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OP032 Efficacy and safety of oral tofacitinib as maintenance therapy in patients with moderate to severe ulcerative colitis: results from a phase 3 randomised controlled trial

Sandborn W.J.1, Sands B.E.2, Danese S.3, D'Haens G.R.4, Vermeire S.5, Schreiber S.6, Feagan B.7, Reinisch W.8,9, Friedman G.10, Woodworth D.10, Zhang H.10, Lawendy N.10, Niezychowski W.10, Su C.10, Panés J.*11

1Division of Gastroenterology, University of California, San Diego, La Jolla, CA, United States 2Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, United States 3IBD Center, Department of Gastroenterology, Humanitas Research Hospital, Milan, Italy 4Department of Gastroenterology, Academic Medical Centre, Amsterdam, Netherlands 5Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium 6Klinik für Innere Medizin I, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany 7Robarts Clinical Trials, Inc., Robarts Research Institute, Western University, London, ON, Canada 8McMaster University, Hamilton, ON, Canada 9Medical University of Vienna, Vienna, Austria 10Pfizer Inc, Collegeville, PA, United States 11Hospital Clinic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain

Background

Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). Efficacy and safety of tofacitinib 10 mg twice daily (BID) were reported in OCTAVE Induction 1 & 2 [1].

Methods

OCTAVE Sustain (NCT01458574) was a Phase 3, randomised, double-blind, placebo (PBO) -controlled study that enrolled PBO or tofacitinib patients (pts) who completed OCTAVE Induction 1 or 2 with at least clinical response (≥3 points and ≥30% decrease from baseline (BL) Mayo score plus a decrease in rectal bleeding subscore of ≥1 or absolute rectal bleeding subscore ≤1). Pts were re-randomised (1:1:1) to maintenance treatment with PBO (N=198), tofacitinib 5 (N=198) or 10 mg BID (N=197) for 52 weeks (wks). The primary endpoint was remission (total Mayo score ≤2, no subscore >1, rectal bleeding subscore of 0) at Wk 52. Key secondary endpoints were mucosal healing (Mayo endoscopic subscore ≤1) at Wk 52, and sustained steroid-free remission (remission at Wks 24 and 52; no steroid use ≥4 wks prior to each visit) among pts in remission at BL.

Results

At Wk 52, tofacitinib 5 and 10 mg BID had significantly greater effect vs PBO for the primary endpoint of remission, and secondary endpoints of mucosal healing, clinical response as well as sustained remission, sustained mucosal healing and sustained clinical response (Table; p<0.001 all comparisons). Among pts in remission at BL, both tofacitinib groups had significantly higher proportions of pts with sustained steroid-free remission vs PBO (p<0.001 all comparisons). Adverse event (AE), serious AE and serious infection rates were similar among all groups. Despite more frequent infections with tofacitinib vs PBO, discontinuations due to AEs were numerically lower for tofacitinib vs PBO. A dose dependent increase in herpes zoster (HZ) rate was observed. There were no deaths, malignancies (excluding non-melanoma skin cancer) or intestinal perforation AEs in either tofacitinib group. Changes in lipid and creatine kinase levels were consistent with results from tofacitinib studies in other populations.

Conclusion

Tofacitinib 5 and 10 mg BID were significantly more effective vs PBO as maintenance therapy over 52 wks in pts with moderately to severely active UC. Despite a dose-dependent increase in HZ, overall, AE rates were similar among both tofacitinib groups. No new safety findings emerged from those previously reported in studies of rheumatoid arthritis.

References:

[1] Sandborn WJ et al, (2016), 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, J Crohns Colitis, 10: S15