Schreiber, Stefan

Abstract Background and Aims Tyrosine kinase 2 is a downstream intracellular mediator of interleukin-23 signaling, which has a key role in the pathogenesis of inflammatory bowel disease. Deucravacitinib is a novel, oral, selective, allosteric tyrosine kinase 2 inhibitor currently approved for the treatment of adults with moderate to severe plaque psoriasis. Methods Here we describe 3 randomized, double-blind, placebo-controlled phase 2 studies of deucravacitinib in patients with moderately to severely active Crohn’s disease (LATTICE-CD [NCT03599622]) or ulcerative colitis (LATTICE-UC [NCT03934216] and IM011-127 [NCT04613518]). Patients were randomized to receive placebo or twice-daily deucravacitinib 3 or 6 mg (LATTICE-CD), 6 mg (LATTICE-UC), or 12 mg (IM011-127) for 12 weeks. Coprimary endpoints for LATTICE-CD were clinical remission and endoscopic response at week 12. The primary endpoint was clinical remission (per modified Mayo score) at week 12 for LATTICE-UC and clinical response (per modified Mayo score) at week 12 for IM011-127. Results A total of 239 (LATTICE-CD), 131 (LATTICE-UC), and 38 (IM011-127) patients were randomized. The primary endpoints were not met for all 3 studies, which resulted in early study termination for LATTICE-CD and IM011-127. High efficacy rates were observed in placebo groups throughout the studies. In all studies, the safety profile of deucravacitinib was consistent with the known safety profile observed in patients with psoriasis, and no new safety signals were observed. Conclusions Deucravacitinib at multiple doses did not demonstrate significant clinical benefit vs placebo in moderately to severely active Crohn’s disease or ulcerative colitis. Deucravacitinib was safe and well tolerated.

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.

Importance The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown. Objective To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis. Design, Setting, and Participants Two phase 3 randomized clinical trials were conducted. The induction trial was conducted at 261 clinical centers (in 41 countries) and enrolled 977 patients from November 5, 2020, to August 4, 2022 (final follow-up on May 16, 2023). The maintenance trial was conducted at 238 clinical centers (in 37 countries) and enrolled 754 patients from August 28, 2018, to March 30, 2022 (final follow-up on April 11, 2023). Eligible patients had moderately to severely active ulcerative colitis; a history of intolerance or inadequate response to 1 or more conventional therapies, advanced therapies, or both types of therapies; and no prior exposure to risankizumab. Interventions For the induction trial, patients were randomized 2:1 to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8. For the maintenance trial, patients with a clinical response (determined using the adapted Mayo score) after intravenous treatment with risankizumab were randomized 1:1:1 to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo (no longer receiving risankizumab) every 8 weeks for 52 weeks. Main Outcomes and Measures The primary outcome was clinical remission (stool frequency score ≤1 and not greater than baseline, rectal bleeding score of 0, and endoscopic subscore ≤1 without friability) at week 12 for the induction trial and at week 52 for the maintenance trial. Results Among the 975 patients analyzed in the induction trial (aged 42.1 [SD, 13.8] years; 586/973 [60.1%] were male; and 677 [69.6%] were White), the clinical remission rates at week 12 were 132/650 (20.3%) for 1200 mg of risankizumab and 20/325 (6.2%) for placebo (adjusted between-group difference, 14.0% [95% CI, 10.0%-18.0%], P < .001). Among the 548 patients analyzed in the maintenance trial (aged 40.9 [SD, 14.0] years; 313 [57.1%] were male; and 407 [74.3%] were White), the clinical remission rates at week 52 were 72/179 (40.2%) for 180 mg of risankizumab, 70/186 (37.6%) for 360 mg of risankizumab, and 46/183 (25.1%) for placebo (adjusted between-group difference for 180 mg of risankizumab vs placebo, 16.3% [97.5% CI, 6.1%-26.6%], P < .001; adjusted between-group difference for 360 mg of risankizumab vs placebo, 14.2% [97.5% CI, 4.0%-24.5%], P = .002). No new safety risks were detected in the treatment groups. Conclusion and Relevance Compared with placebo, risankizumab improved clinical remission rates in an induction trial and in a maintenance trial for patients with moderately to severely active ulcerative colitis. Further study is needed to identify benefits beyond the 52-week follow-up. Trial Registration ClinicalTrials.gov Identifiers: NCT03398148 and NCT03398135

Abstract Background The LIBERTY-CD study demonstrated a broad level of benefit for subcutaneous (SC) infliximab (IFX) maintenance therapy compared with placebo in patients (pts) with moderate-to-severe active Crohn’s disease (CD) who responded to intravenous IFX induction. Characterising subgroups of pts with different levels of response could help to better position SC IFX therapy. Methods This was a post hoc analysis of 231 pts from the CT-P13 SC arm of the randomised, parallel-group, placebo-controlled LIBERTY-CD study (NCT03945019). Unsupervised group-based trajectory modelling (GBTM) was conducted to deconvolute cohort-level data into response trajectories. Longitudinal patient reported outcomes (PRO-2: abdominal pain and stool frequency) were used to investigate whether pts who received SC IFX maintenance therapy cluster into response trajectories. Efficacy endpoints (clinical remission, endoscopic response and remission, corticosteroid-free remission and comprehensive disease control [CDC] rate) were analysed and compared between different trajectories. Trough levels of IFX (TLI) were evaluated by trajectory throughout the treatment period. Baseline characteristics were analysed in a descriptive manner to explore predictors for super-response. Results Four distinct trajectories were clearly separated and stabilised around Week (W) 10–14 (Figure): rapid and sustained improvement (super-responders, n=61), rapid, but slightly less drastic than super-responders, then sustained improvement (fast responders, n=56), gradual then sustained improvement (slow responders, n=63) and partial improvement during the maintenance phase (limited responders, n=51). Super-responders had the highest rates of W54 clinical remission (73.8%; p=0.002), endoscopic response (63.9%; p=0.009), corticosteroid-free remission (63.6%; p=0.007), endoscopic remission (42.6%; p=0.094) and CDC (37.7%; p=0.013) among trajectories (Table). Super-responders also maintained the highest TLI from W10 throughout the maintenance period. Super-responders showed a trend towards lower baseline body weight, body mass index and oral corticosteroid use, but higher Crohn’s Disease Activity Index score and prior biologic/Janus kinase inhibitor use compared to other trajectories. Conclusion Distinct subpopulations with different levels of responses were detected by GBTM using data from a large group of pts with moderate-to-severe active CD who were treated with SC IFX for 1 year. Super-responders with rapid and sustained improvements during SC IFX therapy had a higher likelihood of achieving desirable long-term outcomes, with substantial individual benefit (CDC). Baseline characteristics and TLI were associated with super-response.

Abstract Background Filgotinib (FIL), an oral, once-daily, Janus kinase 1 inhibitor, was approved for Ulcerative Colitis (UC) treatment after the phase 2b/3 SELECTION trial (NCT02914522). In SELECTION, a greater proportion of FIL200 mg (FIL200)-treated than placebo-treated patients achieved comprehensive disease control (CDC), a stringent multi-component endpoint. We examined the long-term outcomes of achieving CDC in patients continuing on FIL200 in the ongoing long-term extension (LTE) study SELECTIONLTE (NCT02914535). Methods This interim analysis included adult patients with UC who completed SELECTION and received ≤144 weeks of FIL200 in the LTE (up to data cut-off 24/02/22). CDC (biomarker remission, endoscopic improvement, IBDQ remission and partial Mayo Clinic Score [pMCS] remission achieved concurrently) was assessed at SELECTION week 58 (LTE baseline [BL]). Mean pMCS and IBDQ score, use of corticosteroids (CS) and incidence of TEAEs and serious TEAEs in the LTE were compared between SELECTION CDC achievers and non-achievers. A mixed model for repeated measures was fitted on pMCS and IBDQ score, with CDC achiever status, study visit and the interaction between CDC achiever status and study visit as fixed effects; p values were nominal. Results We analysed 148 patients (CDC achievers, n=41; CDC non-achievers, n=107). Mean pMCS was stable in CDC achievers (0.44, LTE BL; 0.50, LTE week 144) and decreased in CDC non-achievers (1.49, LTE BL; 0.77, LTE week 144; Figure). Mean IBDQ score was stable in CDC achievers (204.05, LTE BL; 197.21, LTE week 144) and increased in CDC non-achievers (181.55, LTE BL; 196.37, LTE week 144; Figure). There was a significant beneficial effect of achieving CDC on pMCS and IBDQ score overall (pMCS: fixed effect estimate: −0.5542, p=0.0025; IBDQ score: fixed effect estimate: 13.1585, p=0.0042). There was a significant interaction between achieving CDC and study visit for IBDQ score (p=0.0183), with the benefit of achieving CDC lessening by week 144. Generally, a lower proportion of CDC achievers used CS than non-achievers; 2.4–7.3% of CDC achievers used CS vs 1.9–15.9% of CDC non-achievers. Incidence of TEAEs and serious TEAEs were stable over time and similar between CDC achievers and non-achievers. Conclusion Follow-up for ~3 years showed high levels of long-term benefit with continued FIL200 treatment. Achieving comprehensive disease control at the end of the randomized trial with FIL200 was associated with long-term efficacy, improved HRQoL and low overall use of CS. This may demonstrate the value of filgotinib-induced achievement of CDC in UC disease course. The safety profile of FIL200 was consistent between CDC achievers and non-achievers, suggesting an acceptable long-term benefit–risk profile.

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