Danese, Silvio

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.

Abstract Background Vedolizumab (VDZ) is a gut selective, monoclonal anti-α4β7 integrin antibody approved for the treatment of moderately to severely active ulcerative colitis (UC) or Crohn’s disease (CD) and is available in subcutaneous (SC) formulation. This analysis assessed the long-term safety outcomes of specific interest to the SC formulation of VDZ. Methods Patients (pts) who participated in VISIBLE 1 or VISIBLE 2 were eligible to enrol in VISIBLE OLE (NCT02620046). In VISIBLE 1, pts with UC were treated with placebo, VDZ SC or VDZ intravenous (IV). In VISIBLE 2, pts with CD were treated with placebo or VDZ SC. In VISIBLE OLE, pts received VDZ SC 108mg every 2 weeks (Q2W) or weekly. Pts received training on SC administration, and most injections were conducted at home by pt or caregiver. Safety of VDZ SC included assessing anti-VDZ antibody (AVA) status and injection site reaction (ISR) adverse events. Blood specimens for AVA assessment were collected 30 minutes before dosing every 16 weeks, at the final dose and the final safety visit 18 weeks after last dose. Data were assessed by treatment pts received during VISIBLE 1 and 2. Results Overall, 288 pts with UC and 458 pts with CD enrolled in VISIBLE OLE. A mean of 91.1 and 74.2 SC injections were completed by pts with UC and CD, respectively, during the OLE. Among pts with UC, the positive AVA rate was higher in pts previously treated with placebo (17.3%) than those treated with VDZ SC (3.4%) or IV (2.6%) (Table 1). The positive AVA rate was also higher among pts with CD previously treated with placebo (11.4%) than with VDZ SC (1.8%). A total of 14/288 pts (4.9%) with UC reported ISRs (Table 2), most of which were mild and none were serious. Two pts developed moderate ISRs; neither required dose modification and both were resolved. Overall, 19/458 pts (4.1%) with CD reported ISRs (Table 2). The majority of ISRs were mild, 2 were moderate and none were severe, and none required dose modification. No direct correlation between AVA status and ISRs was identified, with 11/14 pts (78.6%) with UC and 17/19 pts (89.5%) with CD who reported ISRs being AVA negative. All 5 pts who were AVA positive and reported an ISR had previously received placebo. The highest rate of ISRs were in pts who received placebo in VISIBLE 1 (13.5%). Conclusion No new long-term safety events were identified with the VDZ SC route of administration compared to IV, except for ISRs. A higher proportion of patients who had previously been treated with placebo than those treated with VDZ during VISIBLE 1 and 2 were AVA positive during VISIBLE OLE, supporting a benefit of continued therapy with VDZ SC after IV induction, rather than cessation of treatment for a period of time.

Abstract Background Vedolizumab (VDZ) is a gut selective, monoclonal anti-α4β7 integrin antibody approved for the treatment of moderate to severe ulcerative colitis (UC) or Crohn’s disease (CD). The subcutaneous (SC) formulation of VDZ was evaluated during the Phase 3 VISIBLE 1 and 2 studies. We report the long-term efficacy among patients (pts) with UC or CD treated with VDZ SC in the VISIBLE open-label extension (OLE) study. Methods Pts with UC or CD in VISIBLE 1/2 could enrol in VISIBLE OLE (NCT02620046). Pts in VISIBLE 1/2 who completed 52 weeks(W) of treatment with VDZ or placebo (randomised completers) and pts without clinical response at W6 who responded at W14 (non-randomised responders) received VDZ SC 108mg every 2W (Q2W) in the OLE. Pts with worsening disease were escalated to QW dosing. Clinical remission (partial Mayo score ≤2, no subscore >1 in UC; HBI score ≤4 in CD) up to W168 was assessed (pts with missing data or escalated to QW dosing were imputed as non-response, irrespective of clinical status). The number of pts who regained clinical response when escalated to QW dosing was also assessed. Results were summarized by prior VISIBLE 1/2 treatment groups. Results Data from 231 pts with UC and 344 pts with CD were included. In pts with UC, baseline OLE clinical remission rates were 55.0%, 91.3% and 77.1% among randomised completers (N=124) previously treated with placebo, VDZ SC and VDZ IV in VISIBLE 1, respectively. At W168, 40.0%, 56.5% and 62.9%, respectively, were in clinical remission on Q2W dosing. In non-randomised responders with UC (N=107), 57.0% were in clinical remission at baseline and 29.9% at W168 (Figure). In pts with CD, baseline OLE clinical remission rates were 60.3% and 62.0% among randomised completers (N=226) previously treated with placebo and VDZ SC in VISIBLE 2. At W168, 32.4% and 37.3% were in clinical remission on Q2W dosing. In non-randomised responders with CD (N=118), 57.6% were in clinical remission at baseline and 27.1% at W168 (Figure). In pts with UC escalated to QW dosing, 22.2% and 38.1% achieved clinical remission and response at W8 after transitioning to QW. Among pts with CD escalated to QW dosing, 38.6% and 53.5% achieved clinical remission and response by W8 after transitioning to QW. Higher rates of remission and response were noted in VDZ completers than non-randomised responders. No new long-term safety signals were noted with VDZ SC vs IV, except for injection site reactions. Conclusion The clinical benefit of VDZ SC was maintained long-term during VISIBLE OLE. A subset of pts who escalated to QW dosing regained response. Findings support VDZ SC as a treatment option for patients with UC or CD who require long-term maintenance therapy.

Abstract Background Vedolizumab (VDZ) is a gut selective, monoclonal anti-α4β7 integrin antibody approved for the treatment of moderately to severely active ulcerative colitis (UC) or Crohn’s disease (CD). The subcutaneous (SC) formulation of VDZ was evaluated during the Phase 3 VISIBLE 1 and 2 studies. This analysis reports hospitalisations and surgeries among patients (pts) with UC or CD treated with VDZ SC enrolled in the VISIBLE open-label extension (OLE) study. Methods Pts who participated in VISIBLE 1 or VISIBLE 2 were eligible to enrol in VISIBLE OLE (NCT02620046) and received VDZ SC 108mg every 2 weeks (Q2W) or weekly. Patients were grouped according to their scenario in VISIBLE 1/2: Pts who withdrew between week (W) 6 and W52 (Scenario 1); pts who completed 52 weeks of treatment with VDZ or placebo (Scenario 2); pts without a clinical response at W6 but who responded at W14 and were not randomised (Scenario 3). The proportions of patients who experienced UC or CD related hospitalisation and/or surgery during VISIBLE OLE were assessed by scenario and treatment received during VISIBLE 1/2. Results A total of 288 pts with UC and 458 with CD enrolled in the VISIBLE OLE. The mean (min., max.) duration of VDZ exposure during VISIBLE OLE was 1276.7 days (127, 2577 days) among pts with UC and 1110.0 days (127, 2770 days) among pts with CD. The proportions of pts who had a UC or CD related hospitalisation or surgery during VISIBLE OLE are displayed in Table 1. Across all scenarios, a total of 8.3% (24/288) of pts with UC had a related hospitalisation. In total, 3/288 pts (1.0%) with UC (from Scenarios 1 and 3) had a colectomy. No pts with UC from Scenario 2 had a colectomy. Among pts with CD, a total of 13.1% (60/458) had a related hospitalisation. A total of 19 pts (4.1%) with CD had bowel surgery. Higher rates of IBD related hospitalisations and surgeries were observed in Scenario 1, both in pts with UC and with CD. Conclusion Findings from VISIBLE OLE showed that few pts with UC and CD treated with long-term VDZ SC required IBD related hospitalisations over the course of the study. Notably, very few patients with UC or CD required colectomies or bowel surgery.

Abstract Background Tumor necrosis factor-like ligand 1A (TL1A) is upregulated in inflammatory bowel disease and believed to promote inflammation and intestinal fibrosis. RO7790121, an anti-TL1A antibody, showed promising results in the phase IIa TUSCANY trial.1 Here we report post-hoc analyses of patient-reported outcomes from the TUSCANY-2 trial. Methods This phase IIb, multicenter, randomized, double-blind, treat-through, dose-ranging study evaluated RO7790121 in patients (pts) aged 18–75 years with moderately to severely active ulcerative colitis (UC) (total Mayo score [MS] ≥6, endoscopic subscore ≥2). Pts were randomized to receive subcutaneous (SC) RO7790121 50mg, 150mg, 450mg or matched placebo (PBO) monthly during the 12-week induction period, and SC RO7790121 50mg, 150mg or 450mg monthly during the 40-week treat-through maintenance period. To assess efficacy of RO7790121 in supporting pts achieving early symptomatic improvement, rectal bleeding (RB), stool frequency (SF) and partial modified MS (RB+SF) were evaluated at baseline and Weeks 2, 4, 8, 12 and 14. The exploratory endpoint of symptomatic remission, defined as a RB subscore of 0 and a SF subscore of 0 or 1, was assessed throughout induction. Safety was assessed throughout the study. Results Overall, 245 pts received ≥1 dose of RO7790121 or PBO. At Week 2, pts receiving RO7790121 were more likely to report a RB subscore of 0 (34% RO7790121; 20% PBO) and less likely to report a RB subscore of 2 or 3 (25% RO7790121; 40% PBO) (Figure). Improvements in SF increased from Week 2 and throughout induction, with ~60% of pts receiving RO7790121 reporting a SF subscore of 0 or 1 at Weeks 12 and 14, vs ~40% for PBO. Greater rates of symptomatic remission were observed in pts receiving RO7790121 vs PBO throughout induction and from Week 2 (17.5% RO7790121; 8.9% PBO) (Table). Treatment-emergent adverse events (TEAEs) were reported during induction in 117/245 pts, the most common (reported in ≥5% of pts in any treatment group) were nausea, urinary tract infection and UC (highest in the 50mg arm), anemia (highest in the placebo arm) and fatigue, headache and pyrexia (highest in the 450mg arm). Serious TEAEs were reported in ten pts during induction (PBO=4; 50mg=3; 450mg=3); two were treatment related (PBO=1; 450mg=1). There were six treatment discontinuations due to TEAEs and a generally similar safety profile was observed during the maintenance period. Conclusion Greater and earlier improvements in RB and SF were observed in pts receiving RO7790121 vs PBO. These results indicate early symptom relief and a favorable safety profile for pts treated with RO7790121, supporting its further clinical development. RO7790121 is currently being evaluated in phase III studies (NCT06589986 and NCT06588855). References 1.Danese S, Klopocka M, Scherl EJ, et al. Anti-TL1A antibody PF-06480605 safety and efficacy for ulcerative colitis: A phase 2a single-arm study. Clin GastroenterolHepatol. 2021;19(11):2324-2332.e6. http://doi.org/10.1016/j.cgh.2021.06.011

SummaryBackgroundFilgotinib, an oral, once‐daily, Janus kinase 1 preferential inhibitor, is an approved treatment for moderately to severely active ulcerative colitis.AimsThe aim of this study is to assess the safety and efficacy of continued filgotinib therapy over ~4 years in the long‐term extension of the phase 2b/3 SELECTION trial (SELECTIONLTE; NCT02914535).MethodsIn this interim analysis of SELECTIONLTE, SELECTION completers (week 10 responders to filgotinib who completed the maintenance study) continued their assigned treatment (double‐blind filgotinib 200 mg [FIL200] or filgotinib 100 mg) and SELECTION week 10 non‐responders received open‐label FIL200. We assessed safety by adverse events (AEs), and efficacy by partial Mayo Clinic Score (pMCS), inflammatory biomarkers and health‐related quality of life (HRQoL). We compared safety and efficacy between achievers and non‐achievers of a multi‐component endpoint, comprehensive disease control (CDC), comprising symptomatic, endoscopic, inflammatory biomarker and HRQoL improvements.ResultsData for completers (n = 250) and non‐responders (n = 372) were reported for ≤202 weeks. AE occurrences were low and consistent with previous analyses. The as‐observed proportion of FIL200‐treated patients in pMCS, biomarker and HRQoL remission during SELECTIONLTE remained high among completers (week 144: 80.0%, 86.4% and 86.0%, respectively) and increased among non‐responders (week 192: 62.1%, 76.7% and 59.3%, respectively). Significantly higher proportions of CDC achievers at SELECTION week 58 achieved pMCS, IBDQ and corticosteroid‐free pMCS remission than non‐achievers, up to LTE week 96.ConclusionsFilgotinib induced and maintained symptomatic remission and improved HRQoL over 4 years. Safety results showed a proven long‐term benefit–risk profile. FIL200‐treated CDC achievers had better long‐term outcomes than non‐achievers.

Background Vedolizumab is an anti-α4β7 integrin antibody used to treat moderate to severe ulcerative colitis (UC) and Crohn’s disease (CD). This post hoc analysis of patient-reported outcomes (PROs) from the VISIBLE 1 (NCT02611830) and 2 (NCT02611817) phase 3 studies evaluated onset of treatment effect on patient-reported symptoms during 6-week vedolizumab induction. Methods Patient-reported stool frequency (SF) and rectal bleeding (RB) (UC Mayo score), and SF and abdominal pain (AP) in CD were collected via electronic diary from VISIBLE patients receiving one or more open-label intravenous (IV) vedolizumab induction doses (weeks 0 and 2). PRO data were analyzed using descriptive statistics. Results Data from 994 patients (UC 383, CD 611) showed mean ratings for all PROs declined consistently week-on-week from baseline through week 6, with early onset of improvement. By week 2, 22% of patients with UC reported RB improvement (≥1-point reduction in RB subscore, 7-day mean), rising to 45% by week 6. By week 6, 18% of patients with UC achieved SF improvement (SF subscore 0; 21% antitumor necrosis factor alpha [anti-TNFα] naive, 13% anti-TNFα experienced). SF improvement in patients with CD (reduction of ≥3 stools, 7-day mean) was achieved by 32% at week 6 (34% anti-TNFα naive, 30% anti-TNFα experienced). Fewer patients with CD reported severe/moderate AP at week 6 (5.1%/28.5%) than baseline (14.6%/61.5%). SF decline appeared greater and faster for anti-TNFα-naive vs. anti-TNFα-experienced patients (UC and CD). Conclusion Results indicate early onset of patient-reported UC and CD symptom improvement during vedolizumab IV induction in VISIBLE 1 and 2.