Incidence of venous thrombo embolic events in patients with ulcerative colitis treated with to facitinib in the ulcerative colitis clinical development programme

Introduction: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). The safety of tofacitinib for the treatment of moderate to severe UC was evaluated in a randomised, placebo‐controlled Phase (P) 2 induction study (NCT00787202),1 2 induction P3 studies (NCT01465763; NCT01458951), 1 maintenance P3 study (NCT01458574),2 and an ongoing, open‐label, long‐term extension (OLE) study (NCT01470612).3 A safety signal for pulmonary embolism (PE) was seen in the tofacitinib 10 mg twice daily (BID) arm of an FDA post‐marketing requirement study in rheumatoid arthritis designed to evaluate the long‐term risk of major cardiovascular events and malignancy. Patients (pts) eligible for this ongoing, open‐label, safety‐endpoint‐driven study had to be ≥50 years of age, have ≥1 cardiovascular risk factor and be on a stable dose of methotrexate. UC is a known risk factor for deep vein thrombosis (DVT) and PE, with reported incidence rates ranging from 0.07 to 0.30 and 0.04 to 0.20, respectively.4,5 Here, we report the incidence of DVT and PE in the tofacitinib UC clinical programme, as of Sep 2018. Aims & Methods: Pts who received placebo, tofacitinib 5 or 10 mg BID were analysed in three cohorts: Induction (P2/P3 induction studies, N=1220), Maintenance (P3 maintenance study, N=592) and Overall (pts receiving tofacitinib 5 or 10 mg BID in P2, P3 or ongoing OLE studies, N=1157). DVT and PE events were identified using preferred terms in the Standardised Medical Dictionary for Regulatory Activities query 'embolic and thrombotic events, venous' and incidence rates (unique pts with events per 100 ptyears [PY] of exposure) were evaluated. For Overall Cohort analysis, pts were categorised based on the average daily dose of tofacitinib: predominant dose (PD) tofacitinib 5 mg BID (average total daily dose < 15 mg) and PD tofacitinib 10 mg BID (average total daily dose ≥15 mg). Results: The Overall Cohort comprised 1157 pts who received ≥1 dose of tofacitinib 5 or 10 mg BID, with 2404 PY of tofacitinib exposure and up to a maximum of 6.1 years of treatment. Results for DVT and PE are shown in the Table. In the Induction and Maintenance Cohorts, 2 pts had DVT and 2 had PE; all had received placebo in the study. In the Overall Cohort, there was 1 pt with DVT and 4 pts with PE; all 5 pts had received PD of tofacitinib 10 mg BID and all events occurred during the OLE study. Pts with PE had the following notable medical history: 1 with prior DVT and PE, 1 with phlebothrombosis and stroke, 1 was receiving oral contraceptives for dysfunctional uterine bleeding, and 1 had cholangiocarcinoma and metastases to the peritoneum, and PE was the cause of death. The pt with DVT was diagnosed following a long‐haul flight and management of an infected leg wound sustained in a recent motorbike accident. Conclusion: In this post‐hoc analysis of pts from the OCTAVE programme, during tofacitinib exposure, 4 pts had PE and 1 pt had DVT. All of the events in pts taking tofacitinib occurred during the OLE study in pts treated with PD of tofacitinib 10 mg BID (83% of pts in the Overall Cohort received a PD of tofacitinib 10 mg BID) and with risk factors for thrombotic events. This post‐hoc analysis is limited by small sample size and limited drug exposure, and further study is needed. (Table Presented).