Gary S. Friedman

Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis

BACKGROUND Tofacitinib, an oral, small‐molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of tofacitinib as induction and maintenance therapy. METHODS We conducted three phase 3, randomized, double‐blind, placebo‐controlled trials of tofacitinib therapy in adults with ulcerative colitis. In the OCTAVE Induction 1 and 2 trials, 598 and 541 patients, respectively, who had moderately to severely active ulcerative colitis despite previous conventional therapy or therapy with a tumor necrosis factor antagonist were randomly assigned to receive induction therapy with tofacitinib (10 mg twice daily) or placebo for 8 weeks. The primary end point was remission at 8 weeks. In the OCTAVE Sustain trial, 593 patients who had a clinical response to induction therapy were randomly assigned to receive maintenance therapy with tofacitinib (either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary end point was remission at 52 weeks. RESULTS In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P=0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P<0.001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5‐mg tofacitinib group and 40.6% in the 10‐mg tofacitinib group versus 11.1% in the placebo group (P<0.001 for both comparisons with placebo). In the OCTAVE Induction 1 and 2 trials, the rates of overall infection and serious infection were higher with tofacitinib than with placebo. In the OCTAVE Sustain trial, the rate of serious infection was similar across the three treatment groups, and the rates of overall infection and herpes zoster infection were higher with tofacitinib than with placebo. Across all three trials, adjudicated nonmelanoma skin cancer occurred in five patients who received tofacitinib and in one who received placebo, and adjudicated cardiovascular events occurred in five who received tofacitinib and in none who received placebo; as compared with placebo, tofacitinib was associated with increased lipid levels. CONCLUSIONS In patients with moderately to severely active ulcerative colitis, tofacitinib was more effective as induction and maintenance therapy than placebo. (Funded by Pfizer; OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain ClinicalTrials.gov numbers, NCT01465763, NCT01458951, and NCT01458574, respectively.)

Tofacitinib in Patients with Ulcerative Colitis: Health-Related Quality of Life in Phase 3 Randomised Controlled Induction and Maintenance Studies

Abstract Background and Aims Tofacitinib is an oral, small molecule Janus kinase [JAK] inhibitor that is being investigated for ulcerative colitis [UC]. We evaluated health-related quality of life [HRQoL] in tofacitinib UC Phase 3 studies. Methods Patients ≥ 18 years old in OCTAVE Induction 1 [N = 598] and 2 [N = 541] with moderately to severely active UC were randomised [1:4] to placebo or tofacitinib 10 mg twice daily [BID] for 8 weeks. Subsequently, OCTAVE Sustain re-randomised [1:1:1] clinical responders [N = 593] from induction studies to placebo, tofacitinib 5 mg BID, or 10 mg BID, for 52 weeks. Inflammatory Bowel Disease Questionnaire [IBDQ] and SF-36v2® Health Survey [SF-36v2] assessed HRQoL. Results In OCTAVE Induction 1 and 2, mean changes from baseline IBDQ were greater with tofacitinib 10 mg BID at Week 8 [40.7 and 44.6] versus placebo [21.0 and 25.0; p < 0.0001]; mean changes from baseline SF-36v2 Physical and Mental Component Summaries [PCS/MCS] were also greater with 10 mg BID [PCS: 6.8 and 6.8; MCS: 6.8 and 7.6] versus placebo [PCS: 2.5 and 4.6; MCS: 3.5 and 4.4; p < 0.01]. In OCTAVE Sustain atWeek 52, changes in IBDQ were maintained with tofacitinib 5 mg [3.7] and 10 mg BID [4.8], and larger with placebo [-26.5; p < 0.0001]. Changes in SF-36v2 PCS/MCS were also maintained with 5 mg [PCS: 0.0; MCS: -1.0] and 10 mg BID [PCS: 0.3; MCS: 0.1] versus placebo [PCS: -5.2; MCS: -6.7; p < 0.0001] at Week 52 in OCTAVE Sustain. Conclusions Tofacitinib 10 mg BID induction therapy significantly improved HRQoL versus placebo at Week 8. Improvements were maintained through 52 weeks’ maintenance therapy with tofacitinib 5 mg and 10 mg BID. ClinicalTrials.gov registration numbers NCT01465763, NCT01458951 and NCT01458574

Tofacitinib Induction Therapy Reduces Symptoms Within 3 Days for Patients With Ulcerative Colitis

BACKGROUND & AIMS: Tofacitinib is an oral, small molecule inhibitor of JAK for the treatment of ulcerative colitis (UC). We evaluated the onset of symptom improvement in post‐hoc analyses of data from 2 phase 3 trials of induction therapy with tofacitinib in patients with UC (OCTAVE Induction 1 and 2). METHODS: The studies comprised patients with moderate to severe active UC who were intolerant to, or failed by previous treatment with, corticosteroids, thiopurines, and/or tumor necrosis factor (TNF) antagonists. Patients received tofacitinib (10 mg twice daily, n = 905) or placebo (n = 234) for 8 weeks. Daily Mayo stool frequency and rectal bleeding subscores were calculated using diary data from the first 15 days of therapy. We analyzed data from subgroups including failure of prior anti‐TNF therapy, baseline corticosteroid use, and baseline serum levels of C‐reactive protein. RESULTS: Mean changes were significantly greater in patients given tofacitinib vs placebo in reductions from baseline stool frequency subscore (tofacitinib: –0.27 vs placebo: –0.11; P < .01), total number of daily bowel movements (–1.06 vs –0.27; P < .0001), and rectal bleeding subscore (–0.30 vs –0.14; P < .01) by day 3. Compared with placebo, more tofacitinib‐treated patients had reductions from baseline in stool frequency subscore (by ≥1 point for tofacitinib, 241/837, 28.8% vs placebo, 39/218, 17.9%) (P < .01) and rectal bleeding subscore (by ≥1 point for tofacitinib, 266/830, 32.0% vs placebo, 43/214, 20.1%) (P < .01) by day 3. A consistent effect of tofacitinib was observed in all subgroups. CONCLUSIONS: In a post‐hoc analysis of data from phase 3 trials of induction therapy with tofacitinib in patients with UC, we found significant improvements in symptoms among patients given tofacitinib compared with placebo within 3 days. These findings indicate the rapid onset of effect of this drug in patients with UC. ClinicalTrials.gov no: NCT01465763 and NCT01458951.

PTU-001 Tofacitinib, an oral jak inhibitor, in the treatment of ulcerative colitis: open-label, long-term extension study

Introduction Tofacitinib is an oral, small molecule JAK inhibitor that is being investigated for ulcerative colitis (UC). The efficacy and safety of tofacitinib was demonstrated as induction and maintenance therapy in 3 Phase 3, randomised, placebo-controlled studies (OCTAVE Induction 1, NCT01465763; OCTAVE Induction 2, NCT01458951; OCTAVE Sustain, NCT01458574) in patients (pts) with moderate to severe UC.1 Methods We present interim safety and efficacy data up to 3 years of treatment (as of 8 July 2016) from an ongoing Phase 3, multicentre, open-label, long-term extension study (OLE; NCT01470612) in pts who had completed or demonstrated treatment failure in OCTAVE Sustain, or who were non-responders after completing OCTAVE Induction 1 or 2. Pts in remission at Week 52 of OCTAVE Sustain received tofacitinib 5u2009mg twice daily (BID); all others received 10u2009mg BID. At Month 2, all pts underwent endoscopy, and non-responders from Induction were mandated to withdraw if no evidence of clinical response was shown. Remission was defined by a Mayo score ≤2 with no individual subscore >1, and rectal bleeding subscore of 0. Binary efficacy endpoints were derived from Mayo score, based on local-read endoscopic subscore. Results 914 pts (5u2009mg BID, n=156 [17.1%]; 10u2009mg BID, n=758 [82.9%]) received ≥1u2009dose of study drug; 381 pts (41.7%) discontinued. The most frequent AE leading to discontinuation was worsening of UC. The most frequent treatment-emergent AEs by system organ class (both doses) were ‘infections/infestations’ and ‘gastrointestinal disorders’, and by preferred term were ‘nasopharyngitis’ and ‘worsening of UC’. Serious infections AEs were reported in 4 (2.6%) and 14 (1.8%) pts with 5 and 10u2009mg BID, respectively. Malignancies excl. NMSC were reported in 9 (1.2%) pts in the 10u2009mg BID group (no clustering of malignancy type); none were reported in the 5u2009mg BID group. No new safety risks were identified. Data ‘as observed’ for remission and mucosal healing at Months 2, 12 and 24 are shown. Conclusions In pts with moderate to severe UC who remained in the OLE study, no new safety concerns emerged compared with those observed with tofacitinib in rheumatoid arthritis. Efficacy results from this OLE study support sustained efficacy with tofacitinib 5 and 10u2009mg BID. Funded by Pfizer Inc.Abstract PTU-001 Table 1 Summary of safety and efficacy is the OLE study Reference 1. Sandborn WJ, et al. N Engl J Med 2017;376:1723–36.