ETRASIMOD INDUCTION THERAPY IN MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE: RESULTS FROM A PHASE 2, RANDOMIZED, DOUBLE-BLIND SUBSTUDY

Background: After successful induction, a subset of patients with Crohn’s disease (CD) experience a secondary loss of response (LoR) to ustekinumab (UST) maintenance therapy. Dose intensification may assist in regaining response. The phase 3b randomized, double-blind, multicenter POWER study evaluated efficacy and safety of a single intravenous (IV) re-induction UST dose vs continued UST subcutaneous (SC) treatment in CD patients with LoR to standard UST every 8 weeks maintenance therapy.
Methods: Adults with moderately–severely active CD who initially responded to UST IV induction therapy per label and subsequently experienced LoR were included. LoR for inclusion was defined as CD activity index (CDAI) score of ≥220 and ≤450, in addition to elevated C-reactive protein (CRP; >3mg/L), fecal calprotectin (fCal; >250mg/kg) or endoscopy performed ≤3 months before Week (W)0 with evidence of active CD (≥1 ulcerations in the ileum and/or colon). At baseline (W0), randomized patients received either ~6mg/kg IV UST/SC placebo (IV arm), or IV placebo/SC UST 90mg (SC arm), followed by SC UST 90mg dosing in both groups at W8/16. Clinical and biomarker assessments were made at W0/8/16 and optional ileocolonoscopy at W0/16. Primary endpoint: clinical response (CRes; decrease of ≥100 points from W0/CDAI <150) at W16. Additional outcome measures included clinical, biomarker, endoscopic and quality of life endpoints assessed at W8/16.
Results: The analysis set comprised 215 patients at W0 (IV, n=108; SC, n=107). At W16, 92.6% and 86.0% completed treatment from IV and SC arms, respectively. In both arms (IV, 58.3%; SC, 57.9%) most patients experienced ≥2 biologic failures before initiating UST (Table 1). At W16, 49.1% in the IV arm and 37.4% in the SC arm achieved CRes (p=0.089). Percentages of patients with normalization of fCal, normalization of CRP and/or fCal, endoscopic remission and improvement, and improvement in IBDQ score were greater in the IV vs SC arm (Table 2). At W16, similar proportions of patients had ≥1 adverse event (AE) (IV, 60.2%; SC, 61.7%) and serious AEs (IV, 5.6%; SC, 5.6%). The proportions of patients with infections were similar between arms (IV, 23.1%; SC, 21.5%), with only 1 serious infection in each arm.
Conclusion: POWER is the first randomized, controlled, double-blind trial to assess the efficacy and safety of UST IV re-induction in patients with LoR during UST maintenance therapy. The CDAI-based primary endpoint at W16 was not met. However, patients in this heavily pre-treated population who received IV re-induction showed clinically meaningful improvements at W16 compared with those receiving SC, particularly for objective endpoints, including inflammatory biomarkers and endoscopic outcomes.

Background: CT-P13 subcutaneous (SC) infliximab formulation showed comparable efficacy and safety with CT-P13 intravenous (IV) infliximab in inflammatory bowel disease (IBD)¹ and rheumatoid arthritis². This study aimed to demonstrate the superiority of CT-P13 SC over placebo SC as maintenance therapy after induction therapy of CT-P13 IV in patients with Crohn’s disease (CD).

Methods: Moderately to severely active CD patients with Crohn’s disease activity index (CDAI) score 220 to 450 and simplified endoscopic activity score for Crohn’s disease (SES- CD) of ≥6 points for ileal-colonic CD or ≥4 points including ulcer score from at least 1 segment for ileal CD or colonic CD) were enrolled LIBERTY-CD study (NCT03945019) and treated with open-label CT-P13 IV 5 mg/kg at Weeks 0, 2 and 6 as induction therapy. At Week 10, patients who had a clinical response were randomized (2:1) to receive either CT-P13 SC 120 mg (CT-P13 SC) or placebo SC every 2 weeks up to Week 54. At Week 54, clinical remission and endoscopic response were assessed as co-primary endpoints. Clinical response, clinical remission (alternative definition), endoscopic remission, and corticosteroid-free remission were assessed at Week 54 as key secondary endpoints. Safety was evaluated up to Week 54.

Results: A total of 396 patients were enrolled and 343 patients (86.6%) were randomized (231 in CT-P13 SC arm and 112 in placebo SC arm) at Week 10. At Week 54, the clinical remission rate was greater in CT-P13 SC arm than placebo SC arm (62.3% and 32.1% respectively, with P <0.0001). The endoscopic response rate was also greater in CT-P13 arm than placebo SC arm (51.1% and 17.9% respectively, with P <0.0001). CT-P13 SC also had significantly greater efficacy on key secondary endpoints results compared to placebo SC arm (Table 1). Safety profiles were generally comparable between CT-P13 SC and placebo SC arms, but a single death was reported during the maintenance phase (Table 2).

Conclusion: CT-P13 SC was more effective than placebo in clinical remission, endoscopic response, clinical response, clinical remission (alternative definition), endoscopic remission, and corticosteroid-free remission than placebo arm at Week 54. No new safety concerns were found during treatment of CT-P13 SC. These results demonstrate that maintenance therapy with CT-P13 SC could provide both a large clinical benefit and the convenience of SC administration to moderately to severely active CD patients.

REFERENCES:
[1] Schreiber et al., 2021. Gastroenterology 2021;160:2340–23
[2] Westhovens et al., 2020. Rheumatology 2020;00:1

Background: The benefit of continuing thiopurine in ulcerative colitis (UC) responders to vedolizumab (VED) is unclear. We aimed to determine the effect of thiopurine withdrawal in VED-treated UC patients on combination therapy.
Methods: This prospective multi-centre, single-blind, randomised controlled trial recruited UC patients on VED 300mg IV q8w and a thiopurine for ≥6 months. Patients in steroid-free clinical remission for ≥ 6 months (partial Mayo score [pMS] ≤2, no subscore > 1) and endoscopic remission/improvement (Mayo endoscopic subscore [MES] ≤1) were randomised 2:1 to withdraw or continue thiopurine. Primary outcome was comparing week 48 VED trough levels. Secondary outcomes were disease relapse (pMS ≥ 3 and faecal calprotectin > 150μg/g or increase in MES ≥ 1 from baseline), centrally-read endoscopic remission (MES=0), centrally-read histologic remission (Nancy index=0), histo-endoscopic remission (MES=0 and Nancy index=0), faecal calprotectin (remission < 150μg/g) and adverse events.
Results: Sixty-two consecutive patients (58% males, median follow-up 23.0 months) were randomised to withdraw (n=42) or continue (n=20) thiopurine. Randomisation was balanced. There was a non-significant trend toward increased disease relapse in the withdrawal group (P=0.12, Figure 1a). In the withdrawal group, baseline histologic activity significantly increased disease relapse (HR:5.8, 95%CI:1.6-20.8, P=0.007, Figure 1b). There was a trend of higher relapse in the withdrawal versus continue groups for bio-exposed patients (50.0% [6/12] vs 0.0% [0/4], P=0.07) but not bio-naïve patients (20.0% [6/30] vs 12.5% [2/16], P=0.52). At week 48, the continue group had significantly higher histologic remission (OR:4.6, 95%CI:1.1-18.9, P=0.03) and histo-endoscopic remission rates (OR:4.6, 95%CI:1.3-16.1, P=0.01, Figure 2) versus the withdrawal group, but similar endoscopic remission rates (P=0.09, Figure 2). Faecal calprotectin remission was significantly higher in the continue (94% [16/17]) versus withdrawal group (70% [28/40], P=0.047) with mean calprotectin 44.5μg/g±SD56.2 vs 209.6μg/g±SD344.2 (P=0.003) respectively. On multivariate analysis, histologic activity at baseline (HR:5.3, 95%CI:1.1-26.2, P=0.04) predicted disease relapse. Week 48 median VED levels were 15.9µg/mL (IQR:10.1-22.7) in the withdrawal group versus 14.7µg/mL (IQR:12.1-18.7) in the continue group (P=0.43). No patients had anti-VED antibodies. There was no significant difference in adverse events between groups.
Conclusion: Although thiopurine withdrawal did not affect VED trough level, it increased calprotectin, histologic and histo-endoscopic activity in UC. In patients with histological activity despite deep remission, thiopurine withdrawal significantly increased the risk of disease relapse.

Background
The randomized STRIDENT (Stricture Definition and Treatment) trial showed that Crohn’s disease symptomatic strictures are responsive to anti-TNF therapy with most patients clinically improved after 12 months treatment with adalimumab +/- thiopurine. Treat to target intensification resulted in greater stricture morphology improvement. We present here 2 year (from study entry) follow up to assess response durability and risk of surgery.
Methods
Patients with symptomatic Crohn’s disease strictures and associated inflammation (elevated faecal calprotectin and CRP) were assessed with imaging (intestinal ultrasound and MRI) and ileo-colonoscopy. The Obstructive Symptom Score (OSS) was used for clinical assessment. Patients were randomized 2:1 to high dose adalimumab induction (160mg weekly for 4 weeks) followed by 40mg fortnightly plus thiopurine, with adalimumab dose increase at 4 and/or 8 months if evidence of ongoing inflammation, versus standard dose adalimumab monotherapy. The primary endpoint was improved OSS at 12 months. Patient interview was conducted at 24 months, assessing drug treatment, symptoms, need for endoscopic therapy, hospitalization and surgery.
Findings
In the initial 12 months study 52 patients were randomised to the intensive and 25 to the standard treatment arm. 64/77 (83%) patients recorded an outcome at 12 months [13/77 (17%) withdrawn: 8 surgery, 5 other], 74/77 (96.1%) patients were followed up at a mean of 25.3 (IQR 24.4-26.3) months. Of these, 59 (79.7%) remained on adalimumab, 10 (13.5%) had switched to another biologic and 5 (6.7%) had ceased biologic therapy. For patients who were on adalimumab at 12 months the risk of surgery by 24 months was 15%. Of patients on adalimumab 40mg fortnightly at 12 months, 12/48 (25%) had been dose escalated by 24 months. Endoscopic balloon dilatation, hospitalization or surgery was required in 6 (8.1%), 14 (18.9%) and 13 (17.5%) respectively; rates were not different between the standard and intensive treatment groups (P = 0.982). Median time to intestinal resection was 12.2 (IQR 6.9-18.6) months. Clinical responders at 12 months, compared to non-responders, had a reduced likelihood of surgery at 24 months (9% vs 42%, P=0.003).
Interpretation
Clinical response to adalimumab for structuring Crohn’s disease is durable in a majority of patients, with most patients remaining on adalimumab and avoiding surgery at two years. Rates of surgery were not different between the standard and intensive therapy arms. Clinical response to adalimumab at 12 months is an important predictor of future surgical risk.

Background: Upadacitinib (UPA), an oral, reversible JAK inhibitor, demonstrated superior efficacy compared to placebo (PBO) in patients with moderate to severe Crohn’s disease (CD) in 2 multicentre, phase 3 induction (U-EXCEL and U-EXCEED), and 1 maintenance (U-ENDURE) trial.^1-3 This sub-analysis assessed endoscopic outcomes in patients with or without a history of biologic failure (inadequate response or intolerance) among those receiving UPA treatment.
Methods: Eligible patients had average daily stool frequency [SF] ≥4 and/or abdominal pain score [APS]≥2, plus a Simple Endoscopic Score for CD (excluding the presence of narrowing component) ≥6 [≥4 for isolated ileal disease]). Patients received UPA 45 mg once daily (QD; UPA45) or PBO (2:1) for 12 weeks (wks). Patients that achieved SF/APS clinical response after 12 weeks of treatment with UPA45 (≥ 30% decrease in daily very soft/liquid SF and/or ≥ 30% decrease in daily abdominal pain APS with neither worse than baseline) were re-randomized (1:1:1) to UPA 30 mg QD (UPA30), UPA15 mg QD (UPA15) or PBO for 52 wks of maintenance. Endoscopic response\remission were evaluated by central reading at wk 12 induction and wk 52 maintenance. Adverse events (AEs) were assessed through wk 52. Statistical significance in comparisons was not assessed due to an inability to control for type I error in subgroup analysis.
Results: Baseline characteristics/demographics were similar across treatment groups. In the pooled induction population (U-EXCEED+U-EXCEL), 72.0% UPA45 and 71.5% PBO patients had history of prior biologic failure. In U-ENDURE, 73.4% UPA15, 75.6% UPA30, and 76.4% PBO patients had history of prior biologic failure. In patients without or with biologic failure, UPA demonstrated higher rates for endoscopic response compared to PBO at wk 12 (52.0%, 35.7% UPA45 vs 16.2%, 5.3% PBO, Figure 1A) and wk 52 (Figure 1B). Similarly, in patients without or with a history of biologic failure, UPA exhibited higher rates of endoscopic remission at wk 12 (36.0%, 19.6% UPA45 vs. 10.1%, 2.8% PBO, Figure 1A) and wk 52 (Figure 1B). Differences from PBO were found in endoscopic response or remission in patients that remained in response/remission from the entry of maintenance to wk 52 for either dose, regardless of prior history of biologic failure (Figure 1C). UPA treatment was well-tolerated, with no new safety risks observed compared to the known safety profile of UPA (Table 1).
Conclusion: Upadacitinib achieved clinically meaningful endoscopic outcomes, which were maintained up to 1 year, irrespective of a patient’s prior biologic treatment, with an acceptable safety profile.

Background: Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P_1,4,5) modulator in development to treat immune-mediated inflammatory disorders. CULTIVATE (NCT04173273) is a seamless phase 2/3 trial comprising 5 substudies designed to evaluate the efficacy, safety, and tolerability of etrasimod in subjects with moderately to severely active Crohn’s disease (CD). Here, we report the induction data from the first substudy (Substudy A).

Methods: Substudy A was a phase 2, randomized, double-blind study using a 14-week induction period followed by a 52-week extension period. Adults (18-80 years) with moderately to severely active CD and an inadequate response, loss of response to, or intolerance to ≥1 conventional or advanced treatments for CD were randomized 1:1 to once-daily etrasimod 2 mg or 3 mg. Subjects were stratified by baseline biologic failure status and oral corticosteroid use. The primary efficacy endpoint was achievement of endoscopic response (defined as endoscopic remission [SES-CD ≤4 and ≥2-point reduction from baseline with no subscore >1] or ≥50% decrease in SES-CD score) at week 14. Secondary/exploratory endpoints included achievement of endoscopic remission, clinical remission (CDAI <150), and IBDQ remission (IBDQ ≥170) at week 14. Outcomes were analyzed in the Full Analysis Set (all randomized subjects treated with ≥1 dose) using NRI or observed data.

Results: Of 83 subjects randomized to etrasimod 2 mg or 3 mg, respectively, 32/42 (76.2%) and 36/41 (87.8%) completed week 14. Overall, 21.4% and 9.8% of subjects in the 2-mg and 3-mg groups, respectively, achieved the primary endpoint of endoscopic response, 14.3% and 7.3% achieved endoscopic remission, 31.0% and 43.9% achieved clinical remission, and 33.3% and 40.0% achieved IBDQ remission at week 14 (Figure 1). Most treatment-emergent AEs were mild or moderate, with more AEs reported in the 3-mg vs 2-mg group. The incidence of serious AEs (4.8% and 2.4%) and AEs leading to discontinuation (4.8% and 7.3%) was low in the 2-mg and 3-mg groups, respectively (Table 1). Two subjects in the 3-mg group experienced second degree atrioventricular block type 1 TEAEs (during 2-mg titration).

Conclusion: Data from this substudy of subjects with moderately to severely active CD suggest endoscopic and clinical improvement with both etrasimod 2 mg and 3 mg. However, the small sample size and lack of placebo arm limit the ability to draw conclusions about efficacy including comparison between the 2-mg vs 3-mg groups. Both doses were well tolerated and safety was consistent with other etrasimod clinical programs. Data from the extension phase of Substudy A and the placebo-controlled, dose-ranging phase 2b Substudy 1 are forthcoming.