Introduction

Tyrosine kinase 2 (TYK2) mediates cytokine signalling in immune-mediated inflammatory diseases, including Crohn’s disease (CD). Zasocitinib (TAK-279) is a highly selective, oral, allosteric TYK2 inhibitor with efficacy and acceptable safety shown in patients with psoriasis and psoriatic arthritis.^1,2 This phase 2b study (NCT06233461) aims to assess the efficacy and safety of zasocitinib in patients with moderately to severely active CD.

Aims & Methods

This is a multicentre, randomized, double-blind induction, placebo-controlled, dose-ranging, treat-through study in patients (18–75 years) with moderately to severely active ileal, ileocolonic or colonic CD (CD Activity Index [CDAI] score 220–450 and ulcerations characteristic of CD defined by ileocolonoscopy at screening and Simple Endoscopic Score for CD [SES-CD] ≥6 or ≥4 for isolated ileitis). Eligible patients must have inadequate/loss of response or intolerance to ≥1 of oral aminosalicylates, corticosteroids, immunosuppressants, biologics, JAK inhibitors (JAKi) or sphingosine-1-phosphate (S1P) receptor modulators. Patients who have also failed <3 classes of advanced therapies will be included. After screening (30 days), approximately 268 patients will be randomized 1:1:1:1 to receive low-, medium- or high-dose zasocitinib or placebo orally once daily for 12 weeks (induction phase), followed by a 40-week maintenance period and a 4-week safety follow-up. At or after Week 12, patients receiving placebo with disease worsening based on PRO2 score will receive active zasocitinib treatment. Study doses are expected to provide ≥90% TYK2 inhibition over the 24-hour dosing interval, and were associated with efficacy in preclinical models.³ Randomization will be stratified based on previous biologic, JAKi or S1P receptor modulator therapies, and steroid use at baseline. The number of patients who received previous biologic, JAKi, S1P receptor modulator, anti-interleukin (IL)-23p19 or anti-IL-12/23p40 therapy will be capped.
Primary endpoint analysis will be conducted using a Cochran–Mantel–Haenszel (CMH) test. Binary secondary endpoints will be analysed similarly to primary endpoints. Longitudinal continuous secondary endpoints up to Week 12 will be analysed using a mixed-effects model with repeated measures. Safety data will be presented by treatment group and assessment period.

Results

The study is actively enrolling with the first patient randomized in March 2024. An open-label extension is planned for zasocitinib responders. The primary efficacy endpoint is the achievement of endoscopic response at Week 12 (>50% decrease in SES-CD from baseline [for patients with isolated ileal disease: SES-CD ≤4 or ≥2-point reduction]). Secondary efficacy endpoints at Week 12 include: clinical remission (CDAI <150), clinical response (CDAI reduction from baseline of ≥100), endoscopic remission (SES-CD ≤4 or ≤2 for patients with ileal disease, no subscore >1), patient-reported symptoms and disease-specific health-related quality of life (HRQoL). Safety and tolerability will be assessed by treatment-emergent adverse events (AEs), serious AEs and AEs of special interest throughout the study. Intestinal ultrasound measurements, using the International Bowel Ultrasound Segmental Activity Score (IBUS-SAS), will be assessed at Weeks 4, 12 and 52 in a subset of patients.

Conclusion

Alongside evaluating the efficacy and safety of zasocitinib in patients with moderately to severely active CD, this unique 52-week treat-through study design will assess the impact of treatment on HRQoL, an area of significant unmet need in this population.

References

1. Armstrong A et al. AAD 2023.
2. Kivitz A et al. Arthritis Rheumatol 2023;75(Suppl 9).
3. Kong KF et al. J Crohns Colitis 2024;18(Suppl 18).

Disclosure

VJ has received: consulting/advisory board fees from AbbVie, Alimentiv, Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris, AstraZeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Genentech, Gilde Healthcare, Gilead, GlaxoSmithKline, Innomar, JAMP, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Prometheus Biosciences, Protagonist, Reistone Biopharma, Roche, Roivant, Sandoz, Second Genome, Sorriso, Synedgen, Takeda, TD Securities, Teva, Topivert, Ventyx and Vividion; and speaker fees from AbbVie, Bristol Myers Squibb, Ferring, Fresenius Kabi, Galapagos, Janssen, Pfizer, Shire and Takeda. VG, LZ, VN, OA, AND, FN, TF, LS and NS are employees and equity holders of Takeda.

Introduction

Urgency is not an IBD Patient Reported Outcome (PRO) in the STRIDE II but it has been assessed at baseline and as an outcome measure in recent pivotal RCTs with newer biologicals and targeted synthetic small molecules in both Crohn’s disease CD) and ulcerative colitis (UC). However, although it is reasonable to assume that UC patients or CD patients with rectal involvement may complain for severe urgency, urgency has been assessed even in patients with Crohn’s ileitis (iCD).

Aims & Methods

The aim of this study was to assess whether urgency is reported by iCD patients with flares or quiescent disease in a Real-World (RW) setting. This prospective, pilot, RW study included CD patients with solely L1 phenotype. L1 location was documented by ileocolonoscopy, histology and, imaging (MRE, US, or capsule endoscopy). Patients with colonic and/or rectal disease, perianal involvement and complicated ileal disease were excluded. Patients were interviewed by office visits during disease flare [HBI>5, CRP <5mg/dl, faecal calprotectin (FC)>250μg/g faecal tissue and SES-CD for terminal ileum >3 if colonoscopy was performed within a month prior to the visit) and during clinical remission (HBI<5, CRP <5mf/dl and FC <200μg/g and ileal SES-CD=0, in a recent ileocolonoscopy). The presence of and severity of urgency was recorded by a Symptom Rating Score of 0-10 (absent to very severe). The presence and severity of abdominal pain, the number and consistency of stools, nocturnal stools, blood and/or mucus in the stools, and the feeling of inadequate evacuation were sought by a structed questionnaire.

Results

During a 15-month period, 85 iCD patients [45 males, median age (range) 33 (18-65) years, median (range) disease duration 9 (0.6-25) years] were enrolled in the study. Patients were receiving a wide range of treatments, including anti-TNF agents (n=35), ustekinumab (N=25), vedolizumab (N=5), azathioprine (n=10), budesonide (n=5) and mesalazine (n=15). Fifty patients had a flare, 65 were in remissionand 30 patients were interviewed sequentially in flare and remission of disease. All patients in disease flare reported abnormal classical PROs of CD. Moderate to severe urgency [median score 5, range 4-8] was reported by 5/50 (10%) patients with disease flare, 8/65 (12%) patients with disease remission and 2/30 (6.5%) patients who were interviewed during flare and remission of disease. 3/50 patients with urgency during a flare of CD did not report urgency during disease remission. Six of the 8 patients who were interviewed only with iCD in remission and reported urgency had concurrently typical Irritable Bowel Symptoms (IBS, abdominal pain relieved by defecation, alternating diarrhoea/constipation, inadequate bowel emptying).

Conclusion

This prospective, pilot, real-world study shows that the reliability of urgency as classical PRO in patients with iCD is questioned and raises doubts whether urgency should be included in the spectrum of PROs for patients with iCD both in RCTs and in RW studies. Validation of the terminology in different ethnic languages may also pose additional barriers in patient understanding and reporting the symptom in the presence of additional IBS-type symptoms. Large studies are needed to assess if urgency is present in patients with iCD and how reliably is reported especially in multinational RCTs.

Disclosure

Dr GJ Mantzaris: Research grants: AbbVie, Genesis, Merck Sharp & Dohme, Takeda; advisor/speaker: AbbVie, Aenorasis, Dr Falk, Ferring, Hospira, Janssen, Merck Sharp & Dohme, MYLAN, Pfizer, Takeda, Vianex.
Dr A Loukou: Nothing to declare

Introduction

This study aimed to analyze the correlation between different attributes of doctors who prescribe colonoscopies and the cleanliness of the intestine to guide the development of colonoscopy application protocols.

Aims & Methods

Data on colonoscopy cases conducted in the gastroenterology department of Hangzhou First People's Hospital between April 2018 and March 2021 were collected. The gender, age, professional attributes of the prescribing doctors, and Boston Bowel Preparation Scale (BBPS) score were recorded. In addition, the correlation between the prescribing doctors' characteristics and the intestine's cleanliness was analyzed.

Results

The study included 22,522 patients with a mean BBPS score of 6.83±1.94. There were 16,459 male and 6,063 female doctors with similar BBPS scores (P = 0.212). The study found no significant difference in BBPS scores between 19,338 physicians and 3,184 non-physicians (P = 0.154). However, BBPS scores differed significantly between 18,168 gastroenterologists and 4,354 non-gastroenterologists (P = 0.016) and between 19,990 intestinal-related specialties and 2,532 non-intestinal-related specialties (P = 0.000). In addition, BBPS scores were significantly different between 18,126 prescribing doctors with colonoscopy ability and 4,352 without (P = 0.014). However, there was no significant difference in BBPS scores among doctors of different ages (P = 0.190). The study found significant differences in BBPS scores between male and female patients and those under or over 40 years (P = 0.000).

Conclusion

To improve colonoscopy preparation quality, priority should be given to doctors in gastroenterology, intestinal-related specialties, and with colonoscopy operation ability. Their expertise may result in better education and improved bowel cleanliness.

Clinical Case Summary

EUS-BD is an alternative therapeutic approach in case of unsuccessful biliary drainage by ERCP (1,2). Our aim is to report another possible indication of EUS-BD as a salvage treatment in a case of post-ERCP perforation around the papilla.
This is a case-report of a 79-years-old woman admitted for obstructive jaundice with bilirubin levels of 18 mg/dL. A MRI displayed marked dilation of intrahepatic bile ducts, gallbladder and choledochus (18-mm) until its distal part where and abrupt stop and a regular stricture was observed. An ERCP failed to cannulate the common bile duct. After a precut procedure, retroperitoneal extravasation of the contrast was observed. After consultation with the surgical team and fully information to the family of the patient about therapeutic alternatives, an EUS-BD was performed immediately after the ERCP as a therapeutic approach aiming to treat simultaneously the perforation and the obstructive jaundice without delay.
EUS-BD was performed according to the standardized technique with a transgastric approach. The intrahepatic bile duct was puncture with a 19-gauge needle. A 0.025” guide-wire was inserted and the fistula was created using a 6French cystostome with pure current. After exchanging the guide-wire for another of 0.035” and passing it to the duodenum, a 6-cm long, fully-covered metal stent was deployed at the stricture as antegrade fashion.
A further CT-scan displayed no collections with decreasing of the bile duct dilation. The clinical outcome of the patient was uneventful, being discharged one-week after the EUS-BD.
One month later, a scheduled pancreaticoduodenectomy was performed. The surgical specimen showed a 4-mm wide distal cholangiocarcinoma.
EUS-BD with fully-covered metal stenting was effective to both drainage and covering perforation site. EUS-BD could be deemed as another potential indication in selected cases as an immediate rescue therapy after ERCP adverse events such as perforation.

References

Nakai Y, Isayama H, Wang HP, Rerknimitr R, Khor C, Yasuda I, et al. International consensus statements for endoscopic management of distal biliary stricture. J Gastroenterol Hepatol. 2020;35(6):967-79.
Huh G, Park DH. EUS-guided transhepatic biliary drainage for next-generation ERCPists. Gastrointest Endosc. 2022;95(3):452-4.

Disclosure

Rafael Romero-Castro is consultant to Cook Medical since February 28th, 2023.

Introduction

Terminal ileitis is the endoscopic manifestation of a wide range of diseases: inflammatory, infectious, vasculitic, ischemic, drug-induced and malignancy. When it comes to asymptomatic terminal ileitis, it is incidentally found on screening ileo-colonoscopy. The prevalence of this entity was not well established and is found in few studies with heterogenous results.

Aims & Methods

We conducted this study to define the prevalence and histopathologic characteristics of asymptomatic terminal ileitis. This is a cross-sectional study. The study population is composed of all the patients that underwent a colonoscopy between September 2020 and March 2023. Selection bias were avoided by excluding patients with inflammatory bowel disease (IBD), sacroiliitis, chronic diarrhea, elevated calprotectin, medical history of ileitis diagnosed either on previous colonoscopy or on imaging showing wall thickening, and those with altered anatomy (colectomy with ileo-colic anastomosis).

Results

A total of 3901 colonoscopies were realized in a single center between September 2020 and March 2023; 3035 met our inclusion criteria based on medical history and the indication of the colonoscopy that excluded the above-mentioned reasons. Ileal intubation was performed in 91.4% (n=2773) of these cases, representing the final study population. Terminal ileitis was found in 5% (n=139) of patients, of whom 58.3% (n=81) were men and 41.7% (n=58) were women. The median age at diagnosis was 50 and and the mean age was 49.43 +/-15.5. The three main indications for colonoscopy were: colorectal cancer screening in 57.5% (n=80) of cases, gastrointestinal red flag symptoms including bleeding, anemia, and weight loss in 28.8% (n=40) of cases, and abdominal pain in 13.7% (n=19) of cases. Biopsies were performed in 90.6% (n=126) of ileo-colonoscopies and showed, regardless of the indication, normal histology, erosive and ulcerated ileitis, and non specific and other findings in 12.7% (n=16), 36.5% (n=46) and 44.4% (n=56) of samples respectively. Definitive Crohn’s disease diagnosis was found in 5.75% (n=8) of asymptomatic ileitis patients.

Conclusion

The prevalence of asymptomatic terminal ileitis was 5% in our population. This finding was not associated with the indication of the colonoscopy, namely colorectal cancer screening, gastrointestinal red flag symptoms including bleeding, anemia, and weight loss and abdominal pain. The clinical significance of this finding requires longitudinal follow-up studies to assess the incidence of IBD or other conditions.

Introduction

The precise aetiology of inflammatory bowel disease (IBD) remains unclear with excess intestinal cell death implicated yet vastly understudied. Necroptosis, a recently described lytic cell death pathway, is emerging as a key player in intestinal inflammation in mouse models of colitis (1, 2), however clinical data are sparse. This non-apoptotic regulated cell death can be initiated by tumour necrosis factor (TNF) receptor activation and is executed by a core axis of proteins, including receptor-interacting protein kinase (RIPK) -1 and -3, and mixed lineage domain-like pseudokinase (MLKL) independent of caspases (3). The pathway is usually repressed by cellular inhibitor of apoptosis protein (cIAP) -1 and -2, and cellular FLICE-like inhibitory (cFLIP_L).
This project proposes the first study to comprehensively assess programmed cell death in intestinal tissue of adult patients with IBD using a novel toolbox of affinity reagents (4). By comparing this with non-inflamed control tissue, we have uncovered a new molecular defect in IBD: loss of essential cellular death brakes, even in tissue with apparent mucosal and histologic healing. This novel finding may underpin the vicious cycle of remission and disease relapse and poses a step towards molecular healing through restoration of these brakes.

Aims & Methods

Aims:

1. Assess cell death prevalence in IBD
2. Determine why cell death brakes disappear in intestinal IBD tissue, regardless of inflammatory status
3. Determine whether IBD phenotypes can be uniquely profiled according to cell death signals

Methods: Matched intestinal biopsies are retrieved endoscopically from patients without IBD (healthy controls) and those with IBD. Patients requiring endoscopy as part of standard of care are screened for eligibility: exclusion criteria comprise active malignancy, non-IBD inflammation, infection, use of non-steroidal anti-inflammatory drugs, and polyposis syndromes. Biopsies from participants with IBD are taken from macroscopically non-inflamed, margin and inflamed areas. Control specimen are taken from healthy-appearing bowel. Specimen are collected fresh for investigation of pertinent targets (Table 1). Clinical/endoscopy activity indices, biochemical markers (C-reactive protein, faecal calprotectin) and blinded histologic (Robarts Histopathology Index) scoring are correlated with laboratory data in a multi-parametric manner.

MEDIUM	TECHNIQUE	PURPOSE
Phosphate buffer system + protease + phosphatase inhibitors	Immunoblotting	Protein quantification of 26 cell death-related proteins
10% formalin	Immunohistochemistry	Visualisation of 12 cell death-related markers
Methanol + 5% acetic acid	Immunofluorescence	Optic microscopy of necroptosis hot-spots
RNA later	RNA sequencing	Shotgun transcriptomics of host microbiome, immune and inflammatory infiltrates
Dulbecco's Modified Eagle Medium: Nutrient Mixture F12 (DMEM F12) + Primocin	Organoid development	Gut organoid challenges to identify factors impacting cell death

Results

Intestinal biopsies from 28 healthy controls and 52 patients with IBD: 25 UC; 25 CD; and 2 pouchitis have been collected. Interim analysis demonstrates suppression of cell death inhibitory proteins- cIAP-1, -2 and cFLIP_L even in non-inflamed tissue in patients with IBD, unleashing apoptosis (hallmarked by a statistically significant increase in cleaved caspase-3) and/or necroptosis (hallmarked by statistically significant increases in phosphorylated RIPK-3) in nearby tissue.

Conclusion

For the first time, we demonstrate that cellular death brakes are removed in intestinal tissue in IBD, despite histologic remission. Our findings challenge current dogma that necroptosis occurs in the absence of apoptosis and that necroptosis is universally increased in all forms of IBD. Disinhibition of programmed cell death is likely intrinsic to the inflammatory sequence underlying disease recurrence and progression.

References

1. Günther C, Martini E, Wittkopf al. Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis. Nature. 2011 Sep 14;477(7364):335-9
2. Patankar JV, Müller TM, Kantham S et al. E-type prostanoid receptor 4 drives resolution of intestinal inflammation by blocking epithelial necroptosis. Nature Cell Biology. 2021 Jul;23(7):796-807
3. Horne CR, Samson AL, Murphy JM. The web of death: the expanding complexity of necroptotic signaling. Trends in Cell Biology. 2023 Feb;33(2):162-174
4. Samson AL,Fitzgibbon C, Patel KM et al. A toolbox for imaging RIPK1, RIPK3, and MLKL in mouse and human cells. Cell Death & Differentiation. 2021 Jul;28(7):2126-2144

Disclosure

AHA is supported by scholarships from the University of Melbourne/Australian Commonwealth Government, Crohn's and Colitis Australia, Avant Foundation, and a grant from the Gastroenterological Society of Australia and Celltrion Healthcare. ALS has received funding from the National Health and Medical Research Council (Grant 2002965). JMM has received funding from the National Health and Medical Research Council (Grants 1172929, 9000719). ALS and JMM contribute to a project developing necroptosis inhibitors with Anaxis Pharma Pty.