From Wikipedia, the free encyclopedia
Jump to: navigation, search
Systematic (IUPAC) name
Clinical data
Trade names Xeljanz, Jakvinus
AHFS/ entry
Licence data US FDA:link
  • US: C (Risk not ruled out)
Legal status
Routes of
Pharmacokinetic data
Bioavailability 74%
Protein binding 40%
Metabolism Hepatic (via CYP3A4 and CYP2C19)
Biological half-life 3 hours
Excretion Urine
CAS Number 477600-75-2
ATC code L04AA29
PubChem CID: 9926791
DrugBank DB08183
ChemSpider 8102425
ChEBI CHEBI:71200 YesY
Synonyms CP-690550
Chemical data
Formula C16H20N6O
Molecular mass 312.369 g/mol

Tofacitinib (trade names Xeljanz and Jakvinus, formerly tasocitinib,[1] CP-690550[2]) is a drug of the janus kinase (JAK) inhibitor class, discovered and developed by the National Institutes of Health and Pfizer. It is currently approved for the treatment of rheumatoid arthritis (RA) in the United States and other countries. It has demonstrated effectiveness in the treatment of psoriasis in Phase 3 studies. It is being studied for treatment of inflammatory bowel disease, and other immunological diseases, as well as for the prevention of organ transplant rejection.


It is an inhibitor of the enzyme janus kinase 1 (JAK1) and janus kinase 3 (JAK 3) , which means that it interferes with the JAK-STAT signaling pathway, which transmits extracellular information into the cell nucleus, influencing DNA transcription.[3]

In a mouse model of established arthritis, tofacitinib rapidly improved disease by inhibiting the production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissue. This efficacy in this disease model correlated with the inhibition of both JAK1 and 3 signaling pathways, suggesting that tofacitinib may exert therapeutic benefit via pathways that are not exclusive to inhibition of JAK3.[4]

Research history[edit]

The potential significance of JAK3 inhibition was first discovered in the laboratory of John O'Shea, an immunologist at the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH).[5] In 1994, Pfizer was approached by the NIH to form a public-private partnership in order to evaluate and bring to market experimental compounds based on this research.[5] Pfizer initially declined the partnership but agreed in 1996, after the elimination of an NIH policy dictating that the market price of a product resulting from such a partnership would need to be commensurate with the investment of public taxpayer revenue and the "health and safety needs of the public."[5] Pfizer worked with O'Shea's laboratory to define the structure and function of JAK3 and its receptors, and then handled the drug discovery, preclinical development, and clinical development of tofacitinib in-house.[6]

In November 2012, the U.S. Food and Drug Administration (FDA) approved tofacitinib for treatment of rheumatoid arthritis. Two rheumatologists interviewed by the magazine Nature Biotechnology complained that they were "shocked" and "disappointed" at the $2,055 a month wholesale price.[6]

A 2014 study showed that tofacitinib treatment was able to convert white fat tissues into more metabolically active brown fat, suggesting it may have potential applications in the treatment of obesity.[7]

Clinical trials[edit]

Rheumatoid arthritis[edit]

Phase II clinical trials tested the drug in rheumatoid arthritis patients that had not responded to DMARD therapy. In a tofacitinib monotherapy study, the ACR score improved by at least 20% (ACR-20) in 67% of patients versus 25% who received placebo; and a study that combined the drug with methotrexate achieved ACR-20 in 59% of patients versus 35% who received methotrexate alone. In a psoriasis study, the PASI score improved by at least 75% in between 25 and 67% of patients, depending on the dose, versus 2% in the placebo group.[8]

The most important side effects in Phase II studies were increased blood cholesterol levels (12 to 25 mg/dl LDL and 8 to 10 mg/dl HDL at medium dosage levels) and neutropenia.[8] Phase III trials testing the drug in rheumatoid arthritis started in 2007 and are scheduled to run until January 2015.[9]

In April 2011, four patients died after beginning clinical trials with tofacitinib. According to Pfizer, only one of the four deaths was related to tofacitinib.[10]

By April 2011, three phase III trials for RA had reported positive results.[11]

In November 2012, the U.S. FDA approved tofacitinib "to treat adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to, or who are intolerant of, methotrexate."[12]


Tofacitinib has demonstrated its effectiveness for plaque psoriasis in Phase 3 randomized, controlled trials in comparison to placebo and to etanercept.[13][14]

Ulcerative colitis[edit]

The OCTAVE study of Tofacitinib in Ulcerative Colitis started in 2012. It is currently enrolling patients, though the NIH trials page states that they expect the trial to close in June 2015.[15]


In a June 2015 study, a 53-year-old woman with vitiligo showed noticeable improvement after taking tofacitinib for five months.[16]

Atopic dermatitis[edit]

The results of using Tofacitinib in 6 patients with recalcitrant atopic dermatitis was published in the September 2015. All saw improvement in their atopic dermatitis without any adverse events.[17]

Safety and side effects[edit]

Tofacitinib was not approved by European regulatory agencies because of concerns over efficacy and safety.[18] Animal studies with tofacitinib conducted prior to human trials showed some carcinogenesis, mutagenesis, and impairment of fertility.[19]

Warnings and precautions[edit]

Xeljanz is required to have a boxed warning on its label about possible injury and death due to problems such as infections, Lymphoma and other malignancies which can arise from use of this drug.[12] Serious infections leading to hospitalization or death, including tuberculosis and bacterial, invasive fungal, viral, and other opportunistic infections, have occurred in patients receiving tofacitinib. Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with tofacitinib while on immunosuppressive medications. Patients are warned to avoid use of tofacitinib citrate during an "active serious infection, including localized infections." Doctors are advised to use it with caution in patients that may be at increased risk of gastrointestinal perforations. Laboratory Monitoring is recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids. Tofacitinib claims to have no contraindications, however doctors are advised to reduce the patient's dosage when combined with "potent inhibitors of Cytochrome P450 3A4 (CYP3A4)," such as ketoconazole), or one or more combined medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 such as fluconazole. Furthermore, "immunizations" with live vaccines should be avoided by tofacitinib users.[19]

Adverse reactions[edit]

The most commonly reported adverse reactions during the first three months in controlled clinical trials (occurring in greater than or equal to 2% of patients treated with tofacitinib citrate monotherapy or in combination with DMARDs) were upper respiratory tract infections, headache, diarrhea, and nasopharyngitis (the "common cold").[19]


  1. ^ Herper, Matthew (2 March 2011). "Why Pfizer’s Biggest Experimental Drug Got A Name Change". Forbes. Retrieved 3 March 2011. 
  2. ^ Kremer, J. M.; Bloom, B. J.; Breedveld, F. C.; Coombs, J. H.; Fletcher, M. P.; Gruben, D.; Krishnaswami, S.; Burgos-Vargas, R. N.; Wilkinson, B.; Zerbini, C. A. F.; Zwillich, S. H. (2009). "The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo". Arthritis & Rheumatism 60 (7): 1895–1905. doi:10.1002/art.24567. PMID 19565475. 
  3. ^ "Tasocitinib". Drugs in R&D 10 (4): 271–284. 2010. doi:10.2165/11588080-000000000-00000. PMC 3585773. PMID 21171673. 
  4. ^ Ghoreschi, K.; Jesson, M. I.; Li, X.; Lee, J. L.; Ghosh, S.; Alsup, J. W.; Warner, J. D.; Tanaka, M.; Steward-Tharp, S. M.; Gadina, M.; Thomas, C. J.; Minnerly, J. C.; Storer, C. E.; Labranche, T. P.; Radi, Z. A.; Dowty, M. E.; Head, R. D.; Meyer, D. M.; Kishore, N.; O'Shea, J. J. (2011). "Modulation of Innate and Adaptive Immune Responses by Tofacitinib (CP-690,550)". J Immunol. 186 (7): 4234–4243. doi:10.4049/jimmunol.1003668. PMC 3108067. PMID 21383241. 
  5. ^ a b c "Seeking Profit for Taxpayers in Potential of New Drug", Jonathan Weisman, New York Times, 18 March 2013 (subscription firewall)
  6. ^ a b Ken Garber (9 January 2013). "Pfizer's first-in-class JAK inhibitor pricey for rheumatoid arthritis market". Nature Biotechnology 31 (1): 3–4. doi:10.1038/nbt0113-3. PMID 23302910. 
  7. ^ Moisan A, et al. White-to-brown metabolic conversion of human adipocytes by JAK inhibition. Nature Cell Biology, 8 December 2014. DOI 10.1038/ncb3075
  8. ^ a b "EULAR: JAK Inhibitor Effective in RA But Safety Worries Remain". MedPage Today. June 2009. Retrieved 9 February 2011. 
  9. ^ Clinical trial number NCT00413699 for "Long-Term Effectiveness And Safety Of CP-690,550 For The Treatment Of Rheumatoid Arthritis" at
  10. ^ Matthew Herper. "Pfizer’s Key Drug Walks A Tightrope". Forbes. 
  11. ^ "Two Phase III Studies Confirm Benefits of Pfizer’s Tofacitinib Against Active RA". 28 Apr 2011. 
  12. ^ a b "FDA approves Xeljanz for rheumatoid arthritis". 6 Nov 2012. 
  13. ^ Papp KA, Menter MA, Abe M, et al. for the OPT Pivotal 1 and OPT Pivotal 2 Investigators. (7 July 2015). "Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: results from two, randomised, placebo-controlled, Phase 3 trials.". Br J Dermatol. doi:10.1111/bjd.14018. PMID 26149717. 
  14. ^ Bachelez H, van de Kerkhof PC, Strohal R, et al. for the OPT Compare Investigators. (Aug 8, 2015). "Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial.". Lancet. 386 (9993): 552–61. doi:10.1016/S0140-6736(14)62113-9. PMID 26051365. 
  15. ^
  16. ^ "This Drug Brought Pigment Back for Woman with Vitiligo". TIME. June 27, 2015. Retrieved June 29, 2015. 
  17. ^ Levy LL, Urban J, King BA (2015). "Treatment of recalcitrant atopic dermatitis with the oral Janus kinase inhibitor tofacitinib citrate". Journal of the American Academy of Dermatology 73 (3): 395–399. doi:10.1016/j.jaad.2015.06.045. PMID 26194706. 
  18. ^ Nordqvist, Christian (27 April 2013). "Pfizer's Arthritis Drug Xeljanz (tofacitinib) Receives A Negative Opinion In Europe". Medical News Today. Retrieved 2 August 2013.