Society and culture

In November 2011, ruxolitinib was approved by the U.S. Food and Drug Administration (FDA) for the treatment of intermediate or high-risk myelofibrosis based on results of the COMFORT-I and COMFORT-II Trials.[19]

In 2014, it was approved in polycythemia vera (PCV) when there has been an inadequate response to or intolerance of hydroxyurea, based on the RESPONSE trial.[20][7]

Research

It is being investigated for plaque psoriasis,[11] alopecia areata,[21] relapsed diffuse large B-cell lymphoma, and peripheral T-cell lymphoma.[22]

In February 2016, a phase III trial for pancreatic cancer was terminated due to insufficient efficacy.[23]

Eight weeks-treatment with ruxolitinib blunted senescent cell-mediated inhibition of adipogenesis and increased insulin sensitivity in 22-month-old mice.[24]

As of September 2019, a clinical trial is in progress to evaluate "Treatment Free Remission After Combination Therapy With Ruxolitinib Plus Tyrosine Kinase Inhibitors".[25]

References
  1. "Jakafi- ruxolitinib tablet". DailyMed. 26 February 2020. Archived from the original on 3 November 2020. Retrieved 16 November 2020.
  2. "Opzelura- ruxolitinib cream". DailyMed. Archived from the original on 1 November 2021. Retrieved 31 October 2021.
  3. "Jakavi EPAR". European Medicines Agency (EMA). Archived from the original on 12 November 2020. Retrieved 16 November 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  4. "Jakafi (ruxolitinib) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 12 December 2018. Retrieved 16 February 2014.
  5. Mesa RA, Yasothan U, Kirkpatrick P (February 2012). "Ruxolitinib". Nature Reviews. Drug Discovery. 11 (2): 103–4. doi:10.1038/nrd3652. PMID 22293561.
  6. Harrison C, Mesa R, Ross D, Mead A, Keohane C, Gotlib J, Verstovsek S (October 2013). "Practical management of patients with myelofibrosis receiving ruxolitinib". Expert Review of Hematology. 6 (5): 511–23. doi:10.1586/17474086.2013.827413. PMC 8201600. PMID 24083419. S2CID 5470231.
  7. Vannucchi AM, Kiladjian JJ, Griesshammer M, Masszi T, Durrant S, Passamonti F, et al. (January 2015). "Ruxolitinib versus standard therapy for the treatment of polycythemia vera". The New England Journal of Medicine. 372 (5): 426–35. doi:10.1056/NEJMoa1409002. PMC 4358820. PMID 25629741.
  8. "FDA approves ruxolitinib for chronic graft-versus-host disease". U.S. Food and Drug Administration (FDA). 22 September 2021. Archived from the original on 23 September 2021. Retrieved 22 September 2021. This article incorporates text from this source, which is in the public domain.
  9. "EU Commission Approval" (Press release). Novartis. 5 May 2022. Archived from the original on 6 July 2022. Retrieved 5 July 2022.
  10. Wysham NG, Sullivan DR, Allada G (May 2013). "An opportunistic infection associated with ruxolitinib, a novel janus kinase 1,2 inhibitor". Chest. 143 (5): 1478–1479. doi:10.1378/chest.12-1604. PMC 5991580. PMID 23648912.
  11. Mesa RA (June 2010). "Ruxolitinib, a selective JAK1 and JAK2 inhibitor for the treatment of myeloproliferative neoplasms and psoriasis". IDrugs. 13 (6): 394–403. PMID 20506062.
  12. Pardanani A, Tefferi A (March 2011). "Targeting myeloproliferative neoplasms with JAK inhibitors". Current Opinion in Hematology. 18 (2): 105–10. doi:10.1097/MOH.0b013e3283439964. PMID 21245760. S2CID 2059415.
  13. Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. (March 2012). "JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis". The New England Journal of Medicine. 366 (9): 787–98. doi:10.1056/NEJMoa1110556. hdl:2158/605459. PMID 22375970.
  14. Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. (March 2012). "A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis". The New England Journal of Medicine. 366 (9): 799–807. doi:10.1056/NEJMoa1110557. PMC 4822164. PMID 22375971.
  15. Tefferi A (March 2012). "Challenges facing JAK inhibitor therapy for myeloproliferative neoplasms". The New England Journal of Medicine. 366 (9): 844–6. doi:10.1056/NEJMe1115119. PMID 22375977.
  16. ASCO Annual Meeting 2011: JAK Inhibitor Ruxolitinib Demonstrates Significant Clinical Benefit in Myelofibrosis Archived 21 November 2011 at the Wayback Machine
  17. "Incyte Announces U.S. FDA Approval of Opzelura (ruxolitinib) Cream, a Topical JAK Inhibitor, for the Treatment of Atopic Dermatitis (AD)". Incyte. 21 September 2021. Archived from the original on 22 September 2021. Retrieved 21 September 2021 – via Business Wire.
  18. "Incyte Announces U.S. FDA Approval of Opzelura (ruxolitinib) Cream for the Treatment of Vitiligo". Incyte. 19 July 2022. Archived from the original on 19 July 2022. Retrieved 19 July 2022 – via Business Wire.
  19. "FDA Approves Incyte's Jakafi (ruxolitinib) for Patients with Myelofibrosis" (Press release). Incyte. Archived from the original on 24 June 2017. Retrieved 2 January 2012.
  20. Kaminskas E (4 December 2014). "Supplemental FDA approval letter for Jakafi (ruxolitinib) tablets" (PDF). U.S. Food and Drug Administration. Archived (PDF) from the original on 11 April 2021. Retrieved 1 May 2016.
  21. Falto-Aizpurua L, Choudhary S, Tosti A (December 2014). "Emerging treatments in alopecia". Expert Opinion on Emerging Drugs. 19 (4): 545–56. doi:10.1517/14728214.2014.974550. PMID 25330928. S2CID 21604470.
  22. Clinical trial number NCT01431209 for "Ruxolitinib Phosphate (Oral JAK Inhibitor INCB18424) in Treating Patients With Relapsed or Refractory Diffuse Large B-Cell or Peripheral T-Cell Non-Hodgkin Lymphoma" at ClinicalTrials.gov
  23. House DW (February 2016). "Incyte bags late-stage development of Jakafi for solid tumors; shares down 10% premarket". Seeking Alpha. Archived from the original on 10 October 2016. Retrieved 11 February 2016.
  24. Xu M, Palmer AK, Ding H, Weivoda MM, Pirtskhalava T, White TA, et al. (December 2015). "Targeting senescent cells enhances adipogenesis and metabolic function in old age". eLife. 4: e12997. doi:10.7554/eLife.12997. PMC 4758946. PMID 26687007.
  25. Clinical trial number NCT03610971 for "Treatment Free Remission After Combination Therapy With Ruxolitinib Plus Tyrosine Kinase Inhibitors" at ClinicalTrials.gov
  • "Ruxolitinib". Drug Information Portal. U.S. National Library of Medicine.
  • "Ruxolitinib phosphate". Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT03112603 for "A Study of Ruxolitinib vs Best Available Therapy (BAT) in Patients With Steroid-refractory Chronic Graft vs. Host Disease (GvHD) After Bone Marrow (REACH3)" at ClinicalTrials.gov
  • Clinical trial number NCT03745638 for "TRuE AD1 - An Efficacy and Safety Study of Ruxolitinib Cream in Adolescents and Adults With Atopic Dermatitis" at ClinicalTrials.gov
  • Clinical trial number NCT03745651 for "TRuE AD2 - An Efficacy and Safety Study of Ruxolitinib Cream in Adolescents and Adults With Atopic Dermatitis" at ClinicalTrials.gov
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