Introduction

Targeting mitochondrial function and oxidative stress is successful in animal models of IBD. NLRX1 is a mitochondrial associated protein upregulating mitochondrial metabolism: It reduces oxidative stress and decreases pro-inflammatory cell differentiation and cytokine release. NX-13 is a first-in-class, orally active, once-daily, gut-selective NLRX1 agonist with low systemic exposure in development for Ulcerative Colitis (UC). In three mouse models of IBD, NX-13 effectively activated NLRX1 to reduce inflammatory responses and disease severity. In two phase 1 studies (56 healthy subjects; 38 UC patients) NX-13 was well tolerated. Low systemic drug exposure relative to stool levels suggested a gut-selective drug distribution. Phase 1B topline results were reported previously¹. We now present data demonstrating target engagement and downstream effects consistent with the preclinical mechanism of action (MOA).

Aims & Methods

In this double-blind phase 1B trial, 36 patients with active UC (Total Mayo Score 4-10; Mayo endoscopic subscore 2-3) were randomly assigned to NX-13 250mg Immediate Release (IR), 500mg IR, 500mg Delayed Release (DR) or Placebo to be taken QD for 4 weeks. We report pharmacodynamic results based on expression of NLRX1 and downstream immunometabolic markers in colonic tissue samples collected at screening and week 4 of treatment. NLRX1 protein levels were measured by immunohistochemistry scored by a blinded pathologist, and immunometabolic markers were measured by qRT-PCR.

Results

All NX-13 treated groups showed target engagement through mean positive increases in NLRX1 expression versus placebo at week 4, with more pronounced upregulation observed in responding patients (Table 1A). Gene expression profiles after 4 weeks of treatment showed upregulation of the mitochondrial metabolism gene MT-ND3, with downstream reductions in HIF1α and NLRP3 in the NX-13 IR groups but not in the placebo group (Table 1B). NX-13 250mg IR dosed patients also displayed downstream decreases in IL-17α and IL-1β gene expression, and the 500mg IR group showed reduction in IL-1β. Changes in NLRX1 expression and immunometabolic markers correlated with clinical response to NX-13 and were numerically greater in responding IR-dosed patients compared to non-responding patients (Table 1).

Conclusion

Treatment with NX-13 induced upregulation of its target, NLRX1, as well as downstream immunometabolic signaling consistent with preclinical MOA studies. Most importantly, target engagement parallels clinical benefit. This novel mechanism of action warrants further study and is currently being evaluated in a phase 2 proof of concept study (NCT05785715).

References

¹ L Peyrin-Biroulet, S Danese, J F Colombel, F Rieder, A Yarur, B Verstockt, S Lichtiger, R Mosig, F Cataldi, B Feagan, P577 A Phase 1b Study to Evaluate Safety, Tolerability, Pharmacokinetics and Clinical Efficacy of the Nucleotide-binding oligomerization domain, Leucine rich Repeat containing X1 (NLRX1) agonist NX-13 in Ulcerative Colitis, Journal of Crohn's and Colitis, Volume 17, Issue Supplement_1, February 2023, Pages i705–i706

Disclosure

BV - AbbVie, Alimentiv, Applied Strategic, Atheneum, Biora Therapeutics, Biogen, Bristol Myers Squibb, Celltrion, Chiesi, Falk, Ferring, Galapagos, Guidepont, Inotrem, Ipsos, Janssen, MSD, Mylan, Pfizer, Progenity, R-Biopharm, Sandoz, Sossei Heptares and Takeda, Tillots Pharma, Truvion and Viatris;
SV - grants from: AbbVie, J&J, Pfizer, Takeda and Galapagos, consulting / speaking fees from: AbbVie, Abivax, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma AG, Zealand Pharma;
BS - consultant for AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Falk, Janssen, Lilly, Pfizer, PredictImmune and Takeda; and received speaker’s fees from AbbVie, BMS, CED Service GmbH, Falk, Ferring, Janssen, Pfizer and Takeda (served as representative of the Charité);
FR - Adnovate, Agomab, Allergan, AbbVie, Arena, Boehringer-Ingelheim, Celgene/BMS, CDISC, Celsius, Cowen, Ferring, Galapagos, Galmed, Genentech, Gilead, Gossamer, Granite, Guidepoint, Helmsley, Horizon Therapeutics, Image Analysis Limited, Index Pharma, Jannsen, Koutif, Mestag, Metacrine, Mopac, Morphic, Organovo, Origo, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Sanofi, Surmodics, Surrozen, Takeda, Techlab, Teva, Theravance, Thetis, UCB, Ysios, 89Bio;
SL – owns Landos Stock;
RM – employee of Landos;
FC – employee of Landos;
SD - AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial, Vifor;

Introduction

Short bowel syndrome (SBS) is a severe complication of extensive small intestinal resection, most commonly occurring in Crohn’s disease (CD), a chronic inflammatory disorder defined by transmural immune infiltration. Cytokines and chemokines are central mediators in the immune cascade driving intestinal inflammation and tissue damage^1,2. Despite advances in care, no biomarkers currently predict SBS onset or progression to intestinal failure (IF). Profiling systemic cytokine and chemokine signatures may thus offer novel insight into disease trajectory and risk stratification.

Aims & Methods

This study investigates circulating inflammatory mediators in patients with established IF/SBS and CD patients at high risk of progression. A total of 150 patients with CD were enrolled and stratified into five groups based on intestinal function and surgical history: A1, SBS with IF requiring parenteral nutrition (PN) or intravenous fluids; A3, SBS without IF and inactive disease; B, high risk of IF with multiple or extensive resections; C1, low risk for IF with no history of resection; and C2, low risk for IF with prior resection. Serum cytokine and chemokine profiles were quantified at baseline (T0) and after six months (T6) using the human 27-PLEX multiplex immunoassay.

Results

Serum cytokines and chemokines profiling at baseline (T0) and after six months (T6) revealed distinct inflammatory patterns across the study groups. Patients with SBS and IF (group A1) showed persistently elevated levels of IP-10, IL-12, MIP-1α, and G-CSF, reflecting sustained immune activation. Whereas, patients at high risk of IF (group B) displayed increased Eotaxin, bFGF, IL-15, and IL-6, indicative of subclinical inflammation and possible tissue remodelling.
A general reduction in cytokine levels was observed at T6, though anti-inflammatory mediators remained minimally modulated, suggesting ongoing low-grade inflammation. Comparisons between groups highlighted divergent cytokine signatures correlating with disease severity and nutritional support requirements.

Conclusion

These findings suggest that specific circulating cytokines may serve as potential biomarkers for early identification of patients at risk of IF. The differential expression patterns observed across groups support their relevance in stratifying disease severity in CD and SBS. Further large-scale studies are needed to validate these preliminary results and to fully establish their prognostic significance.
Funded by: 2.1 “Rafforzamento e potenziamento della ricerca biomedica del SSN”, finanziato dall’Unione europea – NextGenerationEU, CUP C53C22001140007. 2022 PNRR Project “Changing the future of intestinal failure in intestinal chronic inflammation: towards innovative predictive factors and therapeutic targets” code: PNRR-MAD-2022-12376791.

References

1. Friedrich M, Pohin M, Powrie F. Cytokine Networks in the Pathophysiology of Inflammatory Bowel Disease. Immunity. 2019;50(4):992-1006. doi:10.1016/j.immuni.2019.03.017
2. Singh UP, Singh NP, Murphy EA, et al. Chemokine and cytokine levels in inflammatory bowel disease patients. Cytokine. 2016;77:44-49. doi:10.1016/j.cyto.2015.10.008

Introduction

The extent of gastric atrophy(GA) is closely related to the incidence of Intestinal-type gastric cancer (GC). According to the Kimura-Takemoto classification, determining whether the atrophy extends beyond the cardia is key to assess the extent of GA. However, there is significant difficulty in determining whether the cardia is atrophied under endoscopy.

Aims & Methods

This study developed a novel artificial intelligence (AI)-assisted white light endoscopy system for identifying the cardia part and diagnosing cardia atrophy . In this multicenter study, patients undergoing upper gastrointestinal endoscopy at 5 hospitals in China were prospectively included between November 2022 and December 2024. Among them, a total of 895 patients from 2 units were assigned to the training and validation sets (292 with cardia atrophy and 603 without cardia atrophy) to establish a cardia atrophy diagnostic model. 220 patients from our unit (84 with cardia atrophy and 136 without cardia atrophy) were included in the internal test set. Additionally, a total of 354 patients from 3 other units were included in the external test set (106 with cardia atrophy and 248 without cardia atrophy). In the internal and external test sets, 3 senior and 3 junior endoscopists made online diagnoses, comparing the performance differences between physicians with different levles of experience and the AI-assisted cardia atrophy detection system.

Results

This study established a AI-assisted cardia atrophy diagnostic model and tested its diagnostic performance with multicenter image data in internal and external tests. In the internal test dataset, the accuracy, sensitivity, and specificity of the AI-assisted system were 0.927, 0.941, and 0.919, respectively, with a PPV of 0.878, NPV of 0.962, and AUC of 0.967. In the external test dataset, the accuracy, sensitivity, and specificity were 0.918, 0.894, and 0.931 respectively, with a PPV of 0.874, NPV of 0.943, and AUC of 0.953. Further comparison of the diagnostic efficiency of the AI-assisted system with endoscopists of different levels of experience revealed that both in the internal and external test set, the diagnosis accuracy, sensitivity, specificity, PPV, and NPV of the AI-assisted system were all higher than those of senior endoscopists. TheAI-assisted cardia atrophy diagnostic ROC curve area (AUC) was 0.967 and 0.953 in the internal and external test sets, respectively. Heat map analysis further showed a high consistency between theAI-assisted system and endoscopists in cardia atrophy diagnosis.

Conclusion

Our newly developed AI-assisted cardia atrophy diagnostic system shows superior performance in identifying cardia atrophy compared to senior endoscopists, and can be used to guide white light endoscopic judgment and targeted biopsies for cardia atrophy.

Introduction

Perianal fistulas occur in up to 30% of patients with Crohn’s disease (pfCD) and frequently require a combined medical and surgical treatment approach. Hyperbaric Oxygen Therapy (HBOT) has previously shown benefit in treatment-refractory pfCD.

Aims & Methods

In this pilot study, we aim to assess the feasibility of surgical fistula closure 4 weeks after HBOT, and efficacy of combining surgical closure and 8 weeks HBOT.
Patients with complex pfCD refractory to at least 6 months of anti-TNF therapy were included in this study. All patients received a seton prior to starting treatment with 40 sessions (8 weeks) of HBOT (each lasting 110 minutes, with 5-minute air breaks) with 100% oxygen at 2.4 atmosphere. At week 4 the seton was removed, and surgical closure of the internal fistula opening was attempted. All patients continued stable dose of medical treatment during the study. Response was assessed by the fistula drainage assessment (FDA) and the perianal disease activity index (PDAI) at week 9, 26 and 52, and by pelvic MRI at week 9 and 26. MRI response was defined as a decrease of 2 points in MAGNIFI-CD score, MRI remission as a MAGNIFI-CD ≤6. (Serious) Adverse Events (AE) were reported for 52 weeks. Univariate logistical regression was used to explore potential variates associated with PDAI response (≤4) at week 26.

Results

Ten patients completed treatment and were analyzed (Table 1). All patients completed HBOT and underwent a technically successful surgical procedure at week 4. No proctitis was encountered at week 4 during examination under anesthesia. PDAI response was achieved by 30%, 60%, 58% at week 9, 26 and 52, respectively. FDA response/remission was achieved in 50%/20%, 80%/40% and 80%/50% of patients at week 9, 26 and 52, respectively. MRI response/remission was achieved in 60%/10% and 60%/20% of patients at week 9 and 26, respectively. No significant parameters were associated with PDAI response at week 26 in univariate logistical regression. (S)AEs included one patient with a potential oxygen toxicity seizure without long term effects, and one patient reported claustrophobia, no new AEs were reported.

Table 1 Patient and fistula characteristics (n=10)

Conclusion

HBOT is feasible in combination with surgical therapy in patients with complex pfCD refractory to anti-TNF therapy. Patients had long-lasting benefit of the combined treatment approach. Further translational data are currently analyzed to clarify mechanisms of action and to explore potential biomarkers for therapy response.

Disclosure

LM, KB, JT and RvH have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this abstract. JS is President-elect of the European Society of Gastrointestinal and Abdominal Radiology. GD has served as consultant for AbbVie, Astrazeneca, Alimentiv, Bristol-Myers Squibb, Boehringer Ingelheim, Celltrion, Cosmo, Eli Lilly, Galapagos, GSK, Johnson and Johnson, Takeda, Pfizer Inc, Polpharma, Prometheus Biosciences, Tillotts and Ventyx; received speaker fees from AbbVie, Boehringer Ingelheim, Celltrion, Eli Lilly, Johnson and Johnson, Takeda, Pfizer Inc and Tillotts. CB has received grants from Boehringer Ingelheim and Roche; speakers honoraria from AbbVie, Janssen, Galapagos, Takeda, and Tillotts. KG has received grants from Pfizer Inc, Celltrion and Galapagos; consultancy fees from AbbVie, Arena Pharmaceuticals, Galapagos, Gilead, Immunic Therapeutics, Janssen Pharmaceuticals, Novartis, Pfizer Inc., Samsung Bioepis and Takeda and speaker’s honoraria from Celltrion, Ferring, Janssen Pharmaceuticals, Novartis, Pfizer Inc, Samsung Bioepis, Takeda and Tillotts.