Woolcott, John

Abstract Background Patient age can impact the safety and efficacy of ulcerative colitis (UC) treatments. Etrasimod is an oral, once daily (QD), selective sphingosine 1-phosphate1,4,5 receptor modulator for the treatment of moderately to severely active UC. Here, we evaluate the impact of age on etrasimod safety and efficacy in patients with UC in the phase 3 ELEVATE UC clinical program. Methods Data were pooled from ELEVATE UC 52 and ELEVATE UC 12 in patients receiving etrasimod 2 mg QD or placebo. Proportions and incidence rates (IRs) per 100 patient-years of treatment-emergent adverse events (AEs) were stratified by age (<40, 40-59, and ≥60 years). With the same age stratifications, efficacy was evaluated in patients with baseline Modified Mayo scores of 5-9 and 4-9 for the primary efficacy endpoint (clinical remission) and secondary efficacy endpoints. Results Overall, 787 patients were enrolled (<40 years, n = 420 [53.4%]; 40-59 years, n = 276 [35.1%]; and ≥60 years, n = 91 [11.6%]). Arthralgia, fatigue, and hypertension IRs were higher in older patients, irrespective of treatment. Serious AEs and AEs leading to treatment discontinuation were low and consistent across age groups. Significantly more patients receiving etrasimod 2 mg QD vs placebo achieved efficacy endpoints, regardless of age. Conclusions The safety profile of etrasimod 2 mg QD in the ELEVATE UC population was consistent across age groups, with no change in the incidence of AEs. Patients receiving etrasimod vs placebo showed significant clinical benefit, regardless of age. ClinicalTrials.gov NCT03945188; NCT03996369.

Objective The ORAL Surveillance trial found a dose‐dependent increase in venous thromboembolism (VTE) and pulmonary embolism (PE) events with tofacitinib versus tumor necrosis factor inhibitors (TNFi). We aimed to assess VTE incidence over time and explore risk factors of VTE, including disease activity, in ORAL Surveillance. Methods Patients with rheumatoid arthritis (RA) aged 50 years or older with at least one additional cardiovascular risk factor received tofacitinib 5 or 10 mg twice daily (BID) or TNFi. Post hoc, cumulative probabilities and incidence rates (patients with first events/100 patient‐years) by 6‐month intervals were estimated for adjudicated VTE, deep vein thrombosis, and PE. Cox regression models identified risk factors. Clinical Disease Activity Index leading up to the event was explored in patients with VTE. Results Cumulative probabilities for VTE and PE were higher with tofacitinib 10 mg BID, but not 5 mg BID, versus TNFi. Incidence rates were consistent across 6‐month intervals within treatments. Across treatments, risk factors for VTE included prior VTE, body mass index greater than or equal to 35 kg/m 2 , older age, and history of chronic lung disease. At the time of the event, most patients with VTE had active disease as defined by Clinical Disease Activity Index. Conclusion Incidences of VTE and PE were higher with tofacitinib (10 > 5 mg BID) versus TNFi and were generally consistent over time. Across treatments, VTE risk factors were aligned with previous studies in the general RA population. These data highlight the importance of assessing VTE risk factors, including age, body mass index, and VTE history, when considering initiation of tofacitinib or TNFi in patients with active RA.

Abstract Background Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). Previous work has shown age can impact treatment safety and efficacy in patients with inflammatory bowel disease.1 This post hoc analysis investigated the impact of age on the safety and efficacy of etrasimod in patients with UC in the phase 3 ELEVATE UC clinical programme. Methods Data pooled from the ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369) trials were analysed in patients receiving etrasimod 2 mg QD and placebo. ELEVATE UC 52 had a treat-through design comprising a 12-week induction period followed by a 40-week maintenance period. ELEVATE UC 12 was a 12-week induction trial. Proportions and incidence rates (IRs) per 100 patient-years from pooled data of treatment-emergent adverse events (TEAEs) and events of interest were stratified by age (<40 years, 40–59 years, ≥60 years) and analysed in patients who received ≥1 dose of etrasimod or placebo. Efficacy analyses were evaluated in patients with baseline Modified Mayo score (MMS) 5–9 for the primary efficacy endpoint (clinical remission) and select secondary endpoints at Week 12 (both trials) and Week 52 (ELEVATE UC 52) stratified by age. Results There were 787 patients enrolled in the ELEVATE UC programme, of whom 420 (53.4%) were aged <40 years, 276 (35.1%) were aged 40–59 years and 91 (11.6%) were aged ≥60 years. The proportions and IRs of TEAEs and events of interest were mostly similar between age groups and treatment arms (Table). IRs of arthralgia, fatigue, hypertension and pyrexia were higher in older age groups, regardless of treatment arm. Serious AEs and AEs leading to treatment discontinuation were low and consistent across all age subgroups. Serious infections and infection events of interest were balanced across age groups and treatment arms. Regardless of age subgroup, significantly more patients treated with etrasimod 2 mg QD vs placebo achieved the primary and select secondary efficacy endpoints at Week 12 and Week 52 (Figure). Conclusion The safety profile of etrasimod 2 mg QD in the UC population was consistent across age groups, and with no new risks other than the estimated risks associated with increasing age.2 Patients receiving etrasimod in the ELEVATE UC programme showed significant clinical benefit as assessed by clinical remission, symptomatic remission and endoscopic improvement compared with placebo, regardless of age. References 1. Lichtenstein GR et al. Inflamm Bowel Dis 2023; 29: 27–41. 2. Luo J et al. JMIR Med Inform 2016; 4: e30.

Abstract Background Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Patients with inflammatory bowel disease are susceptible to Clostridium difficile infection (CDI). Here, we evaluate CDI in the tofacitinib UC clinical program. Methods Events from 4 randomized, placebo-controlled studies (phase [P] 2 or P3 induction [NCT00787202; NCT01465763; NCT01458951], P3 maintenance [NCT01458574]) and an open-label, long-term extension (OLE) study (NCT01470612), were analyzed as 3 cohorts: Induction (P2/P3 induction), Maintenance (P3 maintenance), and Overall (patients receiving tofacitinib 5 or 10 mg twice daily [BID] in P2, P3, and OLE studies; including final data from the OLE study, as of August 24, 2020). Proportions and incidence rates (unique patients with events per 100 patient-years of exposure) of CDI were evaluated. Results The overall cohort comprised 1157 patients who received ≥1 dose of tofacitinib 5 or 10 mg BID, with a total of 2814.4 patient-years of tofacitinib exposure and up to 7.8 years of treatment. A total of 82.6% of patients received predominantly tofacitinib 10 mg BID. In the induction, maintenance, and overall cohorts, 3 (2 tofacitinib treated, 1 placebo treated), 3 (all placebo treated), and 9 patients had CDI, respectively; the overall cohort incidence rate was 0.31 (95% confidence interval, 0.14-0.59). CDI were all mild–moderate in severity and resolved with treatment in 8 patients. Six of 9 patients continued tofacitinib treatment without interruption. Two patients had events reported as serious due to hospitalization. Two patients were receiving corticosteroids when the CDI occurred. Conclusion CDIs among patients with UC receiving tofacitinib were infrequent, cases were mild–moderate in severity, and most resolved with treatment.