Ulcerative Colitis Clinical Program Research Articles

P956 Pregnancy outcomes after maternal or paternal exposure in the tofacitinib ulcerative colitis clinical programme

Abstract Background Pregnant women with ulcerative colitis (UC) have a higher risk of adverse pregnancy outcomes vs age-matched controls.1 Tofacitinib is an oral Janus kinase inhibitor for the treatment of UC. There are no well-controlled studies on tofacitinib use in pregnant women. It was shown to be teratogenic in rats and rabbits at approximately 73 and 6.3 times, respectively, the maximum recommended human dose of 10 mg twice daily. Tofacitinib affects female fertility, parturition and peri/postnatal development in rats and was secreted into the milk of lactating rats; it had no effects on male fertility or sperm motility/concentration. Methods We report pregnancy outcomes in the tofacitinib UC clinical programme: 4 randomised, placebo-controlled Phase (P)2/3 studies (NCT00787202/NCT01465763/NCT01458951/NCT01458574),2,3 an open-label, long-term extension study (NCT01470612)4 and a randomised P3b/4 study (NCT03281304) were analysed.5 Study protocols excluded pregnant women, required females of childbearing potential to use effective contraception and regularly tested for urine β-hCG. Study drug was discontinued in female patients who became pregnant. Pregnancy outcomes after maternal or paternal tofacitinib exposure were identified from Pfizer’s internal safety database up to March 2023 and categorised as healthy newborn, medical termination, foetal death, congenital malformation, spontaneous abortion or lost to follow-up. Results There were 40 pregnancies with exposure to tofacitinib: 16 cases of maternal exposure (median age 29.5 [range: 24−41] years), all during the 1st trimester (10 [62.5%] healthy newborns, 2 [12.5%] medical terminations, 2 [12.5%] spontaneous abortions, 2 [12.5%] lost to followup); and 24 cases of paternal exposure (18 [75.0%] healthy newborns, 2 [8.3%] spontaneous abortions, 4 [16.7%] lost to follow-up). There were no cases of foetal death or congenital malformation. Conclusion Most known outcomes for maternal and paternal tofacitinib exposure were healthy newborns, similar to previous analyses in other tofacitinib clinical study populations and the general UC population.6,7 Limitations included the low number of reported pregnancies and available follow-up. Tofacitinib should not be used during pregnancy unless necessary.

Association Between Smoking Status and the Efficacy and Safety of Tofacitinib in Patients with Ulcerative Colitis.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). This analysis assessed the impact of cigarette smoking on tofacitinib efficacy and safety in the UC clinical program. Efficacy endpoints and adverse events (AEs) were evaluated by smoking status (ever smokers [current and ex-smokers] and never smokers) in the phase (P)2 induction study (baseline demographics and safety only), P3 studies (OCTAVE Induction 1&2, OCTAVE Sustain, OCTAVE Open), and P3/4b RIVETING study. This post hoc analysis included 1156 patients (ever smokers, n = 416 [36.0%; current smokers, n = 59 (5.1%); ex-smokers, n = 357 (30.9%)]; never smokers, n = 740 [64.0%]; median [range] treatment duration 654 [1-2712] and 615.5 [1-2850] days, respectively). Similar proportions of ever smokers and never smokers achieved efficacy endpoints. AEs were reported in 88.7% of ever smokers and 83.8% of never smokers. Overall, 60.6% of ever smokers had an infection (serious infections, 5.5%; herpes zoster [nonserious and serious], 10.8%; Clostridioides difficile infection, 12.0%; lower respiratory tract infection, 19.5%: corresponding values among never smokers were 53.1%, 3.9%, 6.8%, 8.5%, and 11.4%). Major adverse cardiovascular events were reported in 1.0% of ever smokers and 0.7% of never smokers and thromboembolism events (venous and arterial) in 1.0% of ever smokers and 0.9% never smokers. Deaths, malignancies (excluding non-melanoma skin cancer [NMSC]), and NMSC occurred infrequently in ever smokers (0.5%, 2.5%, and 3.7%, respectively) and never smokers (0.1%, 1.5%, and 1.0%, respectively). Colorectal cancer was reported in 0.6% of never smokers; no cases occurred in ever smokers. Efficacy and safety of tofacitinib were generally similar in ever smokers and never smokers. Overall, serious AEs and, as expected, infections were more frequent in ever smokers versus never smokers. This may inform treatment selection and monitoring strategies. NCT00787202;NCT01465763;NCT01458951;NCT01458574;NCT01470612;NCT03281304.

S905 Impact of Etrasimod on Blood Pressure and Hypertension: Data From the Etrasimod Ulcerative Colitis Clinical Program

S905 Impact of Etrasimod on Blood Pressure and Hypertension: Data From the Etrasimod Ulcerative Colitis Clinical Program

S1072 Hepatic Impact of Etrasimod for Treatment of Moderately to Severely Active Ulcerative Colitis: An Integrated Safety Summary From the Etrasimod Ulcerative Colitis Clinical Program

S1072 Hepatic Impact of Etrasimod for Treatment of Moderately to Severely Active Ulcerative Colitis: An Integrated Safety Summary From the Etrasimod Ulcerative Colitis Clinical Program

Presence of risk factors associated with colectomy among patients with ulcerative colitis: a post hoc analysis of data from the tofacitinib OCTAVE ulcerative colitis clinical program.

Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). To assess colectomy incidence rates (IRs) and baseline characteristics for the presence of identified colectomy risk factors among patients in the tofacitinib OCTAVE UC clinical program. This post hoc analysis evaluated patients in the 8-week OCTAVE Induction 1 and 2, 52-week OCTAVE Sustain, and OCTAVE Open (open-label, long-term extension) studies. IRs [95% confidence interval (CI)] for colectomy were analyzed. Baseline risk factors based on clinical guidelines: aged <40 years at diagnosis, extensive colitis, severe endoscopic disease [Mayo endoscopic subscore (MES) = 3], hospitalization for UC within 12 months, C-reactive protein (CRP) >3 mg/L, and serum albumin <3.5 g/dL. Baseline risk factors were evaluated in patients who underwent colectomy by study and summarized descriptively. Over a maximum of 7.8 years of tofacitinib exposure, 14 patients underwent colectomy: 3/1139 (0.3%) in OCTAVE Induction 1 and 2 [tofacitinib 10 mg twice daily (BID): n = 2; placebo: n = 1], 3/593 (0.5%) in OCTAVE Sustain (placebo: n = 3), and 8/944 (0.8%) in OCTAVE Open (tofacitinib 10 mg BID: n = 8). Colectomy IR per 100 patient-years for all patients who received ⩾1 tofacitinib dose was 0.34 (95% CI: 0.16-0.63). All patients who underwent colectomy had ⩾1 risk factor and prior tumor necrosis factor inhibitor (TNFi) failure, among which the most common risk factors were a MES of 3 (n = 13), CRP >3 mg/L (n = 11), and aged <40 years at diagnosis (n = 9). Among patients with moderate to severe UC receiving tofacitinib, colectomies were infrequent; all patients undergoing colectomy had prior TNFi failure, and most had multiple additional risk factors. This provides important information to discuss with patients and inform management decisions. NCT01465763; NCT01458951; NCT01458574; and NCT01470612.

Assessment of Safety and Efficacy of Tofacitinib, Stratified by Age, in Patients from the Ulcerative Colitis Clinical Program.

In patients with ulcerative colitis (UC), risks of infection and malignancies increase with age. Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of UC. This analysis assessed age as a risk factor for adverse events of special interest (AESI) in the tofacitinib UC clinical program. Data were from phase 2 and 3 induction studies, a phase 3 maintenance study, and an open-label, long-term extension study. Efficacy and/or safety outcomes were analyzed in the Induction, Maintenance, and Overall Cohorts (patients who received ≥ 1 dose of tofacitinib), stratified by age. The effects of baseline demographic and disease-related factors on AESI incidence were assessed by Cox proportional-hazards regression analysis. In the Overall Cohort (1157 patients with ≤ 6.8 years' tofacitinib treatment), age was a statistically significant predictor of herpes zoster (HZ), malignancies excluding nonmelanoma skin cancer (NMSC), and NMSC. Other statistically significant predictors included prior tumor necrosis factor inhibitor failure for HZ, NMSC, and opportunistic infection events, and prior duration of UC for malignancies excluding NMSC. In the Induction and Maintenance Cohorts, a higher proportion of tofacitinib-treated than placebo-treated patients (numerical difference) achieved the efficacy endpoints (endoscopic improvement, clinical remission, clinical response) across all age groups. Older individuals receiving tofacitinib as induction and maintenance therapy to treat UC may have an increased risk of HZ, malignancies (excluding NMSC), and NMSC versus similarly treated younger patients, consistent with findings from the general population. Across all age groups, tofacitinib demonstrated greater efficacy than placebo as an induction and maintenance therapy. NCT00787202; NCT01465763; NCT01458951; NCT01458574; NCT01470612.

S1023 Assessment of Health-Related Quality of Life and Patient-Reported Outcomes With Tofacitinib Treatment Stratified by Age in Patients From the OCTAVE Ulcerative Colitis Clinical Program

S1023 Assessment of Health-Related Quality of Life and Patient-Reported Outcomes With Tofacitinib Treatment Stratified by Age in Patients From the OCTAVE Ulcerative Colitis Clinical Program

S962 Presence of Risk Factors Associated With Colectomy Among Patients With Colectomy in the Tofacitinib OCTAVE Ulcerative Colitis Clinical Program

S962 Presence of Risk Factors Associated With Colectomy Among Patients With Colectomy in the Tofacitinib OCTAVE Ulcerative Colitis Clinical Program

Association of C-reactive Protein and Partial Mayo Score With Response to Tofacitinib Induction Therapy: Results From the Ulcerative Colitis Clinical Program.

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. Patients received tofacitinib 10mg 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 10mg 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. 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. 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.

P563 Association between smoking status and the efficacy and safety of tofacitinib in patients with Ulcerative Colitis: Data from the tofacitinib clinical programme

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Efficacy and safety of tofacitinib were evaluated in randomised, placebo-controlled Phase (P)2 (NCT00787202) and P3 (NCT01465763; NCT01458951; NCT01458574) studies, an open-label, long-term extension (OLE) study (NCT01470612) and an ongoing P3b/4 study (NCT03281304). Ex-smokers have an increased risk of UC, but the response to therapy in these patients (pts) has not been previously evaluated. We assessed the impact of smoking status on the efficacy and safety of tofacitinib in the UC clinical programme. Methods Efficacy endpoints and adverse events (AEs) were evaluated by smoking status (ever smokers [current and ex-smokers] and never smokers) in P2 (safety only)/P3/OLE/P3b/4 studies. Efficacy endpoints were summarised by treatment allocation; pt characteristics and AEs were summarised by tofacitinib predominant dose. Results This analysis included 1156 pts (ever smokers, n=416 [36.0%; current smokers, n=59 (5.1%); ex-smokers, n=357 (30.9%)]; never smokers, n=740 [64.0%]; Table 1). Compared with never smokers, ever smokers were older and more likely to have a prior history of myocardial infarction, diabetes mellitus, or ischaemic or coronary heart disease. The proportion of pts achieving efficacy endpoints was generally similar across tofacitinib treatment groups regardless of smoking status (Table 2). AEs were reported in 88.7% of ever smokers and 83.8% of never smokers. Overall, 60.6% of ever smokers had an infection, specifically 10.8% had herpes zoster (non-serious and serious), 12.0% had a Clostridioides difficile infection and 19.5% had a lower respiratory tract infection; corresponding values for each AE among never smokers were 53.1%, 6.8%, 8.5% and 11.4% (Table 1). Major adverse cardiovascular events were reported in 1.0% of ever smokers and 0.7% of never smokers; thromboembolic events were reported in 1.0% of ever smokers and 0.9% of never smokers. Malignancies (excl. non-melanoma skin cancer [NMSC]) occurred in 2.5% of ever smokers and 1.5% of never smokers; NMSC occurred in 3.7% and 1.0%, respectively. In total, 0.6% of never smokers had colorectal cancer and there were no cases in ever smokers. Conclusion The efficacy and safety of tofacitinib were generally similar in ever smokers and never smokers. This study is limited by the combined analysis of current and ex-smokers and unknown factors such as the degree of smoking and the time between smoking cessation and UC diagnosis. These data are consistent with previous reports in the general population and pts with UC.1,2

P378 Rectal bleeding and stool frequency improvement with tofacitinib dose escalation to, 10 mg BID in patients with Ulcerative Colitis following loss of response on tofacitinib, 5 mg BID maintenance therapy: Results from OCTAVE Open

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). In the tofacitinib UC clinical programme, patients who responded to tofacitinib, 10 mg BID during induction, and experienced treatment failure whilst receiving tofacitinib, 5 mg BID during maintenance (OCTAVE Sustain) and subsequently received tofacitinib, 10 mg BID in the open-label, long-term extension (OLE) study (OCTAVE Open; NCT01470612), comprised the dose escalation subpopulation. The efficacy and safety of tofacitinib in the dose escalation subpopulation have been previously reported.1 Here, we evaluated patient-reported outcomes to assess rectal bleeding and stool frequency improvement in the dose escalation subpopulation in OCTAVE Open. Methods The following efficacy endpoints based on the Mayo subscores were analysed in the overall dose escalation subpopulation and by prior tumour necrosis factor inhibitor (TNFi) failure status: rectal bleeding improvement (≥1 point decrease in rectal bleeding subscore [RBS] from OLE study baseline) and stool frequency improvement (≥1 point decrease in stool frequency subscore [SFS] from OLE study baseline), up to Month (M)6 in the OLE study (full analysis set, non-responder imputation). Changes from baseline in partial Mayo score (PMS), RBS and SFS at M1, by M2 clinical response status, were also analysed (as observed). Results In OCTAVE Open, 57 patients were included in the dose escalation subpopulation, of which, 28 (49.1%) had prior TNFi failure. Overall, at M1 and M6, of OCTAVE Open, 59.6% and, 66.7% of patients had rectal bleeding improvement, respectively (Figure, 1). Corresponding values for stool frequency improvement were, 50.9% and, 64.9%. At most time points, rates of rectal bleeding and stool frequency improvements were similar in patients with and without prior TNFi failure. Patients with a clinical response at M2 had a numerically greater mean decrease from baseline in PMS, RBS and SFS at M1 than those without (Figure 2). Conclusion In this post hoc analysis, in patients with UC who had loss of response after, 8–52 weeks of treatment with tofacitinib, 5 mg BID (following reduction from induction tofacitinib, 10 mg BID), dose escalation back to, 10 mg BID generally resulted in rectal bleeding and stool frequency improvement in the majority of patients by M1, which was maintained to M6, regardless of prior TNFi failure status. Furthermore, early improvement in RBS and/or SFS at M1 may indicate likelihood of recapturing response at M2 with dose escalation from tofacitinib, 5 to, 10 mg BID. Reference 1. Sands BE et al. Aliment Pharmacol Ther, 2020;, 51:, 271–280.

S870 Analysis of Infections of Interest in Patients Treated with Tofacitinib in the Ulcerative Colitis Clinical Program

S870 Analysis of Infections of Interest in Patients Treated with Tofacitinib in the Ulcerative Colitis Clinical Program

S923 Clostridium difficile Infection in Patients Treated With Tofacitinib in the Ulcerative Colitis Clinical Program

S923 Clostridium difficile Infection in Patients Treated With Tofacitinib in the Ulcerative Colitis Clinical Program

The impact of body mass index on efficacy and safety in the tofacitinib OCTAVE ulcerative colitis clinical programme.

SummaryBackgroundObesity may affect efficacy and safety of biologic treatments for ulcerative colitis (UC). Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of UC.AimsTo assess efficacy and safety of tofacitinib in patients with UC, by baseline body mass index (BMI).MethodsThis post hoc analysis evaluated patients with UC receiving placebo or tofacitinib from the 8‐week OCTAVE Induction 1 and 2 (NCT01465763, NCT01458951) and 52‐week OCTAVE Sustain (NCT01458574) studies. Patients were stratified by BMI at OCTAVE Induction 1 and 2 baseline (<25, 25 to <30 and ≥30 kg/m2). Outcomes included remission, endoscopic improvement, clinical response, sustained steroid‐free remission, Inflammatory Bowel Disease Questionnaire total score and Short Form‐36 Health Survey scores. Adverse events were evaluated.ResultsAt Week 8 of OCTAVE Induction 1 and 2, and Week 52 of OCTAVE Sustain, higher proportions of patients receiving tofacitinib 5 or 10 mg twice daily (b.d.) achieved clinical response vs placebo, regardless of baseline BMI subgroup (all P < 0.05). Proportions of patients achieving efficacy endpoints were generally similar across BMI subgroups; in univariate and multivariate regression analyses, BMI was not a significant predictor (all P ≥ 0.05; univariate BMI [continuous] odds ratio for remission: 0.98 [95% confidence interval 0.95, 1.02]). There was no consistent trend between BMI and adverse events. Among patients receiving tofacitinib 10 mg b.d. in OCTAVE Induction 1 and 2, serious infections were numerically greater in the BMI ≥30 subgroup (3.2%) vs other subgroups (0.4%). Limitations included small patient numbers in the BMI ≥30 subgroup.ConclusionsEfficacy and safety of tofacitinib were similar in patients with UC regardless of baseline BMI.

P334 Tofacitinib for the treatment of Ulcerative Colitis: Analysis of malignancy rates from the Ulcerative Colitis clinical programme

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). We present an updated analysis of adjudicated malignancies in the tofacitinib UC clinical programme, including final data from the open-label, long-term extension (OLE) study (as of 24 Aug 2020). Methods Malignancies were evaluated from 3 randomised, placebo-controlled studies (2 Phase [P]3 induction studies [NCT01465763; NCT01458951]; 1 P3 maintenance study [NCT01458574]) and an OLE study (NCT01470612). Three cohorts were analysed: Induction (P3 induction studies), Maintenance (P3 maintenance study) and Overall (patients receiving tofacitinib 5 or 10 mg twice daily [BID] in P3 or OLE studies; data from the previous data cut [May 2019] are also reported for comparison). Analysis was by predominant dose (PD) 5 or 10 mg BID, based on average daily dose &amp;lt;15 mg or ≥15 mg, respectively (82.1% of patients received PD 10 mg BID). An independent adjudication committee reviewed potential malignancies. Proportions and incidence rates (IRs; unique patients with events per 100 patient-years of exposure) were evaluated for malignancies (excluding non-melanoma skin cancer [NMSC]) and NMSC. Results 1124 patients were evaluated for malignancies (2809.4 patient-years of tofacitinib exposure; up to 7.8 years of treatment; median duration of 685.5 days). No malignancies (excluding NMSC) occurred in Induction Cohort patients. Malignancies (excluding NMSC) occurred in 1 Maintenance Cohort patient (who was receiving placebo) and in 25 Overall Cohort patients (IR 0.86 [95% confidence interval (CI) 0.56, 1.27]: PD tofacitinib 5 mg BID n=5, IR 0.63 [95% CI 0.20, 1.47]; PD tofacitinib 10 mg BID n=20, IR 0.95 [95% CI 0.58, 1.46]); 5 new cases since May 2019 (Table).1 NMSC events in the Induction and Maintenance Cohorts were previously reported (Table).1 NMSC events occurred in 21 Overall Cohort patients (IR 0.73 [95% CI 0.45, 1.12]): PD tofacitinib 5 mg BID n=5, IR 0.63 (95% CI 0.21, 1.48); PD tofacitinib 10 mg BID n=16, IR 0.77 (95% CI 0.44, 1.25); 2 new cases since May 2019 (Table).1 Conclusion There was no apparent clustering of types of malignancy, excluding NMSC. Malignancies (excluding NMSC) and NMSC IRs remained stable over time, being comparable to those previously reported in the tofacitinib UC clinical programme.1 In this analysis, malignancies (excluding NMSC) and NMSC IRs were similar to those in patients with UC treated with tumour necrosis factor inhibitors, as reported from claims data (IRs of 0.63 and 1.69, respectively).2 References

P260 An analysis of non-melanoma skin cancer rates in the tofacitinib Ulcerative Colitis clinical programme

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). We present an updated analysis of non-melanoma skin cancer (NMSC) events in the tofacitinib UC clinical programme, including final data from the open-label, long-term extension (OLE) study (as of 24 Aug 2020). Methods NMSC events were evaluated from 3 randomised, placebo (PBO)-controlled studies (2 Phase [P]3 induction studies [NCT01465763; NCT01458951]; 1 P3 maintenance study [NCT01458574]) and an OLE study (NCT01470612), as 3 cohorts: Induction (P3 induction studies [patients (pts) receiving tofacitinib 10 mg twice daily (BID) or PBO]); Maintenance (P3 maintenance study [pts receiving tofacitinib 5 or 10 mg BID or PBO]); Overall (pts receiving tofacitinib 5 or 10 mg BID in P3 or OLE studies). Analysis was by predominant dose (PD) 5 or 10 mg BID, based on average daily dose &amp;lt;15 or ≥15 mg, respectively (82% of pts received PD 10 mg BID). An independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique pts with events per 100 pt-years of exposure) were evaluated for NMSC. A Cox proportional hazards model was used for risk factor analysis. Results 1124 pts were evaluated for NMSC (2809.4 pt-years of tofacitinib exposure; up to 7.8 years of treatment; median duration 685.5 days). NMSC events in Induction and Maintenance were previously reported (Table 1).1 In Overall, NMSC occurred in 21 pts (IR 0.73 [95% confidence interval (CI) 0.45, 1.12]): PD tofacitinib 5 mg BID n=5, IR 0.63 (0.21, 1.48); PD tofacitinib 10 mg BID n=16, IR 0.77 (0.44, 1.25) (Table 1); 2 new cases since May 2019.1 Eleven pts had squamous cell carcinoma and 15 pts had basal cell carcinoma; 5 pts had both. No NMSC was metastatic or led to discontinuation. IRs by time interval and subgroup are reported (Table 2). Prior NMSC (hazard ratio [HR] 12.08 [95% CI 4.20, 34.76]) and age (per 10-year increase, HR 2.01 [1.38, 2.93]) were significant risk factors for NMSC in the multivariable analysis. Prior immunosuppressant use was not a significant risk factor in either the multivariable or univariate analyses. Conclusion In this analysis, NMSC IRs for tofacitinib were similar to those in pts with UC treated with biologics2 and those previously reported in the tofacitinib UC clinical programme.1 NMSC events were more likely to occur in pts with recognised NMSC risk factors: prior NMSC and increasing age.3 Dose dependency of NMSC IR could not be concluded here, as dose changes were permitted. NMSC IRs remained stable over time, up to 7.8 years of exposure. References

Tofacitinib for the Treatment of Ulcerative Colitis: Analysis of Nonmelanoma Skin Cancer Rates From the Ulcerative Colitis Clinical Program.

BackgroundTofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We present integrated analyses of nonmelanoma skin cancer (NMSC) incidence in the tofacitinib UC clinical program.MethodsNonmelanoma skin cancer events were evaluated from 3 randomized, placebo-controlled studies: 2 identical, 8-week induction studies (NCT01465763, NCT01458951), a 52-week maintenance study (NCT01458574), and an open-label, long-term extension study (NCT01470612). Cohorts analyzed were: Induction, Maintenance, and Overall (patients receiving ≥1 dose of tofacitinib 5 mg or 10 mg twice daily [BID]). An independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique patients with events per 100 patient-years of exposure) for NMSC were evaluated. A Cox proportional hazards model was used for risk factor analysis.ResultsNonmelanoma skin cancer was evaluated for 1124 patients (2576.4 patient-years of tofacitinib exposure; ≤6.8 years’ treatment). In the Induction Cohort, NMSC IR was 0.00 for placebo and 1.26 for 10 mg BID. Nonmelanoma skin cancer IR was 0.97 for placebo, 0.00 for 5 mg BID and 1.91 for 10 mg BID in the Maintenance Cohort, and 0.73 (n = 19) in the Overall Cohort. No NMSC was metastatic or led to discontinuation. In the Overall Cohort, Cox regression identified prior NMSC (hazard ratio [HR], 9.09; P = 0.0001), tumor necrosis factor inhibitor (TNFi) failure (3.32; P = 0.0363), and age (HR per 10-year increase, 2.03; P = 0.0004) as significant independent NMSC risk factors.ConclusionsFor patients receiving tofacitinib, NMSC occurred infrequently. Older age, prior NMSC, and TNFi failure, which are previously reported NMSC risk factors in patients with UC, were associated with increased NMSC risk.

Efficacy and Safety of Tofacitinib in Ulcerative Colitis Based on Prior Tumor Necrosis Factor Inhibitor Failure Status

Tofacitinib is an oral, small-molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We summarize the efficacy and safety data of tofacitinib 5 or 10 mg twice daily in the UC clinical program, stratified by prior tumor necrosis factor inhibitor (TNFi) failure status. Efficacy was assessed in the pooled phase 3 OCTAVE Induction 1 and 2 studies (N= 1139), the phase 3 OCTAVE Sustain maintenance study (N= 593), and the dose-escalation subpopulation of the open-label, long-term extension OCTAVE Open study (N= 59). Safety was assessed in OCTAVE Sustain, the dose-escalation subpopulation, and the Overall Cohort, which included patients from OCTAVE Induction 1 and 2, OCTAVE Sustain, and OCTAVE Open (N= 1124; no prior TNFi failure N= 541; prior TNFi failure N= 583; phase 2 data were excluded when stratified by prior TNFi failure status). The dose-escalation subpopulation received tofacitinib 10 mg twice daily in OCTAVE Induction 1 and 2, tofacitinib 5 mg twice daily in OCTAVE Sustain, and tofacitinib 10 mg twice daily in OCTAVE Open. Tofacitinib had greater efficacy than placebo, regardless of prior TNFi failure status. In OCTAVE Sustain and the Overall Cohort, herpes zoster [HZ] (nonserious and serious) rates were numerically higher in tofacitinib-treated patients with vs without prior TNFi failure. Dose escalation to tofacitinib 10 mg twice daily generally recaptured clinical response for most patients. HZ (nonserious and serious) rates were numerically higher in the dose-escalation subpopulation vs the Overall Cohort. Tofacitinib was efficacious in patients with UC regardless of prior TNFi failure status. HZ (nonserious and serious) rates were numerically higher in patients who had previously failed TNFi. ClinicalTrials.gov: A3921063 (NCT00787202); OCTAVE Induction 1 (NCT01465763); OCTAVE Induction 2 (NCT01458951); OCTAVE Sustain (NCT01458574); and OCTAVE Open (NCT01470612).

Tofacitinib for the Treatment of Ulcerative Colitis: Analysis of Infection Rates from the Ulcerative Colitis Clinical Programme.

Background and AimsTofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis. We report integrated analyses of infections in the Phase [P]2 and P3 OCTAVE programmes.MethodsThree cohorts were analysed: Induction [P2/3 induction studies]; Maintenance [P3 maintenance study]; and Overall [all tofacitinib-treated patients in induction, maintenance, or ongoing, open-label, long-term extension studies; as of May 2019]. Proportions and incidence rates [IRs; unique patients with events/100 patient-years] of serious infections [SIs], herpes zoster [HZ] [non-serious and serious], and opportunistic infections [OIs] are reported [censored at time of event].ResultsIn the Induction Cohort [N = 1220], no patients receiving placebo and eight [0.9%] receiving tofacitinib 10 mg twice daily [BID] developed SIs. Maintenance Cohort [N = 592] SI IRs (95% confidence interval [CI]) were 1.94 [0.23–7.00] for placebo and 1.35 [0.16–4.87] and 0.64 [0.02–3.54] for tofacitinib 5 and 10 mg BID, respectively; HZ IRs were 0.97 [0.02–5.42], 2.05 [0.42–6.00], and 6.64 [3.19–12.22], respectively. In the Overall Cohort [N = 1157; 82.9% predominantly received tofacitinib 10 mg BID], SI, HZ, and non-HZ OI IRs were 1.70 [1.24–2.27], 3.48 [2.79–4.30], and 0.15 [0.04–0.38], respectively. No SIs resulted in death.ConclusionsDuring induction, SIs were more frequent with tofacitinib versus placebo. SIs were generally infrequent in the Maintenance and Overall Cohorts, with rates comparable between treatment groups. Maintenance Cohort HZ IR was numerically higher with tofacitinib 10 mg BID versus 5 mg BID. Overall Cohort HZ IRs remained stable over time. Non-HZ OIs and viral infections were rare.

S0901 Tofacitinib for the Treatment of Ulcerative Colitis: An Update on the Analysis of Malignancy Rates From the Ulcerative Colitis Clinical Program as of May 2019

S0901 Tofacitinib for the Treatment of Ulcerative Colitis: An Update on the Analysis of Malignancy Rates From the Ulcerative Colitis Clinical Program as of May 2019