The US FDA has approved tofacitinib (Xeljanz, Pfizer) for the treatment of moderate-severe ulcerative colitis (UC).
- Janus kinase inhibitor (blocks STAT transcription factor activation and inflammatory signaling)
- First oral agent approved for chronic use in UC
- 10 mg tofacitinib PO BID induced remission in 17-18% of patients (vs. 8.2% placebo) after 8 weeks
- Of patients that responded after 8 week trial, 40.6% who continued 10-mg tofacitinib for 52 weeks achieved sustained remission (versus 11.1% placebo)
- Adverse events (common): arthralgia, diarrhea, elevated cholesterol, headache, shingles, rash, and upper respiratory infection
- Adverse events (severe): malignancy (e.g., lymphoma), serious opportunistic infections (FDA black-box warnings)
- 3 Phase III clinical trials (OCTAVE-1, OCTAVE-2, OCTAVE SUSTAIN)
- Randomized, double-blind, placebo-controlled
- 1139 patients for 8 week trials (OCTAVE-1, OCTAVE-2)
- 593 tofacitinib-responsive patients for 52-week trial (OCTAVE SUSTAIN)
- Approved in 2012 for rheumatoid arthritis and 2017 for psoriatic arthritis.
What is UC?
Ulcerative colitis is an inflammatory bowel disorder with a prevalence between 37 and 246 per 100,000 people in the United States. ¹ It is characterized by extensive mucosal inflammation in the colon and rectum. While the underlying causes of UC are not fully understood, both environmental factors and genetic predisposition are believed to play a role in the pathogenesis of the disease.² Patients often present with bloody diarrhea, urgency and tenesmus during defecation. Patients with UC who are having 4-6 stools per day are generally considered to have a moderate form of the disease, whereas more than six stools a day containing blood and evidence of systemic inflammatory response (fever, tachycardia, hypoalbuminemia, anemia) represents a severe form of the disease. Approximately 1/4 UC patients eventually undergo colectomy procedures.
What is Tofacitinib?
Tofacitinib is a partial, reversible janus kinase (JAK) inhibitor, approved for the treatment of rheumatoid arthritis, psoriatic arthritis, and now ulcerative colitis. It is the first oral medication approved for chronic use in moderate-severe UC (other treatments are IV or injected SQ).
Activation of JAK, a non-receptor tyrosine kinase, by extracellular cytokines induces the phosphorylation and dimerization of the transcription factor STAT, resulting in the transcription of genes that contribute to the inflammatory response.³ JAK inhibition by tofacitinib prevents cytokine signal transduction in hematopoietic and immune system cells and thus dampens the inflammatory pathways responsible for ulcerative colitis and rheumatoid arthritis progression.
1. Kappelman MD, Rifas-Shiman SL, Kleinman K, Ollendorf D, Bousvaros A, Grand RJ, Finkelstein JA. The prevalence and geographic distribution of Crohn’s disease and ulcerative colitis in the United States. Clin Gastroenterol Hepatol. 2007; 5:1424-9.
2. Collins P, Rhodes J. Ulcerative colitis: diagnosis and management. BMJ : British Medical Journal. 2006;333(7563):340-343.
3. Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2017 Nov 8. doi: 10.1093/nar/gkx1037