S777 Tofacitinib for the Treatment of Ulcerative Colitis: Up to 7.8 Years of Safety Data from Global Clinical Trials (2021)

Introduction: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. Efficacy and safety of tofacitinib were evaluated in randomized, placebo (PBO)-controlled Phase 2 (NCT00787202) and Phase 3 (NCT01465763; NCT01458951; NCT01458574) studies, and an open-label, long-term extension (OLE) study (NCT01470612).1,2 We report updated tofacitinib safety analyses from the tofacitinib UC clinical program, including final data from the OLE study (as of Aug 24, 2020; exposure up to 7.8 years). Methods: Cohorts analyzed were: Phase 3 Maintenance (592 patients [pts] receiving PBO, tofacitinib 5 or 10 mg BID) and Overall (1,157 pts receiving tofacitinib 5 or 10 mg BID in Phase 2/Phase 3/OLE studies). Proportions and incidence rates (IRs; unique pts with events per 100 pt-years [PY] of exposure) were evaluated for adverse events (AEs) of special interest. Opportunistic infections (OIs), malignancies, major adverse cardiovascular events (MACE), and gastrointestinal perforations were adjudicated. Results: The table shows demographics, clinical characteristics, and safety data. In the Overall Cohort, 1,157 pts received ≥1 dose of tofacitinib 5 or 10 mg BID; 956 (83%) received a predominant dose of 10 mg BID. Median treatment duration was 623 (range 1–2,850) days (2,814.4 PY of exposure). IRs (95% CIs) for AEs of special interest in the Overall Cohort were: deaths, 0.24 (0.10, 0.49); serious infections, 1.72 (1.28, 2.27); herpes zoster (non-serious and serious), 3.38 (2.73, 4.15); OIs, 1.05 (0.71, 1.50); malignancies (excluding non-melanoma skin cancer [NMSC]), 0.86 (0.56, 1.27); NMSC, 0.73 (0.45, 1.12); MACE, 0.28 (0.12, 0.54); deep vein thrombosis, 0.03 (0.00, 0.19); pulmonary embolism, 0.17 (0.06, 0.40); and gastrointestinal perforations, 0.10 (0.02, 0.30). Results were similar to prior Overall Cohort analyses.3 Conclusion: The safety profile of tofacitinib in pts with UC from the tofacitinib UC clinical program was generally consistent with that of other UC therapies, including biologics, with the exception of herpes zoster.4 IRs for AEs of special interest have remained stable over an extended period of time (up to 7.8 years).3Table 1.: Baseline Demographics and Disease Characteristics, and IRs (Unique Pts with Events per 100 PY of Exposure) for AEs of Special Interest in the Tofacitinib UC Clinical Program, by Cohort. Overall Cohort includes final data from the OLE study (OCTAVE Open), as of Aug 2020. a.Data are from screening of P3 induction studies (OCTAVE Induction 1&2) for the Maintenance Cohort, and from Day 1 (start of active treatment in the UC 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 UC program) for the Overall Cohort; c.Data are from baseline of OCTAVE Induction 1 or 2; d.For the Maintenance Cohort, events that occurred > 28 days after the last dose of study drug were excluded; for the Overall Cohort, all events, including those outside the 28-day risk period, were included; e.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); f.Events that occurred > 28 days after the last dose of study drug were excluded; g.Defined as any infection AE that requires hospitalization or parenteral antimicrobials, or meets other criteria that require the infection to be classified as an SAE; h.IRs of HZ in the Maintenance Cohort were numerically higher with tofacitinib 5 mg BID vs PBO and statistically higher with tofacitinib 10 mg BID vs PBO; i.Adjudicated events; N=1,124 (excludes P2) for the Overall Cohort; j.Excludes tuberculosis and HZ with two adjacent dermatomes; k.Invasive ductal breast carcinoma; l.Malignancy (number of events): acute myeloid leukemia (1), breast cancer (3), Bowen’s disease (1), cervical dysplasia (2), cholangiocarcinoma (2), colorectal cancer (4), diffuse large B-cell lymphoma (1), 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), plus secondary malignancies in the liver, peritoneum, and lymph nodes; m.Myocardial infarction; n.Hemorrhagic stroke; o.MACE (number of events): acute coronary syndrome (1), acute myocardial infarction (1), aortic dissection (1), cardiac arrest (1), cerebellar hemorrhage (1), cerebrovascular accident (1), hemorrhagic stroke (1), myocardial infarction (1); p.Pt with DVT was diagnosed following a long-haul flight and management of an infected leg wound sustained in a recent motorbike accident; q.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. One pt had a medical history with no prior risk factors for PE; r.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; BID, twice daily; CI, confidence interval; DVT, deep vein thrombosis; GI, gastrointestinal; HZ, herpes zoster; IR, incidence rate (unique pts with events per 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; OLE, open-label, long-term extension; P, Phase; PBO, placebo; PE, pulmonary embolism; pts, patients; PY, pt-years; SAE, serious AE; SD, standard deviation; SI, serious infection; TNFi, tumor necrosis factor inhibitor; UC, ulcerative colitis; VTE, venous thromboembolic events.