Aims SELECTION (NCT02914522) Maintenance evaluated filgotinib (FIL), a preferential JAK1 inhibitor, as maintenance therapy for patients (pts) with moderately to severely active ulcerative colitis (UC) who achieved clinical remission or Mayo Clinic Score (MCS) response after 10 weeks of FIL 200mg QD, FIL 100mg QD or placebo (PBO) induction. Methods Pts randomized to FIL induction were rerandomized 2:1 to their induction FIL dose or PBO; pts randomized to PBO induction continued PBO maintenance. Steroid tapering was mandatory. The primary endpoint was clinical remission at Week 58. Key secondary endpoints and exploratory endpoints were assessed at Week 58. Results 664 pts were treated in the Maintenance Study (n=93, 270, and 301 from induction with PBO, FIL 100mg and FIL 200mg); efficacy analyses included only FIL induction pts. Baseline demographics and disease characteristics were generally balanced across treatment arms; 40% were biologic experienced. Significantly higher proportion of pts on FIL 200mg or FIL 100mg were in clinical remission vs PBO. Significantly higher proportions of pts achieved key secondary endpoints with FIL 200mg vs PBO. More pts on FIL 200 mg or FIL 100mg achieved an MCS response and endoscopic improvement vs PBO. Incidences of adverse events (AEs), serious AEs and discontinuations due to AEs were similar across arms. Serious infection (<2%) and herpes zoster (<1%) were infrequent among FIL-treated patients. There were no venous thromboses, including pulmonary embolism, among FIL-treated pts. Two pts on FIL 200mg died, both AEs leading to death were considered unrelated to FIL. Conclusions FIL 200mg and FIL 100mg were effective as maintenance treatment for pts with moderately to severely active UC who had achieved clinical response to FIL induction treatment. FIL 200 mg met all key secondary endpoints including endoscopic, histologic and 6-month corticosteroid-free remission. FIL was well tolerated in pts with moderate to severely active UC. Funding Agencies None
Background Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development for the treatment of moderately to severely active ulcerative colitis (UC). Although ≈30% of UC patients initially present with isolated proctitis, most phase 3 trials of systemic therapies in UC excluded this subgroup. We report the efficacy and safety of etrasimod in subjects with isolated proctitis enrolled in the ELEVATE UC programme. Methods In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), subjects (16-80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo (PBO). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 comprised a 12-week induction period. Both trials allowed inclusion of subjects with isolated proctitis (<10 cm rectal involvement) provided they met all other eligibility criteria (enrolment capped at 15%). Predefined endpoints were assessed at week 12 (data pooled from both studies) and week 52 (UC 52 only). Sustained and corticosteroid (CS)-free clinical remission were assessed at week 52 (UC 52 only). Changes from baseline in rectal bleeding (RB) were assessed using pooled data through week 12, and UC 52 data from week 14 through week 52. Urgency Numeric Rating Scale (NRS) was assessed at baseline, week 12 (pooled), and week 52 (UC 52 only). Results This analysis included 64 pooled subjects with isolated proctitis at week 12 (42 etrasimod, 22 PBO) and 36 subjects from UC 52 at week 52 (27 etrasimod, 9 PBO). Greater proportions (P<0.05) of subjects randomised to etrasimod vs PBO achieved clinical remission, endoscopic improvement, symptomatic remission, and endoscopic improvement-histologic remission at week 12 and week 52 and clinical remission and symptomatic remission at week 52 (Figure 1). Differences were also observed in sustained clinical remission and 12-week CS-free clinical remission at week 52. Etrasimod demonstrated numerical decreases in RB subscores as early as week 2 through week 52 (Figure 2). Improvement (P<0.05) in urgency NRS were observed at week 12 (Figure 3). Safety was consistent with results from the overall trial populations. Conclusion Efficacy and safety of etrasimod in subjects with isolated proctitis was consistent with the overall population of the ELEVATE programme.1 The analysis was performed on a small dataset and should be interpreted with caution but informs on the efficacy of etrasimod in a subpopulation of UC subjects commonly excluded from drug development trials. Reference: 1. Sandborn WJ, et al. Presented at: DDW 2022; May 24, 2022. Abstract 968a.
Background Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). In the tofacitinib UC clinical programme, the majority of patients did not have cardiovascular (CV) risk factors at baseline (BL), and increases in lipid levels occurred primarily during induction and remained elevated to Week 61 during maintenance; lipid ratios were relatively unchanged.1 Here, we present updated results of lipid levels in the ongoing, open-label, long-term extension (OLE) study (NCT01470612) and major adverse CV events (MACE) in the Phase 3/OLE tofacitinib UC clinical programme. Methods Lipid levels were assessed at multiple time points, and changes from OLE study BL to Month 48 in the OLE study were evaluated. Lipid-lowering agent (LLA) use (proportion of patients) and adjudicated MACE (proportion of patients and incidence rate [IR; unique patients with events per 100 patient-years] with 95% confidence interval [CI]) were reported in patients with UC in two Phase 3, 8-week, placebo-controlled induction studies (OCTAVE Induction 1 and 2; NCT01465763, NCT01458951), a Phase 3, 52-week, placebo-controlled maintenance study (OCTAVE Sustain; NCT01458574) and the OLE study (data as of May 2019; database not locked). Results No major changes in total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), triglycerides, LDL-c:HDL-c and TC:HDL-c from OLE study BL were observed at Month 48 of the OLE study (Table). In the Phase 3/OLE programme (n = 1124), 7.7% of patients had a new LLA added and 1.9% of patients had their LLA dose increased. Seven MACE were reported (IR 0.26; 95% CI 0.11, 0.54; 2654.66 patient-years); the IR has remained stable since Dec 2016 (IR 0.24; 95% CI 0.07, 0.62).1 Reported MACE was one each of myocardial infarction, acute myocardial infarction, acute coronary syndrome, cerebrovascular accident, haemorrhagic stroke, cerebellar haemorrhage and aortic dissection. Both myocardial infarction events and the acute coronary syndrome event led to temporary tofacitinib discontinuation; the haemorrhagic stroke, cerebrovascular accident and cerebellar haemorrhage led to permanent tofacitinib discontinuation; and the aortic dissection resulted in death. Of the seven patients with MACE, five had CV risk factors at BL. Conclusion At Month 48 of the OLE study, lipid levels and ratios remained generally unchanged from OLE study BL following tofacitinib treatment. MACE were infrequent, with the IR remaining stable since the previous report.1 Limitations include low patient numbers and short tofacitinib exposure duration. Longer-term observation studies will further assess risk. Reference
Background The optimal treatment target for ulcerative colitis (UC) is uncertain. The VERDICT trial in moderate to severe UC aims to determine if a treatment target of corticosteroid (CS)-free symptomatic + endoscopic + histologic remission is superior to CS-free symptomatic remission alone. Trial progress and the study cohort to date are described herein. Methods Our aim is to enrol 660 patients with moderately to severely active UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2). Patients are randomised to 3 treatment targets (2:3:5 ratio): CS-free symptomatic remission (Mayo RBS = 0) (Group 1); CS-free endoscopic remission (MES ≤1) + symptomatic remission (Group 2); or CS-free histologic remission (Geboes score <2B.0) + endoscopic + symptomatic remission (Group 3). Therapy is administered according to a treatment algorithm that is dependent upon each patient’s UC treatment at screening. Early introduction of vedolizumab (VDZ) and dose escalation up to 300 mg every 4 weeks until the target is met are central to each algorithm. Up to 3 opportunities to achieve the assigned target were prespecified in the algorithms (weeks 16, 32, or 48). Patients and central readers for endoscopy/histopathology are blinded to group allocation, and investigators are unblinded. Results As of 2 November 2022, 331 patients were enrolled at 55 sites across 10 North American and European countries. Mean (SD) baseline characteristics (Table) include a UC duration of 8.6 (8.3) years, Mayo Clinic score of 8.7 (1.7), C-reactive protein level of 13.3 (15.6) mg/dL, and a faecal calprotectin level of 1462.3 (1481.3) mg/kg. At baseline, 52% (172/331) and 11% (37/331) of patients were receiving concomitant CS and immunosuppressives, respectively, and 14% (47/331) had current/prior exposure to tumour necrosis factor antagonists. Most patients (85%) were receiving nonbiologic therapy. Of all randomised patients, 43/69 (Group 1), 65/98 (Group 2), and 115/164 patients (Group 3) have reached week 16; and 28 (65%), 25 (39%), and 42 (37%) met their target, respectively. After a median of 35 weeks (IQR 18-53), a total of 30 (Group 1), 32 (Group 2), and 50 patients (Group 3) have met their target and will be followed to relapse or study termination. The serious adverse event rate (8%; 36/483) was similar across groups. Conclusion VERDICT has randomised ~50% of its target enrolment. Enrolled patients represent a typical moderate to severe UC population and are primarily bionaive and receiving early VDZ initiation. Early results suggest the feasibility of achieving each treatment target, specifically histologic remission, and are consistent with expected values. No new VDZ safety signals were identified. Completion of enrolment is anticipated in late 2023.
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