P036 Impact of prior immunosuppressant and tumor necrosis factor inhibitor therapies on tofacitinib efficacy and safety in patients with ulcerative colitis
Authors: Gary Lichtenstein , Benjamin Cohen , Laurent Peyrin-Biroulet , Arif Soonasra , Leonardo Salese , Chudy Nduaka , Ronald Pedersen , Deborah Woodworth , Nervin Lawendy , Gary Friedman , Gary Chan , Chinyu Su 
Published: July 2019

BACKGROUND:
Tofacitinib is an oral small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). The tofacitinib UC program comprises Phase (P)2 and P3 induction studies, a P3 maintenance study, and an ongoing open-label extension study (1). We report efficacy and safety of tofacitinib in the UC program in patients with/without prior tumor necrosis factor inhibitor (TNFi) failure and/or immunosuppressant failure.

METHODS:
Efficacy data are reported from OCTAVE Induction 1 and 2 (NCT01465763 and NCT01458951; pooled data), and OCTAVE Sustain (NCT01458574). We evaluated rates of remission stratified by prior TNFi failure (yes/no) and prior immunosuppressant failure (yes/no). Where there were sufficient adverse events (AEs) to analyze, effects of prior TNFi failure, and prior immunosuppressant exposure on AEs of special interest (herpes zoster [HZ], serious infections, and adjudicated non-melanoma skin cancer [NMSC]), were evaluated using Cox regression analysis in tofacitinib-treated patients in the UC program (December 2016 data cut; N = 1,157; 1,613 patient-years' exposure).

RESULTS:
Among 1,139 patients (placebo: n = 234; tofacitinib 10 mg BID: n = 905) treated in OCTAVE Induction 1 and 2, 51.7% had prior TNFi failure and 71.9% had prior immunosuppressant failure. For patients with TNFi failure, Week (Wk) 8 remission rates were: placebo: 0.8%; 10 mg BID: 11.4% (difference from placebo [Δ] = 10.6%); rates for patients without TNFi failure were 11.8% and 24.1%, respectively (Δ = 12.3%). In patients with immunosuppressant failure, Wk8 remission rates were: placebo 3.2%; 10 mg BID: 15.6% (Δ = 12.4%); rates in patients without immunosuppressant failure were 11.8% and 23.0%, respectively (Δ = 11.1%). Among 593 patients treated in OCTAVE Sustain (placebo: n = 198; 5 mg BID: n = 198; 10 mg BID: n = 197), 44.7% had prior TNFi failure and 69.6% prior immunosuppressant failure at induction baseline. For patients with TNFi failure, Wk52 remission rates were: placebo: 11.2%; 5 mg BID: 24.1% (Δ = 12.9%); 10 mg BID: 36.6% (Δ = 25.3%); rates for patients without TNFi failure were: placebo: 11.0%; 5 mg BID: 41.7% (Δ = 30.7%); 10 mg BID: 44.2% (Δ = 33.2%). For patients with immunosuppressant failure, Wk52 remission rates were: placebo: 7.8%; 5 mg BID: 29.4% (Δ = 21.6%); 10 mg BID: 37.6% (Δ = 29.8%); rates for patients without immunosuppressant failure were: placebo 17.4%; 5 mg BID: 47.3% (Δ = 29.9%); 10 mg BID: 48.2% (Δ = 30.8%). Among all tofacitinib-treated patients in the UC program with prior TNFi failure, 505/583 (86.6%) had AEs and 92/583 (15.8%) had serious AEs. For patients without prior TNFi failure, 431/541 (79.7%) had AEs and 75/541 (13.9%) had serious AEs. Prior TNFi failure (hazard ratio [95% confidence interval]: 1.9 [1.2–3.2]) was identified as a significant risk factor for HZ, and for NMSC (11.3 [1.4–88.3]). Prior immunosuppressant exposure was not identified as a significant risk factor for AEs of special interest in Cox regression analyses.

CONCLUSION(S):
In patients with UC, prior TNFi/immunosuppressant failure did not preclude benefit from tofacitinib induction or maintenance therapy. Prior TNFi failure was associated with greater risk for HZ and NMSC. HZ cases in the UC program were typically non-complicated and manageable with standard antiviral therapy (2).