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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Clinicaltrials.gov registration numbers: NCT00787202; NCT01465763; NCT01458951; NCT01458574; NCT01470612.

Keywords: age; clinical response; safety; tofacitinib; ulcerative colitis.

© 2022 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.

Figures

Graphical Abstract

Figure 1.

Overview of the tofacitinib UC clinical program, showing phase 2, phase 3, and OLE studies, and the transfer of patients from induction studies to maintenance and/or OLE studies. †Final complete efficacy assessment at week 8/52. Treatment continued up to week 9/53. ‡Clinical response in OCTAVE Induction 1 and 2 was defined as a decrease from the induction study baseline total Mayo score ≥ 3 points and ≥ 30%, plus a decrease in rectal bleeding subscore ≥ 1 point or an absolute rectal bleeding subscore of 0 or 1. §Remission was defined as a total Mayo score ≤ 2 with no individual subscore > 1, and a rectal bleeding subscore of 0. Adapted from Winthrop et al.16 (in accordance with the Creative Commons Attribution-NonCommercial License [CC BY-NC] license). Abbreviations: BID, twice daily; N, total number of patients in each treatment group; OLE, open-label, long-term extension; UC, ulcerative colitis.

Figure 2.

Safety and AESI reported by age group in the Overall Cohort from the tofacitinib UC clinical program. Data are as of May 27, 2019; database not locked. All malignancy (excluding NMSC), NMSC, MACE, and death events were counted (including those that were outside the 28-day risk period); all other AESI were counted to 28 days beyond the last dose, with the exception of ongoing patients in the OLE study. The IR was defined as the number of unique patients with events per 100 patient-years of exposure. Exact Poisson (adjusted for patient-years) 95% CIs are provided. †Includes patients who received tofacitinib 5 or 10 mg BID in the phase 2 and phase 3 induction and maintenance studies, and the ongoing OLE study, unless stated otherwise. ‡Adjudicated events; the Overall Cohort does not include data from the phase 2 induction study. §The IR was significantly higher than for the group aged < 30 years, based on nonoverlapping 95% CIs. ¶The IR was significantly higher than for the group aged < 65 years, based on nonoverlapping 95% CIs. ††The IR was significantly higher than for the groups ages 18 to < 30, 30 to < 40, 40 to < 50, and 50 to < 60 years, based on nonoverlapping 95% CIs. Abbreviations: AESI, adverse event of special interest; BID, twice daily; CI, confidence interval; DVT, deep vein thrombosis; GI, gastrointestinal; IR, incidence rate; MACE, major adverse cardiovascular events; N, total number of patients; n, number of patients with the specified event; NMSC, nonmelanoma skin cancer; OLE, open-label, long-term extension; PE, pulmonary embolism; PY, patient-years; UC, ulcerative colitis.

Figure 3.

Predictors of AESI (Cox proportional-hazards regression models) in the Overall Cohort. †Based on adjudicated events, which do not include data from the phase 2 induction study. Abbreviations: AESI, adverse event of special interest; CI, confidence interval; HR, hazard ratio; N, number of patients in analysis; n, number of patients with event; NMSC, nonmelanoma skin cancer; TNFi, tumor necrosis factor inhibitor; UC, ulcerative colitis.

Figure 4.

Proportions of patients receiving placebo or tofacitinib 10 mg BID who achieved (A) endoscopic improvement, (B) clinical remission, or (C) clinical response at week 8 in the Induction Cohort (FAS, NRI). *P < .05; **P < .01; ***P < .001 (P values are from Cochran-Mantel-Haenszel chi-squared test). Values above bars show the difference from placebo (95% CI). Endoscopic improvement was defined as a Mayo endoscopic subscore of 0 or 1. Clinical remission was defined as a total Mayo score of ≤ 2, with no individual subscore exceeding 1 point. Clinical response was defined as a decrease from induction study baseline total Mayo score of ≥ 3 points and ≥ 30%, plus a decrease in rectal bleeding subscore ≥ 1 point or an absolute rectal bleeding subscore of 0 or 1. Abbreviations: BID, twice daily; CI, confidence interval; FAS, full analysis set; n, number of patients with the specified response within the given category; N1, number of patients in the specified category with nonmissing data; NRI, nonresponder imputation.

Figure 5.

Proportions of patients receiving placebo, tofacitinib 5 mg BID, or tofacitinib 10 mg BID who achieved (A) endoscopic improvement, (B) clinical remission, or (C) clinical response at week 52 in the Maintenance Cohort (FAS, NRI). *P < .05; **P < .01; ***P < .001 (P values are from Cochran-Mantel-Haenszel chi-squared test). Values above bars show the difference from placebo (95% CI). Endoscopic improvement was defined as a Mayo endoscopic subscore of 0 or 1. Clinical remission was defined as a total Mayo score of ≤ 2, with no individual subscore exceeding 1 point. Clinical response was defined as a decrease from induction study baseline total Mayo score of ≥ 3 points and ≥ 30%, plus a decrease in rectal bleeding subscore of ≥ 1 point or an absolute rectal bleeding subscore of 0 or 1. Abbreviations: BID, twice daily; CI, confidence interval; FAS, full analysis set; n, number of patients with the specified response within the given category; N1, number of patients in the specified category with non-missing data; NRI, nonresponder imputation.