Tofacitinib for the Treatment of Ulcerative Colitis: Up to 9.2 Years of Safety Data From the Global Clinical Program

Introduction: Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). The safety of tofacitinib was evaluated in the Overall Cohort, which consisted of 6 studies: 4 randomized, placebo-controlled Phase (P)2/3 studies (NCT00787202; NCT01465763; NCT01458951; NCT01458574), an open-label, long-term extension study (NCT01470612), and a randomized P3b/4 study (NCT03281304). We report final safety analyses from the tofacitinib UC clinical program of ≤ 9.2 years of tofacitinib exposure (cut-off date: April 18, 2022). Methods: This analysis included 1,157 patients (pts) receiving tofacitinib 5 or 10 mg twice daily (BID; predominant dose [PD]) in the Overall Cohort and a previously reported 52-week Maintenance Cohort.1,2 Proportions and incidence rates (IRs; unique pts with events/100 pt-years of exposure) were evaluated for deaths and adverse events of special interest (AESI): serious infections; herpes zoster (HZ), non-serious and serious; opportunistic infections (OIs); malignancies (excluding non-melanoma skin cancer [NMSC]); NMSC; major adverse cardiovascular events (MACE); deep vein thrombosis (DVT); pulmonary embolism (PE); and gastrointestinal (GI) perforations. Results: In the Overall Cohort, 1,157 pts received ≥ 1 dose of tofacitinib 5 or 10 mg BID; 938 (81.1%) received a PD of 10 mg BID; 552 (47.7%) pts had received tofacitinib for ≥ 2 years. Median treatment duration was 1.7 years (mean 2.8; range 0.0–9.2). IRs (95% CI) for all tofacitinib in the Overall Cohort (Table 1): deaths 0.24 (0.10, 0.48); serious infections 1.80 (1.37, 2.32); HZ (non-serious and serious) 3.24 (2.63, 3.94); serious HZ 0.24 (0.10, 0.48); OIs 0.96 (0.65, 1.36); malignancies (excluding NMSC) 0.88 (0.59, 1.26); NMSC 0.71 (0.45, 1.07); MACE 0.27 (0.12, 0.52); DVT 0.06 (0.01, 0.22); PE 0.18 (0.07, 0.40); and GI perforations 0.09 (0.02, 0.27). Conclusion: IRs for AESI remained stable over an extended period of time (≤ 9.2 years) with the inclusion of the P3b/4 final data and were consistent with prior Overall Cohort analyses (≤ 7.8 years).12 The safety profile of tofacitinib in the UC clinical program was consistent with that observed in other indications.3,4 References: 1. Sandborn et al. Clin Gastroenterol Hepatol 2019;17:1541–50. 2. Sandborn et al. J Crohns Colitis 2023;17:338–51. 3. Cohen et al. RMD Open 2020;6:e001395. 4. Burmester et al. Drug Saf 2020;43:379–92. Table 1. - Baseline Demographics and Disease Characteristics, and IRs (Unique Pts with Events/100 PY of Exposure) for AESI in the Tofacitinib UC Clinical Program, by Cohort Maintenance Cohort[1][2] (52 weeks) Overall Cohort (≤ 9.2 years) Placebo (N=198; 100.4 PY) Tofacitinib5 mg BID (N=198; 146.2 PY) Tofacitinib10 mg BID (N=196; 154.3 PY) Tofacitinib all (N=394; 300.5 PY) PD tofacitinib5 mg BID (N=219; 902.3 PY) PD tofacitinib10 mg BID (N=938; 2,299.7 PY) Tofacitinib all (N=1,157; 3,202.0 PY) Baseline demographics and clinical characteristics Age (yrs), mean (SD)[a] 43.4 (14.0) 41.9 (13.7) 43.0 (14.4) 42.5 (14.0) 44.0 (14.4) 40.6 (13.7) 41.3 (13.9) TMS, mean (SD)[b][c] 3.3 (1.8) 3.3 (1.8) 3.4 (1.8) 3.4 (1.8) 7.9 (2.4) 8.8 (1.8) 8.6 (2.0) Disease duration (yrs), mean (SD)[b] 8.8 (7.5) 8.3 (7.2) 8.7 (7.0) 8.5 (7.1) 8.3 (6.6) 8.2 (7.1) 8.2 (7.0) Prior TNFi failure, n (%)[d] 89 (44.9) 83 (41.9) 92 (46.9) 175 (44.4) 93 (42.5) 490 (54.1) 583 (51.9) CS use at baseline, n (%)[b] 100 (50.5) 101 (51.0) 86 (43.9) 187 (47.5) 89 (40.6) 434 (46.3) 523 (45.2) AEs Pts with AEs, n (%) 149 (75.3) 143 (72.2) 156 (79.6) 299 (75.9) 205 (93.6) 789 (84.1) 994 (85.9) Pts with serious AEs, n (%) 13 (6.6) 10 (5.1) 11 (5.6) 21 (5.3) 46 (21.0) 208 (22.2) 254 (22.0) Deaths, n (%), IR [95% CI][e] 0 (0.0), 0.00 [0.00, 3.57] 0 (0.0), 0.00 [0.00, 2.48] 0 (0.0), 0.00 [0.00, 2.35] 0 (0.0), 0.00 [0.00, 1.21] 0 (0.0), 0.00 [0.00, 0.40] 8 (0.9), 0.34 [0.14, 0.66] 8 (0.7),[f] 0.24 [0.10, 0.48] Infections, n (%), IR [95% CI][g] SIs[h] 2 (1.0), 1.94 [0.23, 7.00] 2 (1.0), 1.35 [0.16, 4.87] 1 (0.5), 0.64 [0.02, 3.54] 3 (0.8), 0.98 [0.20, 2.87] 10 (4.6), 1.08 [0.52, 1.99] 49 (5.2), 2.07 [1.53, 2.74] 59 (5.1), 1.80 [1.37, 2.32] All HZ (non-serious and serious) 1 (0.5), 0.97 [0.02, 5.42] 3 (1.5),[i] 2.05 [0.42, 6.00] 10 (5.1),[i] 6.64 [3.19, 12.22] 13 (3.3),[i] 4.38 [2.33, 7.50] 23 (10.5), 2.71 [1.72, 4.06] 76 (8.1), 3.44 [2.71, 4.31] 99 (8.6), 3.24 [2.63, 3.94] Serious HZ 0 (0.0), 0.00 [0.00, 3.57] 0 (0.0), 0.00 [0.00, 2.48] 0 (0.0), 0.00 [0.00, 2.35] 0 (0.0), 0.00 [0.00, 1.21] 1 (0.5), 0.11 [0.00, 0.60] 7 (0.7), 0.29 [0.12, 0.61] 8 (0.7), 0.24 [0.10, 0.48] OIs[d][j][k] 1 (0.5), 0.97 [0.02, 5.42] 2 (1.0), 1.36 [0.16, 4.92] 4 (2.0), 2.60 [0.71, 6.65] 6 (1.5), 1.99 [0.73, 4.34] 8 (3.7), 0.89 [0.39, 1.76] 23 (2.5), 0.99 [0.63, 1.48] 31 (2.8), 0.96 [0.65, 1.36] HZ OIs[j] 1 (0.5), 0.97 [0.02, 5.42] 2 (1.0), 1.36 [0.16, 4.92] 4 (2.0), 2.60 [0.71, 6.65] 6 (1.5), 1.99 [0.73, 4.34] 7 (3.2), 0.78 [0.31, 1.61] 19 (2.1), 0.81 [0.49, 1.27] 26 (2.3), 0.80 [0.53, 1.18] Malignancies, n (%), IR [95% CI][d][e][j] Malignancies (excluding NMSC) 1 (0.5),[l] 0.97 [0.02, 5.39] 0 (0.0), 0.00 [0.00, 2.48] 0 (0.0), 0.00 [0.00, 2.35] 0 (0.0), 0.00 [0.00, 1.21] 5 (2.3), 0.54 [0.18, 1.26] 24 (2.7), 1.01 [0.65, 1.51] 29 (2.6),[m] 0.88 [0.59, 1.26] NMSC 1 (0.5), 0.97 [0.02, 5.40] 0 (0.0), 0.00 [0.00, 2.48] 3 (1.5), 1.91 [0.39, 5.59] 3 (0.8), 0.98 [0.20, 2.87] 6 (2.7), 0.66 [0.24, 1.43] 17 (1.9), 0.73 [0.43, 1.17] 23 (2.0), 0.71 [0.45, 1.07] MACE, n (%), IR [95% CI][d][e][j] 0 (0.0), 0.00 [0.00, 3.57] 1 (0.5),[n] 0.68 [0.02, 3.77] 1 (0.5),[o] 0.64 [0.02, 3.54] 2 (0.5), 0.66 [0.08–2.37] 4 (1.8), 0.44 [0.12, 1.12] 5 (0.6), 0.21 [0.07, 0.49] 9 (0.8),[p] 0.27 [0.12, 0.52] VTE, n (%), IR [95% CI][g][j] DVT 1 (0.5), 0.97 [0.02, 5.39] 0 (0.0), 0.00 [0.00, 2.48] 0 (0.0), 0.00 [0.00, 2.35] 0 (0.0), 0.00 [0.00, 1.21] 0 (0.0), 0.00 [0.00, 0.40] 2 (0.2), 0.08 [0.01, 0.30] 2 (0.2),[q] 0.06 [0.01, 0.22] PE 1 (0.5), 0.98 [0.02, 5.44] 0 (0.0), 0.00 [0.00, 2.48] 0 (0.0), 0.00 [0.00, 2.35] 0 (0.0), 0.00 [0.00, 1.21] 0 (0.0), 0.00 [0.00, 0.40] 6 (0.6), 0.25 [0.09, 0.55] 6 (0.5),[r] 0.18 [0.07, 0.40] GI perforations, n (%), IR [95% CI][d][g][j][s] 1 (0.5), 0.97 [0.02, 5.39] 0 (0.0), 0.00 [0.00, 2.48] 0 (0.0), 0.00 [0.00, 2.35] 0 (0.0), 0.00 [0.00, 1.21] 1 (0.5), 0.11 [0.00, 0.60] 2 (0.2), 0.08 [0.01, 0.30] 3 (0.3), 0.09 [0.02, 0.27] The Maintenance Cohort has been reported previously[1,2] and includes pts receiving placebo, tofacitinib 5 mg BID, or tofacitinib 10 mg BID in the 52-week maintenance study (OCTAVE Sustain; NCT01458574); the Overall Cohort includes final data from the open-label, long-term extension study (OCTAVE Open; NCT01470612) and P3b/4 data as of April 18, 2022; in the Overall Cohort, PD tofacitinib 5 mg BID was defined as an average total daily dose of tofacitinib < 15 mg and PD tofacitinib 10 mg BID was defined as an average total daily dose of tofacitinib ≥ 15 mg. [a]Data are from screening of P3 induction studies (OCTAVE Induction 1&2; NCT01465763 and NCT01458951, respectively) for the Maintenance Cohort, and from Day 1 (start of active treatment in the tofacitinib UC clinical program) for the Overall Cohort. [b]Data are from baseline of the P3 maintenance study (OCTAVE Sustain) for the Maintenance Cohort, and from Day 1 (start of active treatment in the tofacitinib UC clinical program) for the Overall Cohort. [c]For the Overall Cohort, N=936 and N=1,155 for the PD tofacitinib 10 mg BID and tofacitinib all groups, respectively. [d]Data are from baseline of OCTAVE Induction 1&2; for the Overall Cohort, N=905 and N=1,124 for the PD tofacitinib 10 mg BID and tofacitinib all groups, respectively (excludes P2, NCT00787202). [e]For the Maintenance Cohort, and generally for the Overall Cohort, events that occurred > 28 days after the last dose of study drug were excluded; for the Overall Cohort, deaths, malignancies, and MACE outside the 28-day risk period were included. [f]Deaths (number of events): aortic dissection (1), cardiac arrest (1), PE (1), hepatic angiosarcoma (1), acute myeloid leukemia (1), malignant melanoma (1), metastatic adenocarcinoma (1), COVID-19 pneumonia/respiratory failure (1). [g]Events that occurred > 28 days after the last dose of study drug were excluded. [h]Defined as any infection AE that required hospitalization or parenteral antimicrobials, or met other criteria that required the infection to be classified as a serious AE. [i]IRs of HZ in the Maintenance Cohort were numerically higher with tofacitinib 5 mg BID vs placebo and all tofacitinib vs placebo, and statistically higher with tofacitinib 10 mg BID vs placebo. [j]Adjudicated events. [k]Excludes tuberculosis and HZ with two adjacent dermatomes. [l]Invasive ductal breast carcinoma. [m]Malignancy (number of events): acute myeloid leukemia (1), breast cancer (3), Bowen’s disease (1), cervical dysplasia (2), cholangiocarcinoma (2), colorectal cancer (5), diffuse large B-cell lymphoma (2), Epstein-Barr virus associated lymphoma (1), essential thrombocythemia (1), hepatic angiosarcoma (1), leiomyosarcoma (1), lung cancer (2), malignant melanoma (2), esophageal adenocarcinoma (1), penile dysplasia (1), renal cell carcinoma (1), vulvar cancer (1), prostate cancer (1). [n]Myocardial infarction. [o]Hemorrhagic stroke. [p]MACE (number of events): acute coronary syndrome (1), acute myocardial infarction (1), aortic dissection (1), cardiac arrest (1), cerebellar hemorrhage (1), cerebrovascular accident (2), hemorrhagic stroke (1), myocardial infarction (1). [q]Pt with DVT was diagnosed following a long-haul flight and management of an infected leg wound sustained in a recent motorbike accident; the second DVT event was assessed as related to the study drug by the investigator. [r]Pts with PE had the following notable medical history: one with prior DVT and PE, one with phlebothrombosis and stroke, one was receiving oral contraceptives for dysfunctional uterine bleeding, and one had cholangiocarcinoma and metastases to the peritoneum, and PE was the cause of death. Two pts had a medical history with no prior risk factors for PE. [s]GI perforation excludes Preferred Terms of pilonidal cyst, perirectal abscess, rectal abscess, anal abscess, perineal abscess, and any Preferred Terms containing the term fistula. AE, adverse event; AESI, AEs of special interest; BID, twice daily; CI, confidence interval; DVT, deep vein thrombosis; GI, gastrointestinal; HZ, herpes zoster; IR, incidence rate (unique pts with events/100 PY of exposure); MACE, major adverse cardiovascular events; N, number of pts treated in the treatment group; n, number of unique pts with a particular AE; NMSC, non-melanoma skin cancer; OI, opportunistic infection; P, Phase; PD, predominant dose; PE, pulmonary embolism; pt, patient; PY, pt-years; SD, standard deviation; SI, serious infection; TMS, total Mayo score; TNFi, tumor necrosis factor inhibitor; UC, ulcerative colitis; VTE, venous thromboembolic events; yrs, years.