Ulcerative Colitis Trials Research Articles

DOP45 Long-term cardiac safety of ozanimod in phase 3 clinical program of Ulcerative Colitis and relapsing multiple sclerosis

Abstract Background Sphingosine-1-phosphate (S1P) receptor modulators may be associated with bradycardia and atrioventricular conduction delays. A previous analysis demonstrated first-dose ozanimod had minimal effects on cardiac function, including in patients (pts) with a known history of cardiovascular disease. This analysis evaluated long-term cardiac safety following continuous ozanimod treatment from the phase 3 ulcerative colitis (UC) True North trial and multiple sclerosis (MS) 12-mo SUNBEAM and 24-mo RADIANCE trials. Methods Ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg)–treated pts from True North and pooled SUNBEAM/RADIANCE trials were included. In True North, pts in Cohort 1 received double-blind ozanimod or placebo and pts in Cohort 2 received open-label ozanimod in the induction period; in the maintenance period, pts with clinical response to ozanimod at 10 weeks were rerandomized to double-blind ozanimod or placebo. In True North, ECGs were monitored at screening, day 1, wk-10, and wk-52; heart rate (HR) was monitored at every visit. In the MS trials, ECGs were monitored at screening, baseline, day 15, and end of treatment (EOT); HR was monitored similarly at the beginning, then every 3 mo until EOT. Cardiac-related treatment-emergent AEs (TEAEs) were reported. Results In the UC trial, continuous ozanimod treatment was not associated with any clinically significant changes in HR or ECG. The incidence of cardiac-related TEAEs with ozanimod during induction in Cohorts 1 and 2 was low (Table). In maintenance, cardiac-related TEAEs were reported in 1.3% (3/230) of pts in the continuous ozanimod group (Table); incidence was numerically higher in ozanimod pts with (2 of 57 pts [3.5%]) versus without (1 of 173 pts [0.6%]) prior history of cardiovascular disease. Cardiac-related serious AEs (SAEs) were uncommon (angina pectoris, coronary artery stenosis, pericarditis in 1 patient each). In the pooled MS studies, no clinically significant HR or ECG changes were associated with chronic treatment up to mo 24. The incidence of cardiac-related TEAEs was low with ozanimod (Table); incidence was similar among pts with (6 of 171 pts [3.5%]) versus without (24 of 711 pts [3.4%]) prior history of cardiovascular disease. Two of 882 patients experienced cardiac-related SAEs resulting in hospitalization with ozanimod in the MS studies (asymptomatic sinus bradycardia [HR 44 bpm] and symptomatic supraventricular tachycardia). Conclusion Ozanimod had a manageable long-term cardiac safety profile with a low incidence of bradycardia and few serious long-term cardiac safety findings in the phase 3 UC and MS ozanimod trials.

P486 Treatment-emergent COVID-19 infections in ozanimod ulcerative colitis and multiple sclerosis clinical trials

BackgroundOzanimod, a sphingosine 1-phosphate (S1P) receptor S1P1 and S1P5 modulator, is approved in the United States for moderately to severely active ulcerative colitis (UC) and in multiple countries for relapsing multiple sclerosis (MS). We describe COVID-19 outcomes in ozanimod-treated UC or MS patients (pts) in active phase 3 open-label extension (OLE) studies.MethodsA database search identified COVID-19 infection reports in ozanimod-treated pts with UC in the True North OLE and MS in the DAYBREAK OLE. The analysis period was November 1, 2019 to either August 31, 2021 (UC) or May 10, 2021 (MS). The last COVID-19 event from all pts with ≥1 event was analyzed.ResultsAmong 2792 ozanimod-treated pts with UC or MS, 258 developed COVID-19 (confirmed: 215); thus, the incidence in these clinical trial settings was 9.2% during the analysis periods. Most pts with confirmed cases (193/215 [89.8%]) had nonserious infections not requiring hospitalization or meeting other International Conference on Harmonisation criteria for a serious event. Of 611 ozanimod-treated pts with UC, 68 (11.1%) developed COVID-19 (confirmed: 55; Fig 1). A majority of UC pts with confirmed cases (45/55 [81.8%]) had nonserious COVID-19; most (54/55 [98.2%]) recovered (2 with sequalae) and 1 was recovering at data cutoff. One UC pt with confirmed COVID-19 discontinued ozanimod (1.8%), 23 temporarily interrupted it (41.8%), and 31 had no change to treatment (56.4%). No COVID-19‒related deaths were reported in UC pts. Of 2181 ozanimod-treated pts with MS, 190 (8.7%) developed COVID-19 (confirmed: 160; Fig 2). Most MS pts with confirmed COVID-19 (148/160 [92.5%]) had nonserious cases; most (158/160 [98.8%]) recovered (5 with sequelae) (Fig 1). No MS pts with confirmed cases discontinued ozanimod, 61 temporarily interrupted it (38.1%), and 99 had no change to treatment (61.9%). Outcomes in 13 additional UC pts (Fig 1) and 30 additional MS pts (Fig 2) with suspected COVID-19 were similar to those with confirmed cases. There were 3 COVID-19‒related deaths in the MS program. One pt died from a presumed pulmonary embolism; this pt had received high-dose corticosteroids for MS relapse immediately before COVID-19 symptom onset. Another pt died from suspected COVID-19‒related respiratory failure. One tetraplegic, cachectic pt died from a lung abscess following COVID-19 infection.ConclusionIn the UC and MS OLE studies, most pts with confirmed COVID-19 had nonserious infections, recovered, and did not require ozanimod discontinuation. There were 3 deaths in MS patients (case-fatality rate 1.6% in MS, 1.2% overall).

P404 Underrepresentation of minorities and lack of race reporting in ulcerative colitis drug development clinical trials

Abstract Background Historically, inflammatory bowel disease (IBD) trials report high enrollment rates for white-caucasian patients. To promote initiatives towards diversifying patients enrolled in clinical trials, we assessed the reporting of race/ethnicity of patients enrolled in pharmaceutical clinical trials for ulcerative colitis (UC). Methods A previous systematic review of all placebo-controlled trials in adult patients with UC examining different therapeutic drug classes was performed from inception to December 2020. Trial and patient characteristics were summarized according to the type of variable. Categorical variables were summarized by displaying the number and percentage of trials or participants for each category. Continuous variables were summarized by displaying the weighted mean, weighted standard deviation, and range. Means and standard deviations (SD) were weighted by the number of participants in each trial. Results Descriptive statistics of trial and patient characteristics for, 95 induction trials and, 29 maintenance trials are summarized in Table, 1. Race was reported in, 37.9% (36/95) of induction studies, with most participants being White (86.3%;, 8610/9976). Furthermore, 21/36 (58.3%) studies reported race as White vs. non-White participants; and, 15/36 (41.7%) studies provided further breakdown, including Black (115/3414 patients [3.4%]), Asian (448/4136 patients [10.8%]), and “Other” (127/4136 patients [3.1%]). Moreover, 3/36 studies misreported race as ethnicity and, only, 3/36 studies reported ethnicities correctly, classifying patients as Hispanic/Latinx vs. Non-Hispanic/Latinx. For maintenance trials, 34.5% (10/29) studies reported race, with majority of participants being White (85.6%;, 2778/3246). Additionally, 6/10 studies reported only a White vs. non-White participants comparison, while, 4/10 reported other races, including Black (45/1145 patients [3.9%]), Asian (40/888 patients [4.5%]), and “Other” (26/1145 patients [2.3%]). No studies reported ethnicity. Conclusion Given the increasing burden of IBD in developing countries, differences amongst racial and ethnic groups are important to understand since they can influence disease phenotype, response to therapy, and safety outcomes.1 We found poor race reporting in UC clinical trials and observed that the vast majority of participants enrolled were White. These findings suggest that the population prevalence of UC amongst different racial groups is not reflected in clinical trial populations, being important to raise awareness of the existing barriers that prevent patients from accessing clinical trials. Reporting of race and ethnicity in UC clinical trials should be mandatory, and a requirement to enroll a certain percentage of non-White patients should be considered.2

P064 IMU-838, a Small Molecule DHODH Inhibitor in Phase 2 Clinical Trial for Ulcerative Colitis, Shows Potent Anti-inflammatory Activity in Cell-Culture-Based and In Vivo Systems

Abstract Background IMU-838 (vidofludimus calcium) is a well-tolerated and orally available small molecule inhibitor of dihydroorotate dehydrogenase (DHODH) and is currently in phase 2 clinical development for ulcerative colitis (UC). Here, we investigated the effect of IMU-838 on different immune cell subsets and analysed the mechanism of action in more detail in T cells. Methods The effect of IMU-838 on regulatory macrophages (Mregs) was investigated by adding IMU-838 or anti-TNFα antibodies (infliximab, adalimumab), alone or in combination, in a mixed lymphocyte reaction assay, determining Mregs (CD206+CD14+) by FACS analysis. To investigate the effect of IMU-838 on human T and B cells, PBMC were stimulated with PHA (48h) or Oligonucleotide 2006-PTO (70h), respectively. An affinity-dependent effect of IMU-838 was assessed on CD8 T cells from OT-I and OT-III mice, containing a high and a low affinity T cell receptor (TCR), respectively, for OVA257-264 peptide. These cells were stimulated with ovalbumin (OVA) peptide loaded splenocytes or anti-CD3/anti-CD28 for 3 days. Oxidative phosphorylation (OXPHOS) and glycolysis in murine T cells was investigated by the Seahorse/Agilent technique in murine CD4 and CD8 T cells activated with anti-CD3/anti-CD28 with or without IMU-838. Results IMU-838 slightly induced Mregs, but strongly and dose-dependently decreased TNFα and IL-6 secretion. Anti-TNFα antibodies alone strongly induced Mregs, but also increased IL-6 levels. When IMU-838 was added, Mregs induction was even higher, and IL-6 was reduced. Besides reducing proinflammatory cytokines secreted by macrophages, IMU-838 also inhibits proliferation of activated B and T cells, as well as inflammatory T cell cytokine secretion, IL-17A, IL-17F and IFNγ, and increased apoptosis up to 3-fold compared to vehicle control. By investigating IMU-838’s role on affinity related activity status of T cells, it was shown that IMU-838 strongly inhibited cell proliferation in the peptide stimulated high affinity, but not in the low affinity, CD8 T cells. Peptide stimulated high affinity T cells show an upregulation of OXPHOS and glycolysis pathways, which are involved in the generation of the cell’s energy supply, compared to low affinity cells. IMU-838 strongly inhibited OXPHOS and glycolysis in both CD4 and CD8 T cells. Conclusion IMU-838 reduces the proinflammatory immune cell response by inducing Mregs, reducing pro-inflammatory cytokine secretion and reducing immune cell proliferation. DHODH is only important in cells that received a strong stimulus and are highly metabolically active. Therefore, IMU-838 will only specifically target these cells and will still allow for a normal immune response, representing a huge safety advantage for treatment of IBD patients.

P236 Interobserver reliability of the Nancy index for ulcerative colitis: An assessment of the practicability and ease of use in a single-centre real-world setting

Abstract Background Histological disease severity assessment in ulcerative colitis has become a mainstay in clinical endpoints definition (“histologic remission”) in clinical trials of ulcerative colitis (UC). Among the several scores that were developed for the microscopical assessment of disease activity, the Nancy index (NI) stands out for the least amount of work load due to the lowest number of scoring items. To which extent histologic assessment using NI is affected by interobserver reliability in the real word setting, is poorly understood. We therefore performed a single-center retrospective analysis of NI assessment in patients with ulcerative colitis. Methods We retrospectively evaluated in two independent cohorts with a total of n=1085 of biopsy samples (sigmoid, rectum) taken from 547 clinically diagnosed UC patients, who underwent colonoscopy between 2007 and 2020. Cohort #1 consisted of 637 biopsies from 312 patients, Cohort #2 consisted of 448 biopsies from 235 patients. The NI of these samples were assessed by two blinded pathologists with a different amount of pathological experience. After each cohort a consensus conference was held where samples that were rated with different NI grades were re-assessed, and a consensual score was given by both observers. We evaluated interobserver reliability and differences in the amount of the several grades of the NI rated by the observers. Results The interobserver-agreement of the NI was very-good after the assessment of the 1085 samples (κ = 0,687 [95%-CI: 0,653-0,720]). An improvement of the interobserver-agreement was found with growing numbers of samples evaluated by both observers (1st cohort: κ = 0,659 [95%-CI: 0,615-0,704]; 2nd cohort: κ = 0,726 [95%-CI: 0,675-0,776]). The biggest number of differences were in NI grade 1 (observer 1: n=128; observer 2: n=236). The smallest number of differences were in NI grades 0 (observer 1: n=504; observer 2: n=479) and 3 (observer 1: n=71; observer 2: n=66). After a consensual score was given the largest part of grades were NI grade 0 (n=504) followed by NI grade 2 (n=309). The least number of samples were given NI grade 3 (n=62). Average time for scoring was less than 2 minutes. Conclusion The NI represents an easy-to-use index with very high interobserver reliability to assess the histological disease activity of UC patients in a real-world setting. Though further improvements of the NI regarding stricter classifications of the several grades need to be done to improve the practicability of the index. While NI grades 0 and 3 having a very high level of agreement between the observers, NI grade 1 has a lower agreement-level. This highlights the clinical need to specify histological characteristic leading to NI grade 1.

EARLY VERSUS DELAYED INITIATION OF VEDOLIZUMAB IN ULCERATIVE COLITIS: TREATMENT RESPONSE IN THE REAL WORLD (RALEE)

Pivotal trials in ulcerative colitis (UC) have indicated that earlier intervention with a biologic is associated with greater likelihood of treatment response. However, in real-world clinical practice, patients with newly diagnosed UC are often prescribed conventional therapies, such as immunomodulators (IM), corticosteroids (CS), and/or 5-aminosalicylates (5-ASA) before biologic treatment, which may result in suboptimal clinical outcomes and high costs. RALEE is an observational study investigating the impact of early versus delayed initiation of vedolizumab (VDZ) on clinical and economic outcomes in patients with inflammatory bowel disease, using administrative data sets.

Pfizer to acquire biotech firm Arena for $6.7 billion

Seeking to add firepower to its efforts to develop autoimmune disease drugs, Pfizer will acquire Arena Pharmaceuticals for about $6.7 billion. Arena’s portfolio includes several development-stage drug candidates, including lead candidate etrasimod, an oral, selective sphingosine 1-phosphate receptor modulator currently in Phase 3 clinical trials for ulcerative colitis and a Phase 2/3 trial for Crohn’s disease. Analysts say the deal will boost Pfizer’s pipeline in inflammation and immunology drugs and diversify the firm beyond Janus kinase inhibitors, inflammation drugs that have come under increasing scrutiny. The US Food and Drug Administration requires new heart safety and cancer warnings for several drugs in the category, including one from Pfizer. Pfizer’s agreement to pay $100 per share for Arena, double its previous closing price, is reasonable, especially given prospects for etrasimod, according to a note from stock analysts at Mizuho Securities. The price premium is mitigated by Pfizer’s profits from the COVID-19

Positioning Infliximab and Vedolizumab in the Treatment of Moderate-to-Severe Ulcerative Colitis

Positioning Infliximab and Vedolizumab in the Treatment of Moderate-to-Severe Ulcerative Colitis

P038 Ozanimod First-Dose Cardiac Effects in Patients with Moderately to Severely Active Ulcerative Colitis and Relapsing Multiple Sclerosis.

Ozanimod, an oral sphingosine 1-phosphate (S1P) receptor modulator that selectively targets S1P1 and S1P5, is approved in the US for treating moderately to severely active ulcerative colitis (UC) and in multiple countries for treating relapsing forms of multiple sclerosis (MS). In a Phase 1 study of ozanimod in healthy participants, first-dose cardiac effects were mitigated with gradual dose escalation. Based on these results, an initial 7-day ozanimod dose escalation regimen was implemented in all Phase 2 and 3 UC and MS trials. The objective of this analysis was to evaluate the number of patients who were excluded from ozanimod treatment due to contraindications of pre-existing cardiac disorders and to evaluate the incidence of cardiac-related treatment-emergent adverse events (TEAEs) following first-dose ozanimod administration in all patients and patients with a history of non-exclusionary cardiac disorders in the UC and MS clinical trials. For UC, the analysis included pooled data from the Phase 2 Touchstone (NCT01647516) and Phase 3 True North (NCT02435992) trials. For MS, the analysis included pooled data from the Phase 3 Radiance (NCT02047734) and Sunbeam (NCT02294058) trials. Patients with clinically relevant cardiac conditions or clinically significant electrocardiogram (ECG) disorders were excluded from the trials. On Day 1, all patients received ozanimod 0.23 mg (equivalent to ozanimod HCl 0.25 mg). Day 1 cardiac monitoring included collection of vital signs (including heart rate) prior to dosing and hourly for at least 6 hours after dosing, and ECG prior to dosing and at Hour 6 after dosing. Among patients screened, 26/2178 (1.2%) in the UC studies and 47/3351 (1.4%) in the MS studies were excluded due to protocol-defined pre-existing cardiac disorders. Of 496 patients who received ozanimod in the UC studies, 1 (0.2%) experienced a cardiac-related TEAE on Day 1 (asymptomatic bradycardia). Of 1774 patients who received ozanimod in the MS studies, 11 (0.6%) experienced a cardiac-related TEAE on Day 1. In both the UC and MS studies, no cases of second- or third-degree AV block were observed. A decrease in mean heart rate from baseline (UC, 0.7 bpm; MS, 1.2 bpm) was observed at first-dose that reached a nadir at Hour 5 and returned to baseline by Hour 6. Among 496 patients with UC who received ozanimod, 34 (6.9%) had a known history of cardiac disorders, of whom 1 experienced a cardiac-related TEAE on Day 1 (asymptomatic bradycardia). Among the 1774 patients with MS who received ozanimod, 96 (5.4%) had a known history of cardiac disorders, of whom 2 experienced symptomatic bradycardia on Day 1. In clinical trials of ozanimod, the number of patients with UC or MS who failed screening because of exclusionary cardiac disorders was low. Most patients with a history of cardiac disorders who were enrolled in ozanimod clinical trials did not have Day 1 cardiac events, and the events that occurred were manageable.

Efficacy of Biologic Drugs in Short-Duration Versus Long-Duration Inflammatory Bowel Disease: A Systematic Review and an Individual-Patient Data Meta-Analysis of Randomized Controlled Trials

Starting biologic treatment early in the course of inflammatory bowel disease (IBD) may be associated with higher efficacy, especially in Crohn's disease (CD). This was a systematic review and individual-patient data meta-analysis of all placebo-controlled trials of biologics approved for IBD at study inception (October 2015), using Vivli data-sharing platform. The primary outcome was the proportional biologic/placebo treatment effect on induction of remission in patients with short-duration (≤18 months) vs long-duration disease (>18 months) analyzed separately for CD and ulcerative colitis (UC). We used meta-regression to examine the impact of patients' characteristics on the primary outcome. We included 25 trials, testing infliximab, adalimumab, certolizumab, golimumab, natalizumab, or vedolizumab (6168 patients with CD and 3227 patients with UC). In CD, remission induction rates were higher in pooled placebo and patients in active arms with short-duration disease of ≤18 months (41.4% [244 of 589]) compared with disease duration of >18 months (29.8% [852 of 2857], meta-analytically estimated odds ratio, 1.33; 95% confidence interval, 1.09-1.64). The primary outcome, proportional biologic/placebo treatment effect on induction of remission, was not different in short-duration disease of ≤18 months (n= 589, odds ratio, 1.47; 95% confidence interval, 1.01-2.15) compared with longer disease duration (n= 2857, odds ratio, 1.43; 95% confidence interval, 1.19-1.72). In UC trials, both the proportional biologic/placebo remission-induction effect and the pooled biologic-placebo effect were stable, regardless of disease duration. Primary outcome results remained unchanged when tested using alternative temporal cutoffs and when modeled for individual patient's covariates, including prior anti-tumor necrosis factor exposure. There are higher rates of induction of remission with biologics and with placebo in early CD, resulting in a treatment to placebo effect ratio that is similar across disease durations. No such relationships between disease duration and outcomes was found in UC. PROSPERO registration: CRD42018041961.

Agreement between local and central reading of endoscopic disease activity in ulcerative colitis: results from the tofacitinib OCTAVE trials

SummaryBackgroundEndoscopy is routine in trials of ulcerative colitis therapies.AimTo investigate agreement between central and local Mayo endoscopic subscore (MES) reads in the OCTAVE programmeMethodsFlexible sigmoidoscopy was performed in tofacitinib induction (OCTAVE Induction 1&2, NCT01465763 and NCT01458951), maintenance (OCTAVE Sustain, NCT01458574) and open‐label, long‐term extension (OCTAVE Open, NCT01470612) studies. Kappa statistics and Bowker's tests evaluated agreement/disagreement between centrally and locally read MES, with potential determinants of differences analysed by logistic regression.ResultsModerate‐to‐substantial agreement was observed between central and local reads at screening (77.1% agreement; kappa 0.62 [95% confidence interval 0.59‐0.66]), OCTAVE Induction 1&2 week (Wk) 8 (63.8%; 0.62 [0.59‐0.66]), OCTAVE Sustain Wk 52 (55.6%; 0.56 [0.50‐0.62]) and for induction non‐responders at OCTAVE Open month 2 (59.9%; 0.54 [0.48‐0.60]). Where disagreements occurred, local reads were systematically lower than central reads at OCTAVE Induction 1&2 Wk 8, OCTAVE Sustain Wk 52 and OCTAVE Open month 2 (Bowker's P < 0.0001); this difference was not observed at screening (P = 0.0852). Using multivariable logistic regression, geographical region, C‐reactive protein (Wk 8), partial Mayo score (Wk 8) and prior tumour necrosis factor antagonist failure were associated with disparity at OCTAVE Induction 1&2 Wk 8 (P < 0.05). In OCTAVE Induction 1&2 and OCTAVE Sustain, significantly higher proportions of patients endoscopic improvement, remission and endoscopic remission with tofacitinib vs placebo, using either central or local reads.ConclusionModerate‐to‐substantial agreement was observed between central and local endoscopic reads. Where disagreements occurred, local reads were systematically lower than central reads at most timepoints, suggesting potential bias.ClinicalTrials.gov identifier: NCT01465763, NCT01458951, NCT01458574, NCT01470612.

Emulation of a randomized controlled trial in ulcerative colitis with US and French claims data: Infliximab with thiopurines compared to infliximab monotherapy.

To understand the validity of real-world evidence (RWE) studies in ulcerative colitis (UC), we emulated the SUCCESS randomized controlled trial (RCT) on the effectiveness of infliximab plus thiopurines, using US and French healthcare insurance claims data. The SUCCESS trial showed improved remission with infliximab plus thiopurines combined compared to infliximab monotherapy in patients with UC. Based on two US commercial claims databases (IBM MarketScan and Optum) and the French nationwide health insurance database (SNDS) from 2004 through 2019, all patients with UC who initiated combination therapy or infliximab alone were identified. The primary outcome of treatment failure was emulated by: Hospitalization related to UC or colectomy, treatment switch to another biologic or immunosuppressant, or use of corticosteroids 16 weeks after infliximab initiation. We estimated risk ratios with 95% confidence intervals after 1:1 propensity score (PS) matching. Among 620 PS-matched pairs of combination therapy and infliximab monotherapy users, treatment failure occurred in 124 (20%) of patients initiating combination therapy and 170 (27%) during monotherapy. Like in SUCCESS, the risk of treatment failure was decreased with combination therapy in the overall cohort (RR=0.73; 95% CI: 0.60-0.90). Findings were consistent across MarketScan, Optum, and SNDS: RR=0.76 (0.57-1.02), 0.82 (0.54-1.24), and 0.61 (0.41-0.90). Similar results were observed for each component endpoint. RWE results across three large claims databases were consistent with RCT findings. These findings provide support for the use of RWE to assess treatment effectiveness in UC.

Systematic Review and Meta-Analysis: Clinical, Endoscopic, Histological and Safety Placebo Rates in Induction and Maintenance Trials of Ulcerative Colitis.

Quantifying placebo rates and the factors influencing them are essential to inform trial design. We provide a contemporary summary of clinical, endoscopic, histological and safety placebo rates in induction and maintenance clinical trials of ulcerative colitis, and identify factors influencing them. MEDLINE, EMBASE and the Cochrane library were searched from April 2014 to April 2020, updating a prior meta-analysis that searched from inception to April 2014. We included placebo-controlled trials of aminosalicylates, corticosteroids, immunosuppressives, small-molecules and biologics in adults with ulcerative colitis. Placebo rates were pooled using random-effects and mixed-effects meta-regression models to assess the associated study-level. In 119 trials [92 induction, 27 maintenance] clinical, endoscopic and histological remission placebo rates for induction trials were 11% (95% confidence interval [CI] 9-13%), 19% [95% CI 15-23%] and 15% [95% CI 11-19%], respectively; for maintenance trials, clinical and endoscopic placebo remission rates were 18% [95% CI 12-25%] and 20% [95% CI 15-25%], respectively. Higher endoscopic subscore and a higher rate of exposure to prior biologic therapy at enrolment were associated with lower clinical and endoscopic placebo remission rates. Absence of central reading was associated with an increase in placebo endoscopic response and remission rates. More follow-up visits and increasing trial duration were associated with higher clinical placebo rates. Placebo rates in ulcerative colitis trials vary according to the endpoint assessed, whether it is for assessment of response or remission, and whether the trial is designed for induction or maintenance. These contemporary rates across different endpoints and drug classes will help to inform trial design.

Fecal microbiota transplantation therapy in Crohn's disease: Systematic review.

The gastrointestinal microbiota is the key antigenic drive in the inflammatory bowel diseases. Randomized controlled trials (RCTs) in ulcerative colitis have established fecal microbiota transplantation (FMT) as an effective therapy. We have conducted a systematic review to evaluate the efficacy of FMT in Crohn's disease. A systematic literature search was performed through to August 2020 (MEDLINE; Embase). Studies were included if they reported FMT administration in patients with Crohn's disease, and reported on clinical outcomes. Fifteen studies published between 2014 and 2020, comprising 13 cohort studies and two RCTs, were included in the analysis. The majority of trials evaluated FMT for induction of remission, with follow-up duration varying from 4 to 52weeks. One RCT in 21 patients, of single-dose FMT versus placebo, following steroid-induced remission, showed a higher rate of steroid-free clinical remission in the FMT group compared to the control group: 87.5% vs 44.4% at week 10 (P=0.23). Another RCT, two-dose FMT in 31 patients, showed an overall clinical remission rate of 36% at week 8, however, with no difference in clinical or endoscopic endpoints between FMT administered by gastroscopy and colonoscopy. Considering all studies, the clinical response rates in early follow up were higher following multiple FMT than with single FMT. FMT dose did not appear to influence clinical outcomes, nor did whether FMT was fresh or frozen. FMT delivered via upper gastrointestinal route demonstrated higher early efficacy rates of 75 to 100% compared with lower delivery route rates of 30% to 58%, but on follow up beyond 8weeks, this difference was not maintained. Whether pre-FMT antibiotic administration was beneficial was not able to be determined due to the limited number of patients receiving antibiotics and varying antibiotic regimens. No serious adverse events were reported. Preliminary studies suggest that FMT may be an effective therapy in Crohn's disease. However large controlled trials are needed. No serious safety concerns have been identified.

Stable Gastric Pentadecapeptide BPC 157 and Wound Healing.

Significance: The antiulcer peptide, stable gastric pentadecapeptide BPC 157 (previously employed in ulcerative colitis and multiple sclerosis trials, no reported toxicity (LD1 not achieved)), is reviewed, focusing on the particular skin wound therapy, incisional/excisional wound, deep burns, diabetic ulcers, and alkali burns, which may be generalized to the other tissues healing. Recent Advances: BPC 157 has practical applicability (given alone, with the same dose range, and same equipotent routes of application, regardless the injury tested). Critical Issues: By simultaneously curing cutaneous and other tissue wounds (colocutaneous, gastrocutaneous, esophagocutaneous, duodenocutaneous, vesicovaginal, and rectovaginal) in rats, the potency of BPC 157 is evident. Healing of the wounds is accomplished by resolution of vessel constriction, the primary platelet plug, the fibrin mesh which acts to stabilize the platelet plug, and resolution of the clot. Thereby, BPC 157 is effective in wound healing much like it is effective in counteracting bleeding disorders, produced by amputation, and/or anticoagulants application. Likewise, BPC 157 may prevent and/or attenuate or eliminate, thus, counteract both arterial and venous thrombosis. Then, confronted with obstructed vessels, there is circumvention of the occlusion, which may be the particular action of BPC 157 in ischemia/reperfusion. Future Directions: BPC 157 rapidly increases various genes expression in rat excision skin wound. This would define the healing in the other tissues, that is, gastrointestinal tract, tendon, ligament, muscle, bone, nerve, spinal cord, cornea (maintained transparency), and blood vessels, seen with BPC 157 therapy.

Vedolizumab in Ulcerative Colitis and Crohn’s Disease-A Systematic Review

Background: Vedolizumab is a fully humanized monoclonal IgG-1 antibody that selectively inhibits the interaction between α4β7 integrin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1). It prevents lymphocyte translocation from the blood into the inflamed gut tissue, resulting in a reduction in local inflammation. Ulcerative colitis (UC) and Crohn’s disease (CD) are inflammatory conditions of the bowel affecting approximately 1.4 million people in the US. The efficacy of the drug was studied. Methods: The outcome measures for Phase 3 and randomized clinical trials in ulcerative colitis and Crohn’s disease, was as per GEMINI 1, 2, and 3 for its efficacy. Results: A total of 309 out of 499 reported vedolizumab AEs. In comparison with all other drugs, 3PRR signals were detected including joint-related symptoms like arthralgia, upper respiratory tract infections like nasopharyngitis and sinusitis, and upper respiratory tract symptoms like oropharyngeal pain. Among the vedolizumab-associated reports with serious outcomes, the drug was used for CD in 52.5% and UC in 27.4% compared with 86.1% and 13.9% for the anti-TNFs-associated reports. Although safety data from both these studies suggest VDZ is safe, larger studies with longer follow-up will be necessary to determine the potential risk for the development of PML. Conclusion: There is limited information on other potential confounders, such as co-morbidities, duration, and severity of disease, disease phenotype, surgical history, smoking, and concurrent IBD treatment. The benefit and risk profile of combining Vedolizumab with anti-TNF-α agents in the treatment of IBD will need to be examined. Vedolizumab is revolutionary in the community of inflammatory bowel disease, especially with the potential advantage for VDZ’s selectivity to the gastrointestinal immune system. Vedolizumab provides an alternate class to biologic therapy with an encouraging response and safety profile.

DOP05 Target engagement and pharmacodynamic biomarker analysis following treatment with the oral gut-targeted HIF-1α stabilizer GB004 in a Phase 1b trial in Active Ulcerative Colitis

Abstract Background Ulcerative colitis (UC) is characterized by the loss of epithelial barrier function and chronic mucosal inflammation. GB004 is an oral, gut-targeted, small molecule stabilizer of hypoxia inducible factor (HIF-1α) that promotes epithelial repair and function. A phase 1b study was conducted in patients with active UC where trends in clinical efficacy favoring GB004 were observed. Here we report the target engagement (TE) and pharmacodynamic (PD) biomarker analysis of colon biopsies and stool samples from the phase 1b study. Methods Subjects with active UC despite 5-ASA treatment were randomized 2:1 to GB004 120 mg solution or placebo (PBO) once daily for 28 days. Colon biopsies (sigmoid and rectum) and stool samples were collected at baseline and Day 28. HIF-1a and myeloperoxidase (MPO) immunohistochemistry was performed on formalin-fixed paraffin-embedded colon biopsies. Gene expression profiling (Affymetrix HTA 2.0) was performed on mRNA extracted from colon biopsies. Fecal calprotectin (FC) and secretory IgA (sIgA) were measured from stool samples. Results presented are overall means for baseline characteristics and differences in mean (HIF-1a, MPO) and median (FC, sIgA) percent change from baseline to Day 28 for GB004 vs PBO. Results Thirty-four subjects (age 45.4 years, Mayo score 7.5, sigmoid colon Mayo endoscopic subscore 2.2, sigmoid colon Robarts Histopathology Index 14.1) were randomized to a GB004 120 mg solution (n=23) or PBO (n=11) group. GB004 demonstrated evidence of TE, with an increase in the percent of HIF-1α positive cells (+11.4%) in sigmoid colon segment sections. Tissue and stool-based PD biomarkers of intestinal inflammation associated with lamina propria neutrophil infiltration and cytotoxicity measured by the MPO+ cell count per mm2 (-7.3%) and FC (-30.4%) levels decreased. Lastly, GB004 resulted in an increase in sIgA levels (+87.16%) and transcriptional changes consistent with enhanced epithelial integrity, such as increases in ITGA6 and TJP1. Conclusion In this phase 1b study, GB004, an oral gut-targeted HIF-1α stabilizer, demonstrated TE in the sigmoid colon and histologic, fecal biomarker, and transcriptional PD effects consistent with a reduction in inflammation and mucosal healing. These observations are consistent with the role of HIF-1α stabilization in improving barrier function in UC patients and support the trends in clinical effects observed, including histologic endpoints. A Phase 2 study of GB004 in patients with mild-to-moderate UC (SHIFT-UC, NCT04556383) is currently ongoing. Sponsored by GB004, Inc., a wholly owned subsidiary of Gossamer Bio, Inc.

P198 Practical deep learning tool for the scoring of ulcerative colitis disease activity in central reading

Abstract Background Central Reading Org.&amp; the pharma industry employ subject matter experts(SMEs)to score videos from sites participating in clinical trials for Ulcerative Colitis(UC).As we are developing Artificial Intelligence(AI)models for scoring purposes,we need to build a new software interface that can incorporate these AI models to aid SMEs,making their determination of the scores for each segment of the video &amp; for the video as a whole.We propose a system that reduces the time for SMEs to review &amp; score videos,improving the accuracy of scoring,with the help of our AI models. Methods We built a web-based interface supported by our AI models which can read,write multiple databases &amp; data stores to read &amp; display videos to be scored by a central reader, as well as the associated metadata required to improve the process.User interface shows a timeline with markers for the segments of the colon,with sections that are blurry,poorly prepped,or unscorable highlighted in different colours.While we could also highlight sections of the video with the precise score assigned to it by the AI,this would bias the central reader’s opinion.We hide the precise score generated by our AI models &amp; instead display 3 colours for low,medium or high disease activity.When a video is loaded to be read by the user,the playback marker is set to the first high disease activity section based on known medical indexes such as the Mayo Endoscopic Subscore(MES) &amp; UCEIS(Ulcerative Colitis Endoscopic Index of Severity),usually consists of a few seconds of video &amp; that video is played back continuously in a loop until the reader selects the appropriate score for that section.When the reader saves the section,the software immediately moves the video cursor to the highest scored section of the video.That way the central reader can review only the relevant portions of the video to confirm the score assigned to each segment.If the central reader’s scores do not align well with the AI scores then the software continues to show more sections of the video to the user,including sections it may have labeled as unscorable,that may be scorable. Results The review of the system by 3 key opinion leaders,user experience was positive.Not only does the system allow the reader’s attention to be more efficiently used,but the interface allows both AI &amp; central reader scores to be saved,allowing for the latter to be used iteratively to re-train &amp; improve the underlying AI model(s).Our tool was also used by a gastroenterologist specialist in order to perform video quality assessment &amp; colon sections scoring. Conclusion We developed an AI tool that can be used to improve the efficiency &amp; accuracy of the central reading process in clinical trials for UC.Further work is ongoing to improve the interface.

ID: 3527087 PRACTICAL DEEP LEARNING TOOL FOR SCORING OF ULCERATIVE COLITIS DISEASE ACTIVITY IN CENTRAL READING

Central Reading Organizations & the pharma industry employ subject matter experts (SMEs)to score videos received from sites participating in clinical trials for Ulcerative Colitis(UC).We are developing one or more Artificial Intelligence (AI) models for the purposes of scoring such videos, there is a need to build a new software interface that can incorporate the AI models to aid SMEs in scoring the video. We propose a system that radically reduces the time it takes for central readers to score videos, with help of our AI models.

Efficacy and safety of biophenol-rich nutraceuticals in adults with inflammatory gastrointestinal diseases or irritable bowel syndrome: A systematic literature review and meta-analysis.

AimBiophenol‐rich nutraceuticals may be an adjuvant treatment for Crohn's disease (CD), ulcerative colitis (UC), symptomatic uncomplicated diverticular disease (SUDD), and irritable bowel syndrome (IBS). This systematic review and meta‐analysis aimed to determine the efficacy and safety of biophenol‐rich nutraceutical supplementation on CD, UC, SUDD, and IBS on gastrointestinal symptoms (GIS), quality of life (QoL), inflammatory and oxidative stress biomarkers, and adverse events compared to usual care or placebo.MethodsPubMed, Embase, CINAHL, and CENTRAL were searched for randomised controlled trials until 27 April 2020. Outcomes were GIS, inflammatory and oxidative stress markers, QoL, and adverse events. The Cochrane Risk of Bias tool and GRADE were used to appraise studies. Data were pooled using Revman.ResultsTwenty‐three trials in CD, UC, and IBS patients were included. Compared with placebo, biophenol‐rich nutraceuticals improved GIS (SMD: 0.43 [95%CI: 0.22, 0.63]; GRADE: very low) in UC, CD, and IBS participants. In UC and CD participants, biophenol‐rich nutraceuticals improved CRP by 1.6 mg/L [95%CI:0.08, 3.11; GRADE: low], malondialdehyde by 1 mmol/L [95%CI:0.55, 1.38; GRADE: low]; but only resveratrol improved QoL (SMD: −0.84 [95%CI: −1.24, −0.44; GRADE: high). Resveratrol (for UC and CD participants) and peppermint oil (for IBS participants) had greater certainty in the evidence for improving GIS and QoL (GRADE: moderate to high). There was no effect on adverse events (P > .05).ConclusionsBiophenol‐rich nutraceuticals may be an effective and safe adjuvant treatment for the management of CD, UC, and IBS; with higher certainty of evidence for resveratrol for UC and CD and peppermint oil for IBS.