Society: AGA

Background
Switching from originator to biosimilar infliximab (IFX) is effective and safe. However, data on multiple switching are scarce. The Edinburgh IBD unit has undertaken three switch programmes: (1) Remicade to CT-P13 (2016), (2) CT-P13 to SB2 (2020), and (3) SB2 to CT-P13 (2021). The primary endpoint of this study was to assess CT-P13 persistence following switch from SB2. Secondary endpoints included persistence stratified by the number of biosimilar switches (single, double and triple), effectiveness and safety.
Methods
We performed a prospective, observational, cohort study. All adult IBD patients on IFX biosimilar SB2 underwent an elective switch to CT-P13. Patients were reviewed in a virtual biologic clinic with protocol driven collection of clinical disease activity, CRP, faecal calprotectin (FC), IFX trough / antibody levels, and drug survival.
Results
297 patients (CD n=196 [66%], UC/IBDU n=101, [34%]) were switched. This was the third, second and first IFX switch for 67 /297 (22.5%), 138 /297 (46.5%) and 92 /297 (31%) of the cohort respectively. Patients who underwent multiple IFX biosimilar switches had longer disease duration (p=0.0001) and IFX duration (p=0.0001) and were less often on combination therapy with an immunomodulator (p=0.0001).
90.6% of patients remained on IFX during a median follow-up of 7.5 months [6.8-8.1] (figure 1). The number of switches was not independently associated with IFX persistence after adjusting for confounders (table 1). Clinical (p=0.77), biochemical (CRP ≤5mg/mL; p=0.75) and faecal biomarker (FC<250µg/g; p=0.63) remission were comparable at baseline, week 12 and week 24.
Conclusion
Multiple successive switches from IFX originator to biosimilars are effective and safe in patients with IBD, irrespective of the number of IFX switches.

Recently, a subcutaneous formulation of biosimilar infliximab (CT-P13) (SC-IFX) has been approved for inflammatory bowel disease (IBD). Aim: to evaluate efficacy, safety, pharmacokinetics and patient experience following a switching to SC-IFX in patients who are in clinical remission on IV-IFX maintenance treatment. Methods: Multicentre, descriptive, and observational study including Crohn’s disease (CD) and ulcerative colitis (UC) patients who were going to be changed from IV-IFX to SC-IFX on the ENEIDA registry (a large, prospectively maintained database of the Spanish Working Group in IBD–GETECCU). All patients were on clinical and biological remission at least 24 weeks before changing. Demographic and disease data, clinical activity (Harvey-Bradshaw index for CD and mayo index for UC), analytical data (C reactive protein (CRP) and fecal calprotectin (FC), as well as trough levels were collected at baseline, at 12 and 24 weeks. Results:
One hundred and fifty-five patients were included: 54 UC (35%) and 91 (65%) CD; 44% women and 56% men; age 45.5 years (32-55). IV-IFX was mainly administered due to active disease (72%) and perianal disease (7%) and during 32 months [range 14-56]. Pre-switch, 78 (50.3%) were on 8-weekly dosing of IV-IFX, 77 (49.7%) were with intensification dose and the half (50.3%) were on concomitant immunomodulatory therapy. SC-IFX was mainly switching by COVID-19 pandemic (60%), to increase through levels (15%) or patient request (25%). The majority of patients (140, 90%) remained with standard dose, 8 (5%) required dose intensification (120 mg weekly in 4 and 240 mg every 2 weeks in 4) and 7 (4.5%) had successful de-escalation (120 mg every 3 weeks in 4 and 120 mg every 4 weeks in 3). Clinical indices, CRP levels and FC remained unchanged (Figure). Median SC-IFX levels significantly increased from baseline of 4.5 μg/dl [range 2.6-9.2] to 14 μg/dl [range 9.5-16.2] at 12 weeks and 13.2 μg/dl [range 10.4-19.7] at 24 weeks No factors (immunossupresor, body mass index, disease location) were associated with the increase of IFX trough levels. During 24 weeks of follow-up, 16 of the 78 (20.5%) patients stopped immunosuppressant treatment. The adverse events were recorded in 9 patients (5.8%), 4 (2.6%) were hospitalized and 4 (2.6%) had surgery (one of them for perianal disease). Nine patients (5.8%) stopped SC-IFX (1 primary failure, 2 loss of response, 4 adverse events, 1 voluntarily, and 1 surgery). Conclusion: The switch from IV to SC IFX maintains clinical remission safely in IBD, offers higher drug levels and a good patient acceptance. However, the significance of higher drug levels with SC-IFX requires further exploration.

Objective: Tumor necrosis factor–like cytokine 1A (TL1A) regulates pro-inflammatory cytokines and fibrosis. PRA023 is an anti-TL1A monoclonal antibody in development for multiple inflammatory/fibrotic diseases incorporating a precision approach with a predictive genetic-based diagnostic (Dx) tool. This placebo-controlled, double-blind phase 2 study assessed efficacy and safety of PRA023 induction treatment in adults with moderately to severely active ulcerative colitis (UC).
Methods: Patients with a modified Mayo score (mMS) of 4 to 9, centrally read endoscopy subscore of ≥2, rectal bleeding subscore of ≥1, and history of insufficient response, loss of response, and/or intolerance to conventional and/or advanced therapies (≤4 advanced agents from ≤3 classes allowed) were eligible. Patients were stratified by prior biologic exposure and Dx status and randomized 1:1 to placebo or intravenous PRA023 (1000 mg on day 1, 500 mg at weeks 2, 6, and 10). The primary endpoint was clinical remission per mMS at week 12. Analyses of ranked secondary endpoints were multiplicity-controlled.
Results: Of the 135 patients, 60/67 (89.6%) in the placebo arm and 68/68 (100%) in the PRA023 arm completed the 12-week induction period. Baseline characteristics were similar (Table 1A). A significantly greater proportion of patients who received PRA023 achieved the primary endpoint of clinical remission (26.5% PRA023 vs 1.5% placebo, Δ25.0%, p<0.0001) at week 12 (Table 1B). All ranked secondary endpoints for cohort 1 significantly favored drug relative to placebo, including symptomatic remission (19.1% PRA023 vs 6.0% placebo, Δ13.1%, p=0.02), mucosal healing (30.8% PRA023 vs 3.5% placebo, Δ27.3%, p<0.0001), and IBDQ response (82.4% PRA023 vs 49.3% placebo, Δ33.1%, p<0.0001; Table 1B). Exposure to prior advanced therapy, antidrug antibody status, and concomitant therapy did not have a major effect on efficacy (Table 1C). Statistically significant reductions in symptom scores were observed as early as week 2 (Figure 1A) and at each visit where C-reactive protein and fecal calprotectin were collected (Figure 1B and 1C). An enhanced treatment effect was observed for the prespecified Dx+ subgroup, with 37.5% for both placebo-adjusted clinical remission and endoscopic improvement. The rates of treatment-emergent adverse events (AEs) were similar between the 2 arms with no serious AEs or AEs leading to study drug discontinuation in the PRA023 arm. There were no safety signals identified from the study.
Conclusions: PRA023 was effective with favorable tolerability for the induction of clinical remission and endoscopic improvement in moderately to severely active UC. A phase 3 study will be conducted to confirm these findings. The enhanced treatment effect in the Dx+ subgroup from cohort 1 is being further evaluated in the Dx+ expansion cohort 2.

Figure 1

Background:
Modulation of the gut microbiota is emerging as a promising therapeutic approach in ulcerative colitis (UC). We aimed to evaluate repeated administration of a standardized preparation of encapsulated freeze-dried fecal microbiota for patients with active UC.

Methods:
A pilot, randomized, double-blinded, placebo-controlled trial of microbiota transplant therapy (MTT) was performed in patients with active UC (endoscopic Mayo score ≥ 1 involving ≥ 20 cm of colon proximal to anus) on stable maintenance therapy. Participants were randomized 1:1 to active or placebo capsules daily for eight weeks. The active treatment consisted of lyophilized donor fecal microbiota (compound MTP-101C) given at a dose of ~2 × 10¹¹ bacteria contained in two capsules. The primary outcome was engraftment of donor microbiota at weeks eight and 12 (measured using the Bayesian software, SourceTracker). Donor engraftment in placebo controls was measured using in silico donors matched temporally in time to participants receiving MTT. Secondary outcomes included clinical disease activity using the partial Mayo (pMayo) score and safety.

Results:
27 people were randomized (13 MTT and 14 placebo). Baseline characteristics between groups were similar, although those randomized to MTT trended to more moderate-severe disease (46% with a pMayo ≥ 5) than placebo (14% with a pMayo ≥ 5), (p=0.1). Approximately one-third of participants in both groups were biologic-naïve. At four weeks, those randomized to MTT had a significant decrease in pMayo score (delta -1.46, p=0.02) compared to placebo (delta -0.4, p=0.5). This trend held at eight weeks, however by 12 weeks (four weeks since the last MTT dose), pMayo scores were not statistically different from baseline (Figure 1). At week four, 38% in the MTT group experienced a clinical response (decrease in pMayo ≥ 2 and no systemic steroid use) compared to zero percent in the placebo group (p=0.02). At weeks eight and 12, response rates were similar between the groups. The alpha diversity (Shannon and Chao1 indices) did not significantly differ between MTT and placebo at weeks four, eight, and 12. The median proportion of donor engraftment was significantly higher in the MTT group. This was seen at the first measured fecal sample at week one and persisted at each subsequent time point (Figure 2). Adverse events were similar between the groups, and no severe adverse events were noted.

Conclusions:
Repeated oral administration of standardized encapsulated fecal microbiota results in rapid microbiota engraftment and improvement of clinical symptoms. No safety concerns were noted with MTT in conjunction with standard-of-care medications for UC. MTT should be studied for clinical use for induction of remission in patients with UC.

Introduction. Patients with inflammatory bowel disease (IBD) often come to the clinic with a simple question; “what should I eat?”. We therefore designed The PRognostic effect of Environmental factors in Crohn’s and Colitis (PREdiCCt) study to determine which aspects of habitual diet are associated with disease flare in IBD.

Methods. 2629 patients with Crohn’s disease (CD) and ulcerative colitis (UC) in clinical remission were prospectively recruited from 49 adult and pediatric UK centers between 17/11/2016 and 31/03/2020. Main exclusion criteria were active steroid use, recent surgery or change in IBD therapy. Detailed baseline data were collected along with stool for microbial metagenomics and calprotectin (FCAL). Habitual diet over the prior 2-3 months was assessed using Food Frequency Questionnaire (FFQ). Patients were followed up for a minimum of 2 years by monthly electronic questionnaire, with end-of-study phenotyping from the patient records.
The primary endpoint was time to first flare. 'Soft flares' were derived from IBD-Control response; 'hard flares' were defined as increase in symptoms plus elevation in CRP/FCAL and a change in IBD therapy. Only cases with complete FFQ, sex, smoking status and social deprivation data were included in this analysis (n=1017; CD=497, UC=520). Dietary intake measures were divided into quartiles, with hazard ratios calculated using Cox frailty regression for risk of flare. Analyses were adjusted for smoking, total energy intake, gender and social deprivation score with a random effect for sites.

Results. The hard flare rate was 5.6 % per year with no difference by IBD subtype; in contrast patient reported soft flares accumulated rapidly (Figure 1a). Median follow up was 1481.5 (IQR: 1111-1805) days (Figure 1a). Baseline FCAL predicted hard flare not only with levels of >250mcg/g, but also at 50-250mcg/g (Figure 1b).
Baseline total protein intake was 91.9 g/day of which 35.8 g/day was from meat sources. Habitual meat intake was associated with hard flare in UC but not CD (Figure 2). The hazard ratio between highest and lowest quartiles of meat intake in UC was 2.08 (95% CI 1.14-3.80; p=0.017). No associations with hard flare were seen for total dietary fiber intake, N-6 polyunsaturated acids and ultra processed foods (using the NOVA score).

Conclusion. These are the first prospective data of habitual diet and IBD flare in a Western population. We show that habitual meat intake is associated with an increased risk of flare in patients with UC. Thus dietary modification merits investigation as a method of reducing flare risk. These data are consistent with data that meat intake is associated with increased risk of UC development. We hypothesize that this link is due to diet-induced alterations in the gut microbiome and will further explore this once metagenomic sequences of the PREdiCCt stool samples are complete.

Figure 1. Panel A demonstrates hard (blue line) and soft (red line) flares during follow-up in the PREdiCCt cohort for Crohn's disease and UC. Panel B demonstrates time to hard flare in UC by baseline faecal calprotectin level with <50mcg/g (blue line), 50-250mcg/g (red line) and >250mcg/g (green line).

Figure 1. Panel A demonstrates hard (blue line) and soft (red line) flares during follow-up in the PREdiCCt cohort for Crohn's disease and UC. Panel B demonstrates time to hard flare in UC by baseline faecal calprotectin level with <50mcg/g (blue line), 50-250mcg/g (red line) and >250mcg/g (green line).

Figure 2. Time to first hard flare by quartile of habitual dietary meat intake in Crohn's disease (panel A) and in UC / IBD-unclassified (panel B). Quartiles of meat intake are colour coded with red line indicating lowest intake and blue line highest intake (all values in g/day).

Figure 2. Time to first hard flare by quartile of habitual dietary meat intake in Crohn's disease (panel A) and in UC / IBD-unclassified (panel B). Quartiles of meat intake are colour coded with red line indicating lowest intake and blue line highest intake (all values in g/day).

Beatriz Gros

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