The Efficacy of Tofacitinib and Other JAK Inhibitors in Ulcerative Colitis

Ulcerative Colitis
Ulcerative Colitis
Tofacitinib is the first JAK inhibitor approved by the FDA for the treatment of UC in patients whose disease worsened or did not improve with conventional therapy.

Ulcerative colitis (UC) is commonly treated with biological therapies, including anti-tumor necrosis factor (TNF) agents; however, these therapies have limitations, including immunogenicity. Janus kinase (JAK) inhibitors are a novel therapy for UC that effectively modulate the response of a variety of proinflammatory cytokines involved in disease development.¹ A large body of evidence has established that JAK-dependent cytokines play important roles in the pathogenesis of immune-mediated diseases and blocking these cytokines may be an effective treatment route.² In a study published in the Journal of Crohn’s and Colitis, researchers discuss clinical trials supporting the efficacy of the JAK inhibitor tofacitinib in the treatment of moderate to severe UC.

Results from a Phase 2 Study with Tofacitinib

Oral tofacitinib was evaluated in 194 adult patients with moderate-to-severe UC in a dose-finding, double-blind, placebo-controlled phase 2 trial. Patients were randomly assigned to receive either placebo or a specified dose of tofacitinib during the 8-week study period. The primary endpoint, which was clinical response at week 8 defined as a 3-point and 30% decrease in Mayo score and rectal bleeding, was achieved by 42% of patients who received placebo, compared with 48%, 61%, and 78% of patients who received 3 mg, 10 mg, and 15 mg tofacitinib, respectively.¹

Results from a Phase 3 Program with Tofacitinib

The efficacy of oral tofacitinib in UC was also evaluated in the phase 3 OCTAVE program, which consisted of 2 randomized, double-blind, placebo-controlled induction trials of 8 weeks; a randomized, double-blind, placebo-controlled maintenance trial of 52 weeks; and an open-label extension (OLE) trial.¹

In the 2 induction trials, patients were randomized 1:4 to placebo and 10 mg tofacitinib; the maintenance trial included patients who responded to tofacitinib in the induction trials and who were randomized 1:1:1 to placebo, 5 mg, or 10 mg of tofacitinib. Overall, 54% of patients had previously been treated with anti­-TNF agents, and 46% had been using oral prednisone at baseline.¹

In both induction trials, the primary endpoint of clinical remission at week 8 occurred more frequently in patients who received 10 mg tofacitinib compared with patients who received placebo (18.5% vs 8.2%, P =.007 for induction trial 1; 16.6% vs 3.6%, P <.001 for induction trial 2). In the maintenance trial, clinical remission at week 52 occurred more frequently in both of the groups that received tofacitinib compared with the group that received placebo (34.3% in the 5 mg group, 40.6% in the 10 mg group, and 11.1% in the placebo group, P <.001). Tofacitinib was also shown to be significantly more effective than placebo in all secondary endpoints, including clinical response, mucosal healing, endoscopic remission, and Inflammatory Bowel Disease Questionnaire remission.¹

Patients who did not achieve clinical response by week 8 in the OCTAVE induction trials with tofacitinib were given the opportunity to participate in the OLE trial. At week 8 of the OLE trial, 51.2% of patients had achieved clinical response with 10 mg doses of tofacitinib. Results from the OLE trial supported the long-term efficacy of tofacitinib; patients in remission at week 52 of the maintenance trial who continued to receive 5 mg doses of tofacitinib experienced clinical response, clinical remission, and mucosal healing rates of 65.8%, 55.9%, and 62.5%, respectively at month 36.¹

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Real-World Evidence with Tofacitinib in Ulcerative Colitis

Since 2018, 7 retrospective cohort studies have evaluated the efficacy of tofacitinib for UC; however, these studies were limited by small sample sizes, unclear definitions of outcome measures, and missing data.

In a study from the University of Chicago, patients with UC, Crohn disease, or pouchitis were treated with 5 mg or 10 mg tofacitinib for at least 8 weeks. By week 8, 36% of patients achieved clinical response, defined as symptomatic improvement but not resolution, while 33% achieved clinical remission, defined as complete resolution of clinical symptoms. Steroid-free clinical remission was achieved in 26% of patients at week 8.¹

In a small French study that included 37 patients with ulcerative colitis who were treated with 10 mg tofacitinib, the primary endpoint of survival without colectomy at week 24 was achieved by 76.9% of patients, while 62.6% were still on tofacitinib at week 24. Clinical response occurred in 40.5% of patients, and 32.4% were in steroid-free clinical remission.¹

In the remaining 5 studies, tofacitinib was shown to produce high clinical response rates and improvements in ulcerative colitis symptoms—further supporting tofacitinib as a valid treatment option for patients with moderate to severe disease. Presently, tofacitinib is usually only used as a second-line therapy for patients whose disease worsened or did not progress on biological therapies.¹

The Use of Other JAK Inhibitors in Ulcerative Colitis

Other JAK inhibitors, including peficitinib and upadacitinib, have also been evaluated for the treatment of UC.¹

In a trial comparing the efficacy of peficitinib vs placebo, patients who took 150 mg peficitinib were significantly more likely to be in clinical remission (27.3% vs 7.0%, P <.05) or have mucosal healing (45.5% vs 18.6%, P <.05). In a trial evaluating the efficacy of upadacitinib vs placebo, patients who received upadacitinib had significantly higher endoscopic improvement and clinical response in Mayo score rates than patients who received placebo.¹

Many other JAK inhibitors are currently undergoing evaluation in clinical trials for the treatment of UC and Crohn disease, including filgotinib, TD-1473, PF-06651600 (JAK3 inhibitor), and PF-06700841 (TYK2/JAK1 inhibitor).¹ JAK inhibitors are also being evaluated as therapeutic strategies for other immune-mediated inflammatory disorders, including rheumatoid and psoriatic arthritis. When tested in rats with rheumatoid arthritis, oral filgotinib was effective at reducing paw swelling, inflammatory cell infiltration, and the degradation of bone and cartilage.³


Tofacitinib is the first JAK inhibitor approved by the FDA and European Medicines Agency for the treatment of UC in patients whose disease worsened or did not improve with conventional therapy or a biological agent. Future trials may further support the efficacy of this and other JAK inhibitors for the treatment for UC.

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1. Ferrante M, Sabino J. Efficacy of anti-JAK inhibitors in ulcerative colitis [published online December 27, 2019]. J Crohns Colitis. doi:10.1093/ecco-jcc/jjz202

2. Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O’Shea JJ. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov. 2017;17(1):78.

3. Westhovens R. Clinical efficacy of new JAK inhibitors under development. Just more of the same? [published online February 26, 2019]. Rheumatology (Oxford). doi:10.1093/rheumatology/key256