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OP019 Efficacy and safety of oral tofacitinib as induction therapy in patients with moderate-to-severe ulcerative colitis: results from 2 phase 3 randomised controlled trials

W. J. Sandborn1, B. E. Sands2, G. D’Haens*3, S. Vermeire4, S. Schreiber5, S. Danese6, J. Panés7, B. G. Feagan8, W. Reinisch9, W. Niezychowski10, G. Friedman10, N. Lawendy10, D. Yu10, D. Woodworth10, A. Mukherjee11, P. Healey11, H. Zhang10, C. Su10

1Division of Gastroenterology, University of California, San Diego, California, United States, 2Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, United States, 3Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands, 4Dept of Gastroenterology, University Hospitals Leuven, Leuven, Belgium, 5Klinik für Innere Medizin I, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany, 6IBD Centre, Department of Gastroenterology, Humanitas Research Hospital, Milan, Italy, 7Hospital Clinicas de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain, 8Robarts Research Institute, London, Ontario, Canada, 9McMaster University, Hamilton, Canada, 10Pfizer Inc, Collegeville, Pennsylvania, United States, 11Pfizer Inc, Groton, Connecticut, United States

Background

Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). Here we investigated efficacy and safety of tofacitinib as induction therapy in patients with active UC.

Methods

Patients (≥ 18 years old) in 2 identically-designed phase 3 studies (OCTAVE Induction 1, NCT01465763; OCTAVE Induction 2, NCT01458951) were randomised (4:1) to receive tofacitinib 10 mg twice daily (BID) or placebo for 8 weeks. Patients had moderately to severely active UC defined by full Mayo criteria, and previously failed treatment with ≥ 1 of corticosteroids, azathioprine, 6-mercaptopurine, or tumour necrosis factor inhibitors (TNFi). Primary endpoint was remission at week 8, defined as total Mayo score ≤ 2, no sub score >1, and rectal bleeding sub score of 0. Mucosal healing at week 8 (Mayo endoscopic sub score ≤ 1) was a key secondary endpoint. Other secondary endpoints included clinical response (decrease from baseline Mayo score of ≥ 3 points and ≥ 30%, plus decrease in rectal bleeding sub score ≥ 1 or absolute sub score ≤ 1), and partial Mayo score. Endoscopic scores were read centrally. Statistical significance was assessed using a fixed-sequence procedure to preserve Type-1 error.

Results

At baseline, 53%–58% of patients had prior TNFi exposure across treatment groups in both studies. At week 8, significantly more patients receiving tofacitinib 10 mg BID achieved remission, mucosal healing, and clinical response in both studies compared with the placebo (Table 1). Efficacy was similar for TNFi-treated vs TNFi-naïve patients. Improvements in partial Mayo score were rapid and significantly greater with tofacitinib vs placebo at weeks 2, 4, and 8.

Adverse event (AE) rates were similar across groups; rates of serious AEs were not higher with tofacitinib vs placebo. Rates of AEs of special interest are listed in the table. One patient died (tofacitinib 10 mg BID; dissecting aortic aneurysm). Increases in serum lipid (total cholesterol, low-density and high-density lipoprotein) and creatine kinase levels were seen with tofacitinib treatment.

Conclusion

Tofacitinib demonstrated significantly greater efficacy vs placebo based on remission and mucosal healing endpoints. Efficacy was similar in TNFi-treated vs TNFi-naïve-patients. Improvements in week 2 partial Mayo score (first post-baseline assessment) support early onset of treatment effect. Safety data from this 8-week induction study showed no new or unexpected observations from results in the tofacitinib studies in other populations.

Summary of efficacy and safety endpoints