Citations

Summary Background Filgotinib 200 mg (FIL200) is an approved treatment for adults with moderately to severely active ulcerative colitis (UC). Aim To report integrated safety data from the phase 2b/3 SELECTION study (NCT02914522) and its ongoing long‐term extension study SELECTIONLTE (NCT02914535). Methods Safety outcomes were analysed in adults with moderately to severely active UC who received FIL200, filgotinib 100 mg (FIL100) or placebo once daily throughout the 11‐week SELECTION induction study, the 47‐week SELECTION maintenance study (if applicable) and SELECTIONLTE (if applicable). Exposure‐adjusted incidence rates (EAIRs) per 100 censored patient‐years of exposure with 95% confidence intervals were reported for treatment‐emergent adverse events (AEs). Certain AE data were presented in subgroups, including age and prior biologic exposure status. Results This interim analysis included 1348 patients representing 3326.2 patient‐years of exposure. Baseline characteristics of patients entering SELECTION were similar across treatment groups. EAIRs for serious infection, thromboembolic events and major adverse cardiovascular events (MACE) were consistently low across treatment groups. Most patients with MACE had cardiovascular risk factors. The EAIR for herpes zoster was numerically higher for FIL200 than for placebo. Infection incidences were numerically higher in biologic‐experienced than biologic‐naive patients. Higher incidences of certain AEs in patients 65 years of age or older were as expected. Four deaths occurred, including three cardiovascular deaths, none of which was considered related to filgotinib. Conclusion FIL200 and FIL100 were well tolerated with no unexpected safety signals in patients with moderately to severely active UC, regardless of previous biologic exposure or age. ClinicalTrials.gov Identifiers (NCT numbers) NCT02914522, NCT02914535.

INTRODUCTION: Patients with ulcerative colitis (UC) regard rapid onset of action among the most important aspects of their treatment. We used the partial Mayo Clinic Score (pMCS) and component patient-reported subscores to assess the rapidity and sustainability of response to filgotinib, a once-daily, oral Janus kinase 1 preferential inhibitor, in adults with moderately to severely active UC in the phase 2b/3 SELECTION trial. The association between early symptomatic improvements and health-related quality of life (HRQoL) outcomes was also assessed. METHODS: In these post hoc analyses of the double-blinded, randomized, placebo-controlled 58-week SELECTION trial (NCT02914522), rectal bleeding and stool frequency diary data on days 1–15 and pMCS remission and response at multiple time points including weeks 10 and 58 were evaluated. HRQoL was assessed using the Inflammatory Bowel Disease Questionnaire at weeks 10 and 58. RESULTS: Filgotinib 200 mg relative to placebo improved rectal bleeding and stool frequency within 7 days ( P < 0.05). By week 2, greater proportions of filgotinib 200 mg-treated patients than placebo-treated patients achieved pMCS remission (biologic-naive, 15.1% vs 8.0%, P = 0.0410; biologic-experienced, 10.3% vs 4.2%, P = 0.0274). A similar treatment effect was observed at week 58 ( P < 0.0001). Day 7 rectal bleeding and stool frequency subscores were associated with the Mayo Clinic Score response at weeks 10 and 58. Patients in pMCS remission at weeks 10 and 58 had greater improvements in the Inflammatory Bowel Disease Questionnaire score than those not in pMCS remission. DISCUSSION: Filgotinib 200 mg daily resulted in rapid and sustained improvements in both UC symptoms and HRQoL.

Abstract Background Use of inflammatory biomarkers is common practice in ulcerative colitis (UC) management1. This study examined the utility of faecal calprotectin (FCP), C-reactive protein (CRP), and albumin biomarkers and their combination, for predicting outcomes of clinical remission and disease control (composite of clinical, endoscopic and histologic disease activity measures2) in patients (pts) with UC under therapy with vedolizumab (VDZ) or adalimumab (ADA) in the VARSITY study. Methods VARSITY was a phase 3b, randomized, double-blind, double-dummy, active-control trial evaluating VDZ (anti-α 4β 7 integrin) vs ADA (anti-tumour necrosis factor-α) treatment in pts aged 18–85 years with moderate-to-severe UC (NCT02497469; EudraCT:2015-000939-33). Pts received either VDZ IV infusions (300 mg) on Day 1 and at Weeks (WKs) 2, 6, 14, 22, 30, 38, and 46 or ADA SC injections (40 mg), total dose 160 mg at WK1, 80 mg at WK2, and 40 mg every 2 weeks thereafter until WK50. In this post hoc analysis of data from 769 pts, the probability of clinical remission (total Mayo score ≤2, no subscore &gt;1) and disease control (pt-reported outcome-2 [PRO2, Mayo subscores of stool frequency and rectal bleeding]; Mayo endoscopic subscore ≤1 [endoscopic improvement], and Robarts Histopathology Index score &lt;5, [absence of histologic active disease]) were assessed at WK52 based on baseline and WK14 levels of dichotomized FCP (high-risk: ≥100 µg/g), CRP (high-risk: ≥5mg/L), and albumin (high-risk: &lt;45 g/L) including the composite of high-risk CRP and FCP termed ‘inflammatory burden’ (IB). Results In comparison with biomarkers measured at baseline, FCP at WK14 was the most predictive of WK52 clinical remission after VDZ or ADA treatment3; WK14 FCP was also predictive of disease control using a combined endpoint of PRO2, endoscopy and histologic remission/response. VDZ-treated pts with low-risk FCP (&lt;100 µg/g) at WK14 had a 76% chance of achieving WK52 clinical remission vs 35% for pts with high-risk FCP (70% vs 33% for ADA-treated pts with low and high-risk FCP, respectively). VDZ-treated pts with IB (high-risk levels of FCP and CRP) at WK14 had a 16% chance of clinical remission at WK52 vs a 57% probability for this endpoint in pts without IB at WK14; the risk difference for this composite biomarker was 42% (Table). Conclusion The addition of CRP to FCP as a composite biomarker of IB at WK14 after treatment initiation can be a useful negative predictor of pts who are likely to achieve significant long-term benefits, including remission and disease control, with VDZ or ADA treatment. References 1. Turner D, et al. Gastroenterology 2021;160(5):1570-38. 2. Danese S, et al. J Crohn’s Colitis 2021;15(Suppl1):S305–S305. 3. Dulai PS, et al. Gastroenterology 2021;160(6):S-46–7.

Abstract Background With a growing prevalence of inflammatory bowel disease (IBD) in elderly patients, there is a clinical requirement to understand the impact of treatment in this population.1 Filgotinib (FIL) is an oral Janus kinase 1 preferential inhibitor. This post hoc analysis of data collected in the phase 2b/3 SELECTION programme evaluated the efficacy and safety of FIL in patients with ulcerative colitis (UC) stratified by age. Methods The SELECTION programme includes two Induction Studies, a Maintenance Study (NCT02914522) and a long-term extension (LTE) study (NCT02914535). Adults aged 18–75 years with moderately to severely active UC were randomized 2:2:1 to receive FIL 200 mg or 100 mg or placebo once daily for 11 weeks. Responders at week 10 were re-randomized 2:1 to continue assigned FIL treatment or placebo from week 11–58. In LTE, patients with disease worsening and those completing week 58 continued assigned treatment before receiving open-label FIL. We assessed the efficacy and safety of FIL at any dose in the overall cohort of SELECTION and LTE, stratified into five age groups: &lt;30, ≥30–&lt;40, ≥40–&lt;50, ≥50–&lt;60 and ≥60 years. Clinical remission was evaluated at week 10 and pMCS remission was assessed at week 10, 58 and LTE weeks 2, 4, 12 and 24. Exposure-adjusted incidence rates (EAIRs) were calculated for adverse events (AEs). A data cut-off of 28 February 2020 was used. Results Baseline disease activity and previous and concomitant treatments were comparable across age groups in each treatment arm. While there were fewer patients in the ≥60 years group, patient distribution was similar in all other age groups. FIL induced clinical (~16%) and pMCS (~36%) remission in similar proportions of patients across all age groups at week 10 (Figure 1). At week 58, pMCS remission was achieved in ~53% of FIL-treated patients across age groups (Figure 2). In LTE, the proportion of FIL-treated patients in pMCS remission generally increased with time and remained similar across all age groups (Figure 3). FIL-treated patients aged ≥60 years had higher EAIRs of any AE, infections, herpes zoster, malignancies, NMSC and MACE than younger patients (Table). One thromboembolic event occurred in a FIL-treated patient aged &lt;30 years. Three deaths related to cardiovascular disease occurred in FIL-treated patients aged ≥50 years. Conclusion These findings suggest FIL is efficacious in inducing and maintaining symptomatic remission and could have an acceptable safety profile in adults with UC of all ages, including ≥60 years old. Age-related increases in incidences of certain AEs might be expected in patients with IBD; however, the number of patients ≥60 years limits comparison of these data with reported rates. Reference 1Zammarchi et al. BMC Gastroenterol 2020;20;147

Abstract Background Upadacitinib (UPA), an oral, reversible JAK inhibitor engineered for increased selectivity for JAK1 over JAK2, JAK3, or tyrosine kinase 2 (TYK2), demonstrated significantly greater efficacy compared with placebo (PBO) for induction of remission in patients with moderately to severely active ulcerative colitis (UC) in two phase 3 trials, U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026). This analysis evaluated the efficacy of UPA on early symptomatic improvement for the first 14 days, using pooled data from U-ACHIEVE Induction and U-ACCOMPLISH. Methods U-ACHIEVE and U-ACCOMPLISH were multicentre, double-blind, PBO-controlled trials that enrolled patients who have had moderately to severely UC with an Adapted Mayo Score of 5 to 9 points and centrally reviewed endoscopy subscore of 2 to 3. A total of 998 patients were randomized to receive UPA 45mg once daily (QD) (n=658) or PBO (n=328) for 8 weeks (wks) in a 2:1 ratio. First dose of study drug was administered on Day 0. Improvement in symptoms including stool frequency subscore (SFS), rectal bleeding subscore (RBS), abdominal pain, and bowel urgency were analysed from daily symptom diary data. Multivariate regression analysis was used to determine if early changes in UC symptoms could be used to evaluate a potential correlation with patients’ likelihood of achieving clinical response or clinical remission per Adapted Mayo score at the end of induction. Results Baseline characteristics were similar between both treatment groups. Patients treated with UPA 45 mg QD experienced significant improvement in daily symptoms, with significantly more subjects achieving SFS≤1 (p&lt;0.001), RBS of 0 (p&lt;0.05), and SFS of 0 (p&lt;0.05) as early as day 1 and maintained through day 14 (Figure 1). A significantly higher percentage of patients who received UPA 45 mg QD compared to PBO, achieved abdominal pain=0 and the absence of bowel urgency within 3 days of beginning treatment through day 14 (p&lt;0.05). Multivariate analysis revealed that patients who achieved day 7 SFS≤1 (OR 2.42, 95% CI, 1.53–3.82) were more likely to attain clinical response (Table). Patients who attained day 7 SFS≤1 (OR 2.53, 95% CI 1.59–4.00) or day 7 bowel urgency absent (OR 2.40, 95% CI 1.52–3.79) were more likely to achieve clinical remission at week 8. Conclusion UPA 45 mg QD significantly improved UC symptoms as early as day 1, providing patients with rapid symptom relief. Patients who achieved early symptom improvement were more likely to attain clinical remission or clinical response at week 8. [Clinicaltrials.gov, U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026)]