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Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We report a model-informed drug development approach for bridging efficacy from immediate-release (IR) to extended-release (XR) tofacitinib formulations in patients with UC. IR-XR efficacy bridging was supported by exposure-response analysis of phase 3 induction/maintenance studies of the IR formulation in UC to identify exposure metrics relevant for efficacy. Pharmacokinetic studies in healthy subjects were used to confirm similarity of relevant exposure metrics of tofacitinib IR 5 mg twice daily to XR 11 mg once daily, and tofacitinib IR 10 mg twice daily to XR 22 mg once daily, thereby bridging efficacy between IR and XR formulations. Food effect was evaluated at both XR formulation dose levels. Exposure-response analysis demonstrated that area under the plasma concentration-time curve (average plasma concentration) was a relevant predictor of efficacy. Pharmacokinetic studies demonstrated that area under the plasma concentration-time curve was equivalent between formulations under single-dose and steady-state conditions, and other exposure metrics were also similar. These results also supported bridging of safety data for IR-XR formulations. Food had no impact on tofacitinib XR exposure. These data support efficacy/safety bridging of IR-XR formulations in patients with UC.

Background and Aims Tofacitinib is an oral small molecule Janus kinase [JAK] inhibitor for the treatment of ulcerative colitis. We report an integrated summary of tofacitinib safety [exposure: ≤7.8 years] from the global clinical programme. Methods Patients receiving tofacitinib 5 or 10 mg twice daily [BID] from completed phase [P]2/3 placebo-controlled studies, an open-label, long-term extension study [final data cut-off: August 24, 2020], and interim analysis of a P3b/4 study (interim data cut-off: February 20, 2020; Overall plus P3b/4 [2020] Cohort) were included. Proportions with adverse events [AEs] and serious AEs, and incidence rates [IRs; unique patients with events/100 patient-years] for deaths and AEs of special interest [AESI] were evaluated. Opportunistic infections, malignancies, major adverse cardiovascular events [MACE] and gastrointestinal perforations were adjudicated. Results In total, 1157 patients received one or more dose of tofacitinib (mean duration: 946.9 days); 955/1157 [83%] received a predominant dose of 10 mg BID; 412/1157 [35.6%] received tofacitinib for >4 years; 992/1157 [85.7%] had AEs, 244/1157 [21.1%] had serious AEs and 134/1157 (11.6%) discontinued use due to AEs. IRs [95% confidence intervals] for all tofacitinib doses were: deaths, 0.23 [0.09–0.46]; serious infections, 1.69 [1.26–2.21]; herpes zoster [non-serious and serious], 3.30 [2.67–4.04]; opportunistic infections, 1.03 [0.70–1.46]; malignancies (excluding non-melanoma skin cancer [NMSC]), 0.84 [0.55–1.24]; NMSC, 0.73 [0.45–1.10]; MACE, 0.29 [0.13–0.55]; deep vein thrombosis, 0.03 [0.00–0.18]; pulmonary embolism, 0.19 [0.07–0.42]; gastrointestinal perforations, 0.10 [0.02–0.28]. Conclusions AESI IRs were stable to 7.8 years and generally JCC Topic/keyword selection: 3. Clinical trials

Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). These post hoc analyses assessed associations between C-reactive protein (CRP), partial Mayo score (PMS), and efficacy outcomes during tofacitinib induction in UC. Methods Patients received tofacitinib 10 mg twice daily (BID) in an 8-week, phase 2 induction study and 2 identical, 8-week, phase 3 induction studies (OCTAVE Induction 1&2); induction nonresponders (IndNR) received an additional 8 weeks of tofacitinib 10 mg BID in an open-label, long-term extension study. Associations between CRP and PMS, and efficacy outcomes (clinical response, clinical remission, endoscopic improvement, and endoscopic remission) were analyzed using univariate and multivariable logistic regression and receiver operating characteristic curves. Results Changes from baseline in the logarithm of CRP ([log]CRP) and PMS at week 4 were associated with clinical response at week 8 (univariate: per unit, odds ratio [OR], 0.55 [95% confidence interval (CI), 0.48-0.62]; and 0.42 [0.37-0.47], respectively). Among IndNR, change from baseline in PMS at week 8 was associated with clinical response at week 16 (univariate: per unit, OR, 0.59; 95% CI, 0.46-0.75). C-reactive protein at week 4 (area under the curve [AUC] > 0.6) and PMS at weeks 2 and 4 (AUC, > 0.7) generally exhibited predictive value for week 8 efficacy outcomes. Conclusions Patients who achieved clinical response at week 8 had larger decreases in CRP and PMS at week 4 than patients who did not. IndNR who achieved clinical response at week 16 with extended tofacitinib induction had a larger decrease in PMS at week 8 vs those who did not. ClinicalTrials.gov:NCT00787202;NCT01465763;NCT01458951;NCT01470612.

Background and Aims Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. We present primary completion analysis from RIVETING, an ongoing, double-blind, randomised, parallel-group trial evaluating efficacy and safety of tofacitinib dose reduction to 5 mg twice daily [BID] versus remaining on 10 mg BID in patients in stable remission on tofacitinib 10 mg BID maintenance therapy. Methods Patients had received tofacitinib 10 mg BID for ≥ 2 consecutive years and been in stable remission for ≥ 6 months before enrolment. The primary endpoint was modified Mayo score remission at Month 6. Safety was assessed up to February 20, 2020 [data cut-off]. Results In all, 140 patients were randomised [1:1] to tofacitinib 5 or 10 mg BID; 77.1% and 90.0% of patients in the 5 and 10 mg BID groups, respectively, were in modified Mayo score remission at Month 6 (adjusted difference 12.9%; 95% confidence interval [CI] 0.5–25.0). Smaller differences between treatment groups were seen in patients with baseline endoscopic subscore of 0 versus 1 [9.8%; –3.0–22.6, and 21.1%; –6.1–48.2, respectively], and in patients without versus with prior tumour necrosis factor inhibitor [TNFi] failure [9.5%; –6.6–25.6, and 17.4%; –1.6–36.3, respectively]. Adverse events [AE] and serious AE rates were similar across treatment groups; no deaths were reported. Conclusions Most patients in stable remission on 10 mg BID maintenance therapy maintained remission following dose de-escalation. For patients who dose de-escalated, those in deep endoscopic remission and those without prior TNFi failure were more likely to maintain remission. Efficacy data were limited to the first 6 months; a longer duration of follow-up during RIVETING will further characterise the impact of dose reduction on maintenance of remission. Safety findings were consistent with the established safety profile of tofacitinib., Graphical Abstract Graphical Abstract

Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). RIVETING (NCT03281304) is an ongoing, double-blind, randomised, parallel-group study designed to evaluate the efficacy and safety of dose reduction to tofacitinib 5 mg twice daily (BID) vs remaining on 10 mg BID in patients (pts) with UC in stable remission on tofacitinib 10 mg BID maintenance therapy. Eligible pts had received tofacitinib 10 mg BID for ≥2 consecutive years in an open-label, long-term extension (OLE) study (NCT01470612), and had been in stable remission for ≥6 months (M) and corticosteroid (CS)-free for ≥4 weeks prior to enrolment.1 We aimed to evaluate tofacitinib efficacy outcomes by the number of prior tumour necrosis factor inhibitors (TNFi) failed and by prior CS use. Methods We evaluated the efficacy of tofacitinib 5 mg BID at Month 6 of RIVETING, based on the number of prior TNFi failed (0, 1 or >1), CS use (yes/no) and CS dose ( Results Of the 70 pts randomised to dose-reduce to tofacitinib 5 mg BID, 43 pts had no prior TNFi failure, 17 pts had previous failure with 1 TNFi and 10 pts had previous failure with >1 TNFi. At Month 6, modified Mayo (mMayo) score remission was maintained in 79.1%, 70.6% and 80.0% of pts who had previous failure with 0, 1 and >1 TNFi, respectively. At Month 6, the change from RIVETING BL total Mayo score, mMayo score, partial Mayo score (PMS) and modified PMS was similar across TNFi subgroups (Table 1). Of pts who enrolled into RIVETING, 26 pts were receiving CS (9 received Conclusion In pts who were in stable remission for >6M, efficacy endpoints were maintained following dose reduction to tofacitinib 5 mg BID, regardless of the number of prior TNFi failures or prior CS use. These analyses are post hoc and limited by the small sample size. Reference

Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). RIVETING (NCT03281304) is an ongoing, double-blind, randomised, parallel-group study designed to evaluate the efficacy and safety of dose reduction to tofacitinib 5 mg twice daily (BID) vs remaining on 10 mg BID in patients (pts) with UC in stable remission on tofacitinib 10 mg BID maintenance therapy. Eligible pts had received tofacitinib 10 mg BID for ≥2 consecutive years in an open-label, long-term extension study (NCT01470612), and had been in stable remission for ≥6 months and corticosteroid-free for ≥4 weeks prior to enrolment.1 We aimed to determine if faecal calprotectin (FCP), C-reactive protein (CRP) or partial Mayo score (PMS) can be used as predictors of maintaining remission after dose reduction. Methods Median FCP levels, median CRP levels and mean PMS at baseline (BL), Month 1 and Month 3 were analysed by efficacy endpoint status at Month 6 in pts who dose-reduced to tofacitinib 5 mg BID. The proportions of pts who achieved efficacy endpoints at Month 6 were analysed by stool frequency (SF) subscore, rectal bleeding (RB) subscore and modified PMS. Results Seventy pts were randomised to receive tofacitinib 5 mg BID in RIVETING. For pts in modified Mayo score remission at Month 6, PMS was relatively stable over time, whereas PMS increased from BL to Month 1 and Month 3 in pts not in modified Mayo score remission at Month 6; mean change from BL at Month 3 was 0.1 vs 0.7, respectively (Table 1). This trend was also observed for other efficacy endpoints (Table 1). Median FCP levels did not change from BL to Month 3 in pts who achieved Month 6 efficacy endpoints, whereas median FCP levels increased from BL to Month 3 in pts who did not achieve Month 6 efficacy endpoints (except remission) (Table 1). For all efficacy endpoints, no trend was observed in median CRP levels over time in pts who did and did not achieve Month 6 efficacy endpoints (Table 1). A numerically higher proportion of pts with a SF subscore, RB subscore or modified PMS of 0 at Month 1 or Month 3 achieved efficacy endpoints at Month 6 compared with pts with respective subscores >0 (Table 2). Conclusion These analyses suggest that in pts previously in stable remission, an increase in FCP levels at Month 3, or PMS as early as Month 1, may help predict loss of efficacy after dose-reduction from tofacitinib 10 mg BID to 5 mg BID. A SF subscore, RB subscore or modified PMS of 0 at either Month 1 or Month 3 could indicate the likelihood of maintaining efficacy with tofacitinib 5 mg BID at Month 6. These analyses are post hoc, exploratory and limited by the small sample size. Reference

Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). RIVETING (NCT03281304) is an ongoing, double-blind, randomised, parallel-group study designed to evaluate the efficacy and safety of dose reduction to tofacitinib 5 mg twice daily (BID) vs remaining on 10 mg BID in patients (pts) with UC in stable remission on tofacitinib 10 mg BID maintenance therapy. Eligible pts had received tofacitinib 10 mg BID for ≥2 consecutive years in an open-label, long-term extension study (NCT01470612), and had been in stable remission for ≥6 months (M) and corticosteroid-free for ≥4 weeks prior to enrolment.1 We aimed to evaluate the association between the duration of remission prior to enrolment into RIVETING and the efficacy of tofacitinib 5 and 10 mg BID. Methods Pts who were in partial Mayo score (PMS) remission (a PMS of ≤2 with no individual subscore >1, and a rectal bleeding subscore of 0) at RIVETING baseline were included in this analysis. Pts were randomised to dose-reduce to tofacitinib 5 mg BID or remain on 10 mg BID. We evaluated efficacy endpoints at Month 6 in RIVETING, stratified by duration of PMS remission (0–12, 12–24, 24–36, 36–48, >48 M) at RIVETING baseline. Results At RIVETING baseline, 139 of 140 pts were in PMS remission: 69 pts dose-reduced to tofacitinib 5 mg BID and 70 pts remained on tofacitinib 10 mg BID. In both treatment groups, compared with pts with 24M; these pts also generally had a numerically lower change from baseline modified Mayo and total Mayo scores at Month 6 (Table). At Month 6, following dose reduction to tofacitinib 5 mg BID, PMS remission was maintained in 66.7%, 60.0%, 82.4%, 75.0% and 90.0% of pts with baseline PMS remission durations of 0–12M, 12–24M, 24–36M, 36–48M and >48M, respectively. Corresponding values for pts who continued to receive tofacitinib 10 mg BID were 80.0%, 88.9%, 91.7%, 100.0% and 100.0%. At Month 6, the proportion of pts achieving modified Mayo remission, remission and modified PMS remission was generally higher in pts with baseline PMS remission of >24M vs pts with PMS remission of Conclusion Following dose reduction from tofacitinib 10 to 5 mg BID, rates of modified Mayo remission, remission and PMS remission were numerically higher in pts with a PMS remission duration of >24M vs pts with Reference

Background Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). In patients with UC, associations between endoscopic findings and patient-reported outcomes, such as stool frequency (SF) and rectal bleeding (RB), are not well described. Here, we evaluated the diagnostic accuracy of Mayo SF and RB subscores to predict mucosal healing (MH) in OCTAVE Induction 1 and 2 (NCT01465763; NCT01458951). Methods This post hoc analysis used data from OCTAVE Induction 1 and 2, two identical, randomised, placebo-controlled, 8-week, Phase 3 studies of tofacitinib for the treatment of patients with moderately to severely active UC.1 SF (Mayo subscore 0–3), RB (Mayo subscore 0–3) and endoscopic findings (Mayo endoscopic subscore [ES] 0–3) were assessed at baseline and at Week 8. MH and endoscopic normalisation were defined as an ES of 0 or 1, or an ES of 0, respectively. Based on two-by-two contingency tables, diagnostic test characteristics for SF and RB were evaluated: positive and negative predictive values, sensitivity and specificity. Kappa statistics (chance-corrected measure of agreement) and Pearson correlations (a measure of association) were also calculated. All available data at Week 8 were used. Results A total of 614 and 547 patients received treatment (tofacitinib 15 or 10 mg BID, or placebo) in OCTAVE Induction 1 and 2, respectively. Two-by-two contingency table analyses showed that dichotomised SF (0 vs. ≥1) and RB (0 vs. ≥1) were each or both not good predictors of MH (ES of 0 or 1 vs. ≥2) or endoscopic normalisation (ES 0 vs. ≥1), as ≥1 of the four diagnostic test characteristics was Conclusion In patients with UC treated with tofacitinib or placebo in OCTAVE Induction 1 and 2, SF and RB subscores had slight-to-moderate agreement with ES, but were not predictive of MH or endoscopic normalisation. The presence of blood at Week 8 strongly indicated that patients had endoscopic activity, but the absence of blood was associated with MH in Reference

Background Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). In a Phase 2 study, changes from baseline in C-reactive protein (CRP) levels as early as Week 4 and partial Mayo scores (PMS) as early as Week 2 were shown to correlate with clinical and endoscopic outcomes at Week 8 in patients with UC receiving tofacitinib.1 We aimed to determine whether CRP levels and/or PMS can be early predictors of clinical or endoscopic outcomes at Week 8 in OCTAVE Induction 1 and 2 (NCT01465763; NCT01458951).2 Methods In OCTAVE Induction 1 and 2, patients received placebo or tofacitinib 10 mg twice daily (BID) for 8 weeks. Mean CRP levels at baseline and Week 4, and PMS at baseline and Weeks 2 and 4, were analysed by secondary endpoint (clinical response, clinical remission, mucosal healing and endoscopic remission) status at Week 8. Univariate logistic regression analyses were performed to evaluate if CRP levels (log-transformed) or PMS were associated with these endpoints. Results In patients treated with tofacitinib 10 mg BID, numerically greater decreases from baseline were observed in CRP levels at Week 4 in patients who achieved a clinical response at Week 8 vs. those who did not achieve a clinical response (Table). Similarly, numerically greater decreases from baseline were observed in PMS at Weeks 2 and 4 in patients who achieved clinical response, clinical remission, mucosal healing and endoscopic remission at Week 8 vs. those who did not achieve these endpoints (Table). Logistic regression results showed that PMS at Weeks 2 and 4, and CRP levels at Week 4, were significantly (p < 0.001) associated with a clinical response at Week 8 (odds ratio [95% confidence interval] 0.578 [0.529, 0.631]; 0.483 [0.437, 0.533]; 0.631 [0.572, 0.695], respectively). This was also true for clinical remission (0.523 [0.467, 0.587]; 0.426 [0.367, 0.495]; 0.582 [0.508, 0.666]), mucosal healing (0.650 [0.600, 0.705]; 0.599 [0.548, 0.655]; 0.576 [0.515, 0.643]) and endoscopic remission (0.659 [0.574, 0.756]; 0.604 [0.513, 0.712]; 0.663 [0.549, 0.802]) at Week 8. Conclusion These post hoc analyses showed that PMS as early as Week 2 and CRP levels as early as Week 4 may be predictors of improved clinical and endoscopic outcomes in patients with moderately to severely active UC treated with tofacitinib 10 mg BID. These results are in alignment with the findings reported from the Phase 2 trial.1 References