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 Real-world treatment of ulcerative colitis (UC) requires a patient-centric, holistic definition of ‘comprehensive remission' that goes beyond standard regulatory definitions. In an international initiative, we reviewed aspects of UC that affect patients and attempted to achieve consensus on which aspects should be considered in a definition of ‘comprehensive remission’, using a modified Delphi process. This initiative summarized expert consensus recommendations on aspects of UC that are important to patients and that affect their lives, how to measure and score these aspects, and objective markers of mucosal inflammation that are relevant to evaluate in remission, such as endoscopic and histological activity and inflammatory biomarkers. Methods The Delphi consensus panel comprised 10 physicians with expertise in UC and one patient advocate, and two additional physicians chaired the process. To inform the Delphi statements, we asked 18 patients about their experiences of living with UC in remission, asked panel members about their experience of treating patients and systematically reviewed associations between outcome measures in UC. Panel members voted on a 6-point Likert scale in three rounds of anonymous voting, the final round of which was preceded by a live discussion. Consensus was met if ≥ 67% of the panel agreed with the statement (4–6 on the 6-point Likert scale). Statements not meeting consensus in voting rounds 1 and 2 were revised and any not meeting consensus by the end of voting round 3 were discarded (Figure 1). Results The panel agreed that a definition of comprehensive remission should include aspects of UC that are currently measured in clinical trials (blood in stools, stool frequency, disease-related quality of life [QoL], endoscopic remission, histological inflammatory activity, inflammatory biomarkers and discontinuation of corticosteroids), but also additional patient-reported symptoms should be added. These were bowel urgency, abdominal pain, extra-intestinal manifestations, fatigue and sleep disturbance (Table 1). Suggestions for how the severity could be measured and thresholds for remission were agreed for each aspect, with the exception of extra-intestinal manifestations. Disease activity evaluated using ultrasound was voted as important to consider but was not recommended to be included in a measure of comprehensive remission at this stage. Conclusion We used a robust methodology to reach agreement and provide recommendations on the aspects of UC that can be used to define comprehensive remission and assessed in clinical practice. We plan to develop this as a combined measure which may also have applicability in clinical trials.
Background The unmet need in Crohn’s disease (CD) exists for new medications with an optimized risk-benefit ratio with avoidance of systemic side effects. This Phase 2 study evaluated the efficacy and safety of the oral, once-daily, gut-selective pan-Janus kinase inhibitor izencitinib as an induction therapy for CD. Methods This trial was a multicentre, randomized, double-blind, Phase 2 study of adults with moderately-to-severely active CD (≥220 and ≤ 450 CDAI with SES-CD score of ≥6 [or ≥4 if isolated ileal disease]) who were corticosteroid-dependent or had demonstrated failure to aminosalicylates, corticosteroids, immunosuppressive agents, and/or biologic therapies. Patients were randomised 2:3:3 to receive placebo or izencitinib, 80, or 200 mg once daily for 12 weeks. The primary endpoint was change in CDAI score from baseline to week 12 and was analysed using a mixed-model repeated measures analysis. Change from baseline in SES-CD was analysed with an analysis of covariance model and binary endpoints were analyzed using a stratified Cochran-Mantel-Haenszel chi-square test. Results 159 and 145 patients were included in the safety and modified ITT populations, respectively. At week 12, the LS mean change in CDAI was -105.6 (SE: 12.7) and -117.9 (12.4) points for patients randomized to izencitinib 80 and 200 mg, respectively, vs -104.86 (SE: 15.496) for those randomized to placebo. There were no improvements observed in change from baseline in SES-CD. There were non-significant numerical improvements in clinical and endoscopic response between placebo and the highest dose 200mg. No improvements were observed in CDAI-based clinical remission or PRO2 (SF/AP)-based remission at any dose of izencitinib relative to placebo. As expected, plasma izencitinib exposure was low. Serious adverse events (AEs; n = 13) were well balanced among the treatment groups and not considered related to study treatment; no deaths were observed. Exacerbation of Crohn’s Disease, headache, rash, abdominal pain and nausea were the most common treatment-emergent AEs observed with izencitinib treatment. No clinically important changes in laboratory values, electrocardiography parameters, or vital signs were noted in patients treated with izencitinib compared with placebo, and no drug-related AEs of special interest were observed. Conclusion In patients with moderately-to-severely active Crohn’s Disease, izencitinib treatment for 12 weeks did not demonstrate a statistically significant reduction in CDAI or endoscopic severity. Izencitinib at both doses was well tolerated without a new safety signal.
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