Onset of Efficacy of Tofacitinib for Induction Therapy in Patients with Active Ulcerative Colitis in Two Multinational, Phase 3 Clinical Trials

Abstract

Introduction: Tofacitinib is an oral, small molecule JAK inhibitor that is being investigated for ulcerative colitis (UC). Two Phase 3 randomized placebo-controlled studies (OCTAVE Induction 1 and 2: NCT01465763, NCT01458951) demonstrated efficacy of tofacitinib 10 mg twice daily (BID) vs placebo as induction therapy for patients (pts) with moderate to severe UC.1 Here, we investigated how response and remission based on partial Mayo score (PMS) at Week (Wk) 2 correlate with clinical efficacy endpoints at Wk 8.Table 1: Summary of PMS response and PMS remission by treatment group over time (A), and at Wk 2 as predictors of efficacy endpoints at Wk 8 (B)Methods: Adults with moderately to severely active UC (Mayo score of ≥6, rectal bleeding subscore ≥1 and endoscopic subscore ≥2) were randomized (4:1) to receive treatment with tofacitinib 10 mg or placebo BID for up to 9 wks. Pts had previous failure or intolerance to ≥1 of corticosteroids, thiopurines, or tumor necrosis factor inhibitors (TNFi). Endpoints included Wk8 remission (primary endpoint, Mayo score ≤2, no subscore >1 and rectal bleeding subscore of 0); Wk 8 clinical response (decrease from baseline Mayo score of ≥3 points and ≥30%, plus decrease in rectal bleeding subscore ≥1 or absolute subscore ≤1); Wk 8 mucosal healing (Mayo endoscopic subscore ≤1); Wks 2, 4 and 8 PMS; Wks 2, 4 and 8 PMS response (PMS ≥2 decrease from baseline); and Wks 2, 4 and 8 PMS remission (PMS ≤2 with no individual subscore >1). The chi-square test was used to test if PMS response and PMS remission at Wk 2 correlated with remission, mucosal healing and clinical response at Wk 8. Results: Treatment difference with tofacitinib 10 mg BID vs placebo was achieved at Wks 2, 4 and 8: of 905 pts treated with tofacitinib 10 mg BID, 53.9%, 66.6% and 69.1% achieved PMS response, and 21.3%, 34.0% and 43.2% achieved PMS remission at Wks 2, 4 and 8, respectively (Table A). Both PMS response and PMS remission, at Wk 2, were significantly associated(p < 0.0001) with clinical endpoints at Wk 8 (Table B). Similar results were obtained in TNFi-naïve and -experienced subpopulations. Conclusion: In pts with moderate to severe UC treated with tofacitinib 10 mg BID, tofacitinib demonstrated induction efficacy based on PMS as early as Wk 2, the first time point measured in this study. Efficacy at Wk 2 is a good predictor of efficacy at Wk 8, regardless of prior TNFi therapy. Pts who have not achieved remission or response at Wk 2 based on PMS may still achieve improvements in Mayo score at Wk 8. Funded by Pfizer Inc. 1. Sandborn WJ et al. J Crohns Colitis 2016;10(S1):S15.