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ISM5411, A NOVEL GUT-RESTRICTIVE PROLYL HYDROXYLASE-2 INHIBITOR FOR INFLAMMATORY BOWEL DISEASE: RANDOMIZED, DOUBLE-BLINDED, PLACEBO-CONTROLLED FIRST-IN-HUMAN PHASE I STUDY TO EVALUATE SAFETY, TOLERABILITY AND PK PROFILES

Hanyang Li 1, Carol Satler 2, Heng Zhao 1, Yunxuan Jiang 1, Yuan Lv 1, Sujata Rao 2, Feng Ren 1, Alex Zhavoronkov 3

Affiliations

1 Insilico Medicine Ltd, Shanghai, China

2 Insilico Medicine US Inc., Boston, Cambridge MA, United States

3 Insilico Medicine AI Limited, Abu Dhabi, United Arab Emirates|||Insilico Medicine Ltd, Shanghai, China

Summary

AI Generated

ISM5411, an oral gut-restrictive PHD2 inhibitor designed to stabilize HIF-1α and protect intestinal mucosal barrier, demonstrated safety and tolerability in a first-in-human Phase I study in 76 healthy subjects across single doses of 50-1000 mg and multiple doses of 200-800 mg daily for 14 days.

No serious adverse events or deaths occurred; one Grade 1 rectal hemorrhage led to discontinuation in the 200 mg cohort but was judged unrelated to ISM5411, and all other treatment-emergent adverse events in ISM5411 groups were Grade 1
ISM5411 was rapidly absorbed and metabolized to ISM5411-M15 with very low plasma exposure and more than 30% fecal excretion in prototypic form, demonstrating the intended gut-restrictive pharmacokinetic profile
Systemic erythropoietin levels increased post-dose then decreased with most changes within normal range, and no clear trend was observed in systemic VEGF levels across cohorts
ISM5411 is advancing to a Phase 2a proof-of-concept study in ulcerative colitis patients to evaluate safety, pharmacokinetics, and clinical efficacy following completion of Phase I studies in Australia and China

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Abstract

Introduction

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disease characterized by intestinal inflammation, mainly including Crohn’s Disease (CD) and Ulcerative Colitis (UC), both of which will cause swelling and ulceration in the inner wall of gastrointestinal tract ^[1]. ISM5411 is an oral gut-restrictive small molecule inhibitor targeting PHD2 to stabilize hypoxia inducible factors (HIF-1α), thus promoting the expression of intestinal mucosal protective genes, maintaining the integrity and functions of intestinal barrier to finally achieve the purpose of protecting and repairing intestinal mucosal barrier together with anti-inflammation. Preclinical studies demonstrated that ISM5411 can significantly alleviate the symptoms of multiple animal models of colitis without significant increase in systemic erythropoietin (EPO) or vascular endothelial growth factor (VEGF) ^[2]. The first-in-human Phase I study in Australia was completed to evaluate safety, tolerability, pharmacokinetics and food effect in healthy subjects.

Aims & Methods

ISM5411-101 was a randomized, double-blinded, placebo-controlled, single and multiple-dosed and food effect first-in-human Phase I study conducted in healthy subjects at a single site in Australia. Seven dose levels from 50 mg to 1000 mg of single ascending doses and three dose levels from 200 mg to 800 mg once daily for 14 days of multiple doses of ISM5411 were administrated. Safety and tolerability, pharmacokinetics (PK) parameters (plasma, urine and feces) and biomarkers (EPO and VEGF levels) were evaluated.

Results

Seventy-six subjects were dosed with no serious adverse events (SAEs) or deaths recorded. One treatment emergent adverse event (TEAE) leading to discontinuation of ISM5411 occurred (Grade 1, rectal hemorrhage) in 200 mg once daily ISM5411 cohort was reported and judged as not related to ISM5411. The incidence of TEAEs was 25.0% and 55.0% in ISM5411 pooled cohort (n=56) and placebo cohort (n=20). All TEAEs reported in ISM5411 pooled cohorts were Grade 1. After single and multiple doses administration, ISM5411 was rapidly absorbed and metabolized to metabolite (ISM5411-M15). The plasma exposure of both analytes was very low without apparent dose-proportional manner. ISM5411 was excreted in the feces in its prototypic form by more than 30%. Systemic EPO level increased post-dose in most cohorts then decreased, and most changes were within normal range. No clear trend was observed in the change of mean systemic VEGF levels across cohorts.

Conclusion

ISM5411 tablets were safe and well-tolerated and demonstrated good gut-restrictive property, consistent with the intended PK profile. Another Phase I study in China was also completed. Phase 2a proof of concept study of ISM5411 is under planned in patients with ulcerative colitis to explore the safety, PK and clinical efficacy.

References

Chang JT. Pathophysiology of Inflammatory Bowel Diseases. N Engl J Med, 2020 Dec 31;383(27): 2652-2664
Fu, Y., Ding, X., Zhang, M. et al. Intestinal mucosal barrier repair and immune regulation with an AI-developed gut-restricted PHD inhibitor. Nat Biotechnol (2024).

Conference

UEG Week Berlin 2025

Topics

IBD

Submission format

Abstract

Session

Intestinal epithelial functions in IBD (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

The use of the modified Aldrete score for the assessment of recovery after gastrointestinal endoscopy

Eleni Kyvelou

TARGETED PHAGE INTERVENTION IMPROVES BACTERIAL-DRIVEN COLITIS AND RESPONSE TO TOPICAL CORTICOSTEROIDS BY ATTENUATING VIRULENCE OF CROHN’S DISEASE-ASSOCIATED BACTERIA

Elena Verdu

NEW PATHOGENIC MUTATIONS IN AN EPITHELIAL JUNCTION GENE CONTRIBUTING TO VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE

Siyan Cao

Interfering substances effect endoscope reprocessing

Annette Rittich

THERAPEUTIC AND HOSPITALISATION OUTCOMES AFTER FIRST-LINE ANTI-TNF IN INFLAMMATORY BOWEL DISEASE: INSIGHTS FROM THE EPITHERA STUDY USING DATA FROM THE FRENCH NATIONAL HEALTH DATA (SNDS)

Lucine Vuitton

AFIMKIBART (ANTI-TL1A) IS EFFECTIVE IN THE BLOCKADE OF CELLULAR SIGNALING INDUCED BY ACTIVE TL1A

Vishnu Mohanan

UEG Presentation

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The use of the modified Aldrete score for the assessment of recovery after gastrointestinal endoscopy

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The use of the modified Aldrete score for the assessment of recovery after gastrointestinal endoscopy

Eleni Kyvelou 1

Affiliations

1 None, None, Greece

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Abstract

Event

UEG Week Berlin 2025

Topics

Nurses

Session

Patient care: Differences matter

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

The use of the modified Aldrete score for the assessment of recovery after gastrointestinal endoscopy

Eleni Kyvelou

TARGETED PHAGE INTERVENTION IMPROVES BACTERIAL-DRIVEN COLITIS AND RESPONSE TO TOPICAL CORTICOSTEROIDS BY ATTENUATING VIRULENCE OF CROHN’S DISEASE-ASSOCIATED BACTERIA

Elena Verdu

NEW PATHOGENIC MUTATIONS IN AN EPITHELIAL JUNCTION GENE CONTRIBUTING TO VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE

Siyan Cao

Interfering substances effect endoscope reprocessing

Annette Rittich

THERAPEUTIC AND HOSPITALISATION OUTCOMES AFTER FIRST-LINE ANTI-TNF IN INFLAMMATORY BOWEL DISEASE: INSIGHTS FROM THE EPITHERA STUDY USING DATA FROM THE FRENCH NATIONAL HEALTH DATA (SNDS)

Lucine Vuitton

AFIMKIBART (ANTI-TL1A) IS EFFECTIVE IN THE BLOCKADE OF CELLULAR SIGNALING INDUCED BY ACTIVE TL1A

Vishnu Mohanan

UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

TARGETED PHAGE INTERVENTION IMPROVES BACTERIAL-DRIVEN COLITIS AND RESPONSE TO TOPICAL CORTICOSTEROIDS BY ATTENUATING VIRULENCE OF CROHN’S DISEASE-ASSOCIATED BACTERIA

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TARGETED PHAGE INTERVENTION IMPROVES BACTERIAL-DRIVEN COLITIS AND RESPONSE TO TOPICAL CORTICOSTEROIDS BY ATTENUATING VIRULENCE OF CROHN’S DISEASE-ASSOCIATED BACTERIA

Kyle Jackson 1, Heather Galipeau 2, Amber Hann 2, Marco Constante 2, Megan Zangara 3, Alexandra Fuentas 2, Chiko Shimbori 2, Premysl Bercik 2, Brian Coombes 3, Zeinab Hosseinidoust 1, Elena Verdu 2

Affiliations

1 McMaster University, Hamilton, Canada|||Farncombe Family Digestive Health Research Institute, Hamilton, Canada

2 Farncombe Family Digestive Health Research Institute, Hamilton, Canada

3 McMaster University, Hamilton, Canada

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Abstract

Introduction

Current therapies for inflammatory bowel disease (IBD) suppress inflammation rather than inhibiting underlying microbial drivers. Treatment failures of frontline interventions, including corticosteroids, can lead to dose escalation and risk of adverse effects.^1,2 Bacteria with pro-inflammatory potential, like adherent-invasive Escherichia coli (AIEC), have been postulated as a possible microbial driver in Crohn’s disease (CD), however, targeting these bacteria with precision in IBD remains challenging.^3,4 Most antibiotics have broad-spectrum activity and disturb the background microbiome, which may exacerbate inflammation.⁵ Attention has shifted towards bacteriophages, yet their underlying mechanisms of treating IBD, and how they may work as an adjunctive therapy, remains elusive.

Aims & Methods

We aimed to assess whether and how phage therapy, specific for a CD-associated bacterium, reduces colitis severity using gnotobiotic mouse models.
In vitro kill curves and biofilm challenges were used to identify lytic phage candidates. Adult germ-free C57BL/6 mice were colonized with altered Schaedler-flora (ASF) and E. coli NRG857c (NRG), a CD-associated isolate. After 3 weeks, mice were treated with an NRG-specific lytic phage (1x10⁹ PFU/dose; daily or TIW) or vehicle (PBS) for 2 weeks (n=6/group) and then exposed to 1 cycle of dextran sulfate sodium (2%; DSS) in drinking water. PBS-treated mice (n=6) not exposed to DSS served as controls. Phage treatment was also tested in a spontaneous model of colitis using C57BL/6NTac-Il10^em8Tac (IL-10^-/-) mice, treated weekly. Mice were monitored daily for weight, stool consistency, and occult blood. Fecal contents were cultured to determine bacterial load, and the expression of NRG fimS was quantified using qPCR as an assessment of virulence. At endpoint, colon tissues were collected for histological and immunohistochemistry analysis to quantify colitis severity and NRG infiltration, respectively. Additional C57BL/6 mice were colonized and treated as previously described. During colitis induction, mice received a low-dose of budesonide (2μg/day)⁶ (n=5) or vehicle (n=5) until endpoint. Mice were monitored daily for disease activity and colon tissues were collected for histological analysis. HPLC was used to determine active budesonide levels.

Results

HER259 was identified as a lytic phage against CD-associated AIEC NRG. In ASF and NRG colonized mice, HER259 reduced clinical symptoms (p< 0.001, p< 0.001) and histological scores (p< 0.0001, p< 0.001) in chemical induced and spontaneous colitis, respectively. A 1-log reduction in NRG bacterial load was observed in HER259-treated mice (p< 0.001). Reisolated NRG exhibited a reduced FimS ON/OFF ratio (p-value < 0.01). Immunohistochemistry revealed reduced infiltration of NRG into the lamina propria following HER259 treatment, with greater accumulation in the epithelium. HER259 treatment increased the efficacy of a sub-therapeutic dosing regimen of budesonide (p< 0.001), which was independent of microbial-based drug metabolism as determined by HPLC.

Conclusion

Our results demonstrate that lytic phage targeting a CD-associated bacterium attenuates colitis in two gnotobiotic mouse models. The intervention did not lead to complete eradication of the disease-driving agent, but instead modulated bacterial virulence mechanisms and enhanced responses to corticosteroid therapy. The data suggests that alternative mechanisms should be considered when translating phage therapy to treat IBD in clinical trials.

References

1. Yan, Y. et al. Commensal bacteria promote azathioprine therapy failure in inflammatory bowel disease via decreasing 6-mercaptopurine bioavailability. Cell Rep Med 4, 101153 (2023).
2. Nagayama, M., Gogokhia, L. & Longman, R. S. Precision microbiota therapy for IBD: premise and promise. Gut Microbes 17, 2489067 (2025).
3. Darfeuille-Michaud, A. et al. High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn’s disease. Gastroenterology 127, 412–421 (2004).
4. A, D.-M. et al. Presence of adherent Escherichia coli strains in ileal mucosa of patients with Crohn’s disease. Gastroenterology 115, 1405–1413 (1998).
5. Nelson, R. L., Suda, K. J. & Evans, C. T. Antibiotic treatment for Clostridium difficile-associated diarrhoea in adults. Cochrane Database Syst Rev 3, (2017).
6. Bercik, P. et al. Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice. Gastroenterology 139, (2010).

Event

UEG Week Berlin 2025

Topics

Gut Microbiota IBD

Submission format

Abstract

Session

New tales of the gut microbiome: From profiling to new therapies

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

The use of the modified Aldrete score for the assessment of recovery after gastrointestinal endoscopy

Eleni Kyvelou

TARGETED PHAGE INTERVENTION IMPROVES BACTERIAL-DRIVEN COLITIS AND RESPONSE TO TOPICAL CORTICOSTEROIDS BY ATTENUATING VIRULENCE OF CROHN’S DISEASE-ASSOCIATED BACTERIA

Elena Verdu

NEW PATHOGENIC MUTATIONS IN AN EPITHELIAL JUNCTION GENE CONTRIBUTING TO VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE

Siyan Cao

Interfering substances effect endoscope reprocessing

Annette Rittich

THERAPEUTIC AND HOSPITALISATION OUTCOMES AFTER FIRST-LINE ANTI-TNF IN INFLAMMATORY BOWEL DISEASE: INSIGHTS FROM THE EPITHERA STUDY USING DATA FROM THE FRENCH NATIONAL HEALTH DATA (SNDS)

Lucine Vuitton

AFIMKIBART (ANTI-TL1A) IS EFFECTIVE IN THE BLOCKADE OF CELLULAR SIGNALING INDUCED BY ACTIVE TL1A

Vishnu Mohanan

UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

NEW PATHOGENIC MUTATIONS IN AN EPITHELIAL JUNCTION GENE CONTRIBUTING TO VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE

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NEW PATHOGENIC MUTATIONS IN AN EPITHELIAL JUNCTION GENE CONTRIBUTING TO VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE

Kaming Ma 1, Parakkal Deepak 2, Matthew Ciorba 3, Siyan Cao 1

Affiliations

1 Washington University in St. Louis, St. Luis, United States

2 Washington University in St. Louis, St. Louis, United States

3 Matthew Ciorba, MD Professor of Medicine, Director of Inflammatory Bowel Disease Center, Waschington University in Saint Louis, Washington DC, United States

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Abstract

Introduction

Very early onset inflammatory bowel disease (VEO-IBD) is often associated with a severe disease course and unique characteristics including an underlying monogenic defect. In this study, we identified new pathogenic mutations in CGNL1 associated with VEO-IBD and other inflammatory GI disease. CGNL1 (Cingulin Like 1) encodes an epithelial junctional protein whose function was previously unknown in the gastrointestinal tract.

Aims & Methods

Whole exome sequencing (WES) was performed on the affected patient with VEO-IBD and all first-degree relatives with IBD and other inflammatory disease. Intestinal epithelial organoids (IEOs) were generated from the affected patient and were characterized by transepithelial electrical resistance (TEER), FITC-dextran permeability assay on epithelial cell monolayer, immunostaining, RNA sequencing, and transmission electron microscopy (TEM). In addition, we generated a new Cgnl1^-/- mouse model, which was characterized using FITC-dextran permeability assay, TEM, dextran-sodium sulfate (DSS)-induced colitis, and infections by Citrobacter rodentium and Clostridioides difficile. Single-cell datasets were analyzed to determine CGNL1 expression in IBD, primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH).

Results

In the affected patient with VEO-IBD who required early total colectomy and pouch formation with coexistent PSC and celiac disease, WES identified two rare, new, pathogenic variants in the CGNL1 gene. Both pathogenic variants were also present in the patient’s younger sister, who has a similar history including early-onset, fulminant ulcerative colitis requiring total colectomy with ileostomy and PSC-AIH overlap syndrome. Furthermore, multiple relatives of the patient suffer from IBD and other inflammatory conditions including celiac disease, eosinophilic esophagitis, and type-1 diabetes. The RNA and protein levels of CGNL1 were significantly diminished in the patient’s intestinal epithelial cells compared to that of healthy individuals and other IBD patients by RNA-seq, immunoblotting, and immunostaining. The patient’s IEOs from pouch body and pre-pouch ileum formed smaller 3D spheroids with altered cell composition and significantly impaired barrier function compared to those from healthy controls and other IBD patients. Immunofluorescence and TEM demonstrated that CGNL1 is required for the assembly of junctional complexes in human IEOs and an epithelial cell line. Similarly to findings from the patient, impaired junctional complexes in intestinal epithelial cells and elevated intestinal permeability were present in Cgnl1^-/- mice at steady state. Cgnl1^-/- mice showed substantial vulnerability to DSS-induced colitis and bacterial infections that directly compromise the epithelial barrier. In addition, 6-month-old Cgnl1^-/- mice exhibited spontaneous inflammation in the colon and terminal ileum due to disrupted intestinal barrier, which was microbiome-dependent. Furthermore, single-cell analysis revealed diminished expression of CGNL1 in the intestinal and hepatic epithelial cells from patients with IBD or PSC/AIH, respectively.

Conclusion

The pathogenic CGNL1 variants contribute to VEO-IBD by disrupting gut barrier integrity, as demonstrated by patient’s cells and novel murine models. This study expands our understanding of epithelial barrier impairment in the pathogenesis of VEO-IBD, and highlights intestinal epithelium as a therapeutic target in some IBD patients.

Event

UEG Week Berlin 2025

Topics

IBD Mechanisms & Personalised Medicine

Submission format

Abstract

Session

New insights into IBD pathology

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

The use of the modified Aldrete score for the assessment of recovery after gastrointestinal endoscopy

Eleni Kyvelou

TARGETED PHAGE INTERVENTION IMPROVES BACTERIAL-DRIVEN COLITIS AND RESPONSE TO TOPICAL CORTICOSTEROIDS BY ATTENUATING VIRULENCE OF CROHN’S DISEASE-ASSOCIATED BACTERIA

Elena Verdu

NEW PATHOGENIC MUTATIONS IN AN EPITHELIAL JUNCTION GENE CONTRIBUTING TO VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE

Siyan Cao

Interfering substances effect endoscope reprocessing

Annette Rittich

THERAPEUTIC AND HOSPITALISATION OUTCOMES AFTER FIRST-LINE ANTI-TNF IN INFLAMMATORY BOWEL DISEASE: INSIGHTS FROM THE EPITHERA STUDY USING DATA FROM THE FRENCH NATIONAL HEALTH DATA (SNDS)

Lucine Vuitton

AFIMKIBART (ANTI-TL1A) IS EFFECTIVE IN THE BLOCKADE OF CELLULAR SIGNALING INDUCED BY ACTIVE TL1A

Vishnu Mohanan

UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

Interfering substances effect endoscope reprocessing

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Interfering substances effect endoscope reprocessing

Annette Rittich 1

Affiliations

1 None, Hamburg, Germany

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Abstract

Event

UEG Week Berlin 2025

Topics

Nurses

Session

Hygiene: Update 2025

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

The use of the modified Aldrete score for the assessment of recovery after gastrointestinal endoscopy

Eleni Kyvelou

TARGETED PHAGE INTERVENTION IMPROVES BACTERIAL-DRIVEN COLITIS AND RESPONSE TO TOPICAL CORTICOSTEROIDS BY ATTENUATING VIRULENCE OF CROHN’S DISEASE-ASSOCIATED BACTERIA

Elena Verdu

NEW PATHOGENIC MUTATIONS IN AN EPITHELIAL JUNCTION GENE CONTRIBUTING TO VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE

Siyan Cao

Interfering substances effect endoscope reprocessing

Annette Rittich

THERAPEUTIC AND HOSPITALISATION OUTCOMES AFTER FIRST-LINE ANTI-TNF IN INFLAMMATORY BOWEL DISEASE: INSIGHTS FROM THE EPITHERA STUDY USING DATA FROM THE FRENCH NATIONAL HEALTH DATA (SNDS)

Lucine Vuitton

AFIMKIBART (ANTI-TL1A) IS EFFECTIVE IN THE BLOCKADE OF CELLULAR SIGNALING INDUCED BY ACTIVE TL1A

Vishnu Mohanan

UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

THERAPEUTIC AND HOSPITALISATION OUTCOMES AFTER FIRST-LINE ANTI-TNF IN INFLAMMATORY BOWEL DISEASE: INSIGHTS FROM THE EPITHERA STUDY USING DATA FROM THE FRENCH NATIONAL HEALTH DATA (SNDS)

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THERAPEUTIC AND HOSPITALISATION OUTCOMES AFTER FIRST-LINE ANTI-TNF IN INFLAMMATORY BOWEL DISEASE: INSIGHTS FROM THE EPITHERA STUDY USING DATA FROM THE FRENCH NATIONAL HEALTH DATA (SNDS)

Julien Kirchgesner 1, Laurent Peyrin-Biroulet 2, Laurène Gautier 3, Katia Sosnowiez 3, Samira Chaalal 3, Lucien Clevy 3, Hanane Omichessan 3, Vanessa Cohignac 3, Pascaline Rabiéga 4, Geoffray Bizouard 4, Tiffany Nishikawa 4, Alice Huguet 4, Lucine Vuitton 5

Affiliations

1 Institut Pierre Louis d'Epidémiologie et de Santé Publique, Sorbonne University, Saint-Antoine Hospital, Paris, France

2 Inserm U1256, Nancy University Hospital, Vandoeuvre-les-Nancy, France

3 Johnson&Johnson Innovative Medicine, Issy-les-Moulineaux, France

4 IQVIA Operations France, Courbevoie, France

5 Besançon university hospital, Besançon, France

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Abstract

Introduction

Following anti-TNF therapy, treatment options include switching between different anti-TNF agents or swapping to therapies with distinct mechanisms of action. It is essential to evaluate these treatment pathways in real-world settings to improve inflammatory bowel diseases (IBD) management.

Aims & Methods

This retrospective study analyzed data from the French National Health Data System and included all adult patients meeting at least one of the following criteria between 2014 and 2023: i) long-term disease related to IBD ii) at least 2 hospitalizations for IBD iii) one hospitalization for IBD coupled with 3 or more IBD treatment deliveries. The study assessed treatment discontinuation (short-term: 1 year; long-term: 5 years), and hospitalizations for IBD, IBD-related surgeries and serious infections among patients initiating a second line treatment (2L) between 2014 and 2022 following a first anti-TNF therapy. All outcomes were evaluated one year post switching between anti-TNF agents (reference) versus swapping to vedolizumab (VDZ) or ustekinumab (UST) using a propensity score (PS)-matched Cox proportional hazards model. Covariates used to estimate PS were age, gender, and medical history (see full list in Table 1). Covariate balance was assessed through standardized mean difference (SMD).

Results

The cohort consisted of 151,999 CD patients and 152,367 UC patients, with 14.5% of CD patients and 9.3% of UC patients undergoing 2L treatment. After PS matching, the profiles of IBD patients who switched to a 2^nd anti-TNF were comparable to those who swapped to UST or VDZ (SMD<0.1 for all covariates). Main outcomes are summarized in Table 1.
CD patients who swapped to VDZ had higher risks of treatment discontinuation compared to those who switched to a 2^nd anti-TNF (short-term: adjusted hazard ratio (aHR)=1.23 95%CI [1.11-1.36]; long-term: aHR=1.14 95%CI [1.06-1.23]). Conversely, patients who swapped to UST showed lower risks of treatment discontinuation (short-term: aHR=0.76 95%CI [0.70-0.81]; long-term: aHR=0.72 95%CI [0.68-0.76]), and experienced fewer hospitalizations due to IBD (aHR=0.77 95%CI [0.71-0.83]) and serious infections (aHR=0.74 95%CI [0.59-0.93]).
UC patients who swapped to VDZ had lower risks of treatment discontinuation (short-term: aHR=0.81 95%CI [0.75-0.87]; long-term: aHR=0.83 95%CI [0.78-0.87]), but a higher risk of IBD-related hospitalizations (aHR=1.11 95%CI [1.02-1.20]) compared to those who switched to another anti-TNF. In contrast, UC patients who swapped to UST showed decreased risks of treatment discontinuation (short term: aHR=0.58 95%CI [0.49-0.69]; long-term: aHR=0.62 95%CI [0.54-0.71]). For all other outcomes, the results were statistically non-significant and are presented in Table 1.

	CD patients		UC patients
	Switch vs. Swap to vedolizumab N=1,987	Switch vs. Swap to ustekinumab N=5,317	Switch vs. Swap to vedolizumab N=4,324	Switch vs. Swap to ustekinumab N=815
	aHR [95%CI]	aHR [95%CI]	aHR [95%CI]	aHR [95%CI]
Short-term IBD treatment discontinuation (1 year after switching/swapping)	1.23 [1.11-1.36] *	0.76 [0.70-0.81] *	0.81 [0.75-0.87] *	0.58 [0.49-0.69] *
Long-term IBD treatment discontinuation (5 years after switching/swapping)	1.14 [1.06-1.23] *	0.72 [0.68-0.76] *	0.83 [0.78-0.87] *	0.62 [0.54-0.71] *
IBD-related hospitalizations	1.06 [0.94-1.19]	0.77 [0.71-0.83] *	1.11 [1.02-1.20] *	0.84 [0.68-1.03]
IBD-related surgeries	0.94 [0.66-1.32]	1.14 [0.93-1.39]	1.29 [0.89-1.87]	1.08 [0.42-2.79]
Hospitalizations for serious infection	1.20 [0.87-1.67]	0.74 [0.59-0.93] *	0.96 [0.74-1.23]	0.58 [0.30-1.14]
*p-value <0.05; aHR: adjusted hazard ratios; CD: Crohn’s disease; CI: confidence interval; UC: ulcerative colitis Covariates used to estimate propensity score: age, gender, previous infections, clostridium difficile infections, cardiovascular diseases, end stage kidney disease/kidney transplant, chronic liver diseases, chronic pulmonary diseases, venous thromboembolism, diabetes mellitus, nature of 1L anti-TNF, time to first line of anti-TNF from diagnosis date, disease duration, hospitalisation at induction of new treatment. Additional covariate for CD patients only: history of major IBD-related surgery (colectomy or intestinal resection).

Conclusion

In this large cohort of patients, swapping to UST led to better treatment persistence in both CD and UC while reducing the risks of hospitalizations and serious infections in CD compared to switching between anti-TNF agents. Swapping to VDZ offered better treatment persistence than switching to another anti-TNF agent in UC.

Disclosure

LV received fees from abbvie, amgen, MSD, Ferring, Takeda, Pfizer, Janssen, Lilly, Galapagos, Celltrion, Viatris
LPB received fees from Abbvie, Abivax, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, BMS,
Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK,
Hac Pharma, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD
Norgine, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeuthics, Pandion Therapeuthics, Par' Immune, Pfizer, Prometheus,
Protagonist, Roche, Roivant, Samsung, Sandoz, Sanofi, Takeda, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vifor, Vectivbio,
Ventyx, Ysopia.
JK received fees from Janssen, Takeda, Lilly, Abbvie, Pfizer, Tillots, Amgen, Celltrion, Roche, Gilead, Galapagos.
SC, VC, HO, LG, KS, LC works for Johnson&Johnson Innovative Medicine.
PR, GB, AH, TN works for IQVIA Operations France.

Event

UEG Week Berlin 2025

Topics

Endoscopy IBD

Submission format

Abstract

Session

Tackling IBD in clinics

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Lucine Vuitton

AFIMKIBART (ANTI-TL1A) IS EFFECTIVE IN THE BLOCKADE OF CELLULAR SIGNALING INDUCED BY ACTIVE TL1A

Vishnu Mohanan

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AFIMKIBART (ANTI-TL1A) IS EFFECTIVE IN THE BLOCKADE OF CELLULAR SIGNALING INDUCED BY ACTIVE TL1A

Domagoj Vucic 1, Franklin Fuh 2, Allen Nguyen 1, Eugene Varfolomeev 1, Angela Oh 1, Geil Merana 1, Xiao Tao 1, David Place 1, Karen Lasch 3, Daniela Bojic 4, Pascal Espie 4, Maggie Neighbors 1, Jacqueline McBride 1, Vishnu Mohanan 1

Affiliations

1 Genentech-Roche, South San Francisco, United States

2 Genentech-Roche, South San Francisco, United States|||Genentech-Roche, South San Francisco, United States

3 Roche, South San Francisco, United States

4 F.Hoffman-La Roche Ltd, Basel, Switzerland

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Abstract

Introduction

Tumor necrosis factor-like ligand 1A (TL1A) is a member of the Tumor necrosis factor (TNF) superfamily implicated in the pathogenesis of inflammatory bowel disease (IBD) as a key amplifier of the effector function of several immune cells. TL1A can be expressed by various immune cells, including macrophages, dendritic cells, and some T cell subsets, and exists either as a membrane-bound or as a cleaved soluble trimer. TL1A signals predominantly by activating NF-kB pathway via the only known functional receptor, death receptor 3 (DR3), which has restricted expression mostly on effector T cells and innate lymphoid cells (ILCs). Afimkibart is a fully human anti-TL1A antibody that has shown clinical benefit in Phase 2 clinical studies and specifically blocks the activity of trimeric forms of TL1A. Monomeric TL1A has also been described; however, the relevance of monomeric TL1A in DR3 signaling and disease is unclear. This study aimed to understand the functional characteristics of both monomer and trimer TL1A species in primary cells and cell lines.

Aims & Methods

Immunoassays were used to measure the detection of TL1A species in IBD serum. Recombinant human monomeric and trimeric TL1A proteins were assessed for binding to afimkibart using SPR and in cellular assays using primary immune cells and cell lines for nuclear factor-kappa B (NF-κB) signaling and interferon-gamma (IFNγ) production.

Results

In functional cellular assays with primary immune cells, we demonstrate that trimeric recombinant human TL1A (rhTL1A) protein causes significant NF-κB signaling in human peripheral T lymphocytes, and in the presence of interleukin 12 (IL12) and interleukin 18 (IL18) co-stimulation, a significant increase of IFNγ production by human primary peripheral blood mononuclear cells (PBMCs). In line with the mechanism of action, both the NF-κB signaling and IFNγ production are blocked by afimkibart. In contrast, only high concentrations of monomeric rhTL1A, >100 ng/ml, induced moderate NF-κB signal and demonstrated a minimal increase in IFNγ production above IL12 + IL18 stimulation alone. However, this activity was blocked by afimkibart. Lastly, afimkibart blocks endogenous soluble and membrane-bound TL1A.

Conclusion

Herein, we demonstrate that afimkibart blocks NF-kB signaling and IFNγ production induced by TL1A stimulation. While some signaling activity was observed at high concentrations of monomeric TL1A protein, we hypothesize that any signaling observed with monomeric form is likely due to the formation of trimers, which are efficiently blocked by afimkibart. Overall, any monomeric TL1A present should not be functionally active nor be available as a sink for afimkibart, thus preserving the optimal pharmacokinetic (PK) and pharmacodynamic (PD) properties needed for effective target inhibition.

Disclosure

All the authors are employees of Genentech-Roche.

Conference

UEG Week Berlin 2025

Topics

IBD

Submission format

Abstract

Session

IBD (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

The use of the modified Aldrete score for the assessment of recovery after gastrointestinal endoscopy

Eleni Kyvelou

TARGETED PHAGE INTERVENTION IMPROVES BACTERIAL-DRIVEN COLITIS AND RESPONSE TO TOPICAL CORTICOSTEROIDS BY ATTENUATING VIRULENCE OF CROHN’S DISEASE-ASSOCIATED BACTERIA

Elena Verdu

NEW PATHOGENIC MUTATIONS IN AN EPITHELIAL JUNCTION GENE CONTRIBUTING TO VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE

Siyan Cao

Interfering substances effect endoscope reprocessing

Annette Rittich

THERAPEUTIC AND HOSPITALISATION OUTCOMES AFTER FIRST-LINE ANTI-TNF IN INFLAMMATORY BOWEL DISEASE: INSIGHTS FROM THE EPITHERA STUDY USING DATA FROM THE FRENCH NATIONAL HEALTH DATA (SNDS)

Lucine Vuitton

AFIMKIBART (ANTI-TL1A) IS EFFECTIVE IN THE BLOCKADE OF CELLULAR SIGNALING INDUCED BY ACTIVE TL1A

Vishnu Mohanan

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