Introduction

TPM502 is a mixture of three distinct nanoparticles, each coupled with one celiac disease (CeD)-relevant gluten peptide, representing immunodominant and deamidated CD4⁺ T cell epitopes. TPM502 targets liver sinusoidal endothelial cells, which are unconventional antigen-presenting cells capable of inducing antigen-specific tolerance.

Aims & Methods

TCeD21 (NCT00565136) was a phase 2a double-blind, randomized, placebo-controlled study in HLA-DQ2.5-positive adults with confirmed CeD on a gluten-free diet. Patients achieving a predefined IL-2 response to a single dose (6 g) gluten challenge (GC1) were randomized into four cohorts to receive two intravenous infusions with escalating doses of TPM502 or placebo on day (D) 1 and D15. The GC was repeated 7 days after the second TPM502 dose (GC2). Peripheral blood mononuclear cells collected from each patient at predefined timepoints were analyzed by high-dimensional (30-color) flow cytometry, before and after HLA-DQ2.5-gliadin-specific tetramer (tet) enrichment, using surface staining for various phenotypic markers. The study aimed to characterize the phenotypes of gluten-specific T cells in CeD patients before and after TPM502 treatment to assess its immunomodulatory effects.

Results

Samples from 36 patients completing the study (12 placebo, 24 TPM502) were analyzed across five timepoints. In the placebo group, tet⁺ CD45RA^-CD62L^-CD4⁺ T (Ttet) cells increased after both GCs. By contrast, the TPM502 cohorts exhibited elevated Ttet cell numbers before GC2 (D22) but showed limited expansion afterward (D29), suggesting that TPM502 treatment may prevent further activation-induced expansion. Moreover, the frequency of activated Ttetcells—indicated by activation markers CD38, ICOS, and OX40—significantly decreased across all TPM502 dose levels after GC2 compared to the placebo group (fold change D22 vs D29, all p < 0.0001 by Kruskal-Wallis test). Notably, the diminished gluten response of Ttet cells post-treatment was accompanied by enhanced expression of co-inhibitory receptors TIGIT and PD-1 (D-21 vs D29, p < 0.0001), along with reduced CD127 expression (p < 0.01), indicative of decreased cell survival. These phenotypic changes, consistent with T cell exhaustion or anergy, persisted until study end and were visibly distinct from those in the placebo group, as illustrated by the heatmap of delta log-transformed flow cytometry data of Ttet cells across timepoints, clustered hierarchically. Gliadin-specific CD4⁺ regulatory T cells (CD25⁺CD127^- Ttet) and CD39⁺ Ttet cells increased post-treatment at the highest TPM502 dose, suggesting the induction of regulatory states in these T cells. Moreover, pre-enriched samples showed reduced activation of αEβ7⁺ γδ⁺ and CD8⁺ Tcells after GC2 at the highest TPM502 dose, suggesting potential bystander effects.

Conclusion

Data from the first longitudinal tetramer-based flow cytometry analysis in CeD patients provide evidence that TPM502 induces antigen-specific tolerance through T-cell immunomodulation. These results corroborate other pharmacodynamic outcomes generated in this study, including a significant and dose-dependent reduction in ex vivo IL-2 and IFN-γ secretion by gluten-specific T cells after treatment. In addition to a good safety and tolerability profile of TPM502, this nanoparticle-mediated induction of antigen-specific tolerance may provide a novel therapeutic avenue to treat celiac disease.

Introduction

Human transglutaminase 2 (TG2) plays a key role in celiac disease (CeD) pathogenesis, spurring development of the oral TG2 inhibitor ZED1227. In the phase 2a CEC-003/CEL study in CeD patients on a gluten-free diet (GFD), once-daily treatment with ZED1227 with gluten challenge (3 g/day) for 6 weeks led to significant improvement in the ratio of intestinal villous height to crypt depth (VH:CrD) versus placebo.¹ Despite adherence to a gluten-free diet, up to half of CeD patients report persistent symptoms often combined with varying degrees of small intestinal injury. Hence, potential treatments for CeD should ideally address these symptoms and improve mucosal injury.

Aims & Methods

The aim of the present study was a dose-ranging trial of ZED1227 in CeD patients with residual symptoms and villous atrophy despite a GFD. This was a double-blind, randomized, placebo-controlled phase 2b study. It enrolled adult CeD patients who had followed a GFD for at least one year and who experienced at least one moderate or severe gastrointestinal (GI) symptom in the month prior to baseline. All patients underwent an initial 5-week placebo run-in phase, followed by endoscopy and 1:1:1:1 randomization of patients with VH:CrD ≤2.5. Treatment was placebo thrice-daily (TID) or ZED1227 at doses of 10 mg TID, 25 mg TID, or 50 mg once-daily (QD) for 12 weeks. No gluten challenge was carried out. The primary endpoint was the rate of patients with both improvement by ≥ 0.4 in VH:CrD and improvement by ≥ 15% in either of two symptom scores (non-stool GI or diarrhea severity) on the celiac disease symptom diary (CDSD) from the end of the run-in phase to week 12. Key secondary endpoints included the change in VH:CrD, change in CDSD GI total severity score, and safety.

Results

A total of 397 patients were randomized to the 4 arms, of whom 92.7% completed treatment. The primary endpoint was achieved by 27.1% of patients receiving 10 mg ZED1227 TID, 16.9% for 25 mg TID, 25.3% for 50 mg QD, and 19.3% for placebo, with no significant differences between any treatment arm and placebo. The mean change in VH:CrD ratio from baseline was 0.21 for 10 mg ZED1227 TID, 0.17 for 25 mg TID, and 0.26 for 50 mg QD versus 0.12 for placebo. Within-group changes from baseline to week 12 were statistically significant within each arm, while the between-group difference in changes was significant only for 50 mg ZED1227 QD versus placebo (p<0.05). Similarly, mean changes in the CDSD GI total severity score were -0.96 with 10 mg ZED1227 TID, -0.95 with 25 mg TID, -1.20 with 50 mg QD, and -1.05 with placebo. Improvements within each arm were again statistically significant, with no significant differences between any treatment arm and placebo. There were no notable differences in the rates of adverse events or serious adverse events (SAEs) between the study arms, and no SAEs related to the study drug were reported.

Conclusion

The CEC-004/CEL study did not meet its primary endpoint of combined improvement in histology and symptoms. However, changes in the VH:CrD ratio achieved with 50 mg ZED1227 QD were statistically superior to placebo, consistent with the results of the prior CEC-003/CEL study. Significant within-group improvement from baseline to week 12 in both histologic and symptom outcomes within the placebo group underscored the challenges of clinical trials without deliberate gluten exposure in patients with the heterogeneous symptom and histology typical of partially treated CeD. The favorable safety profile of ZED1227 was confirmed, and no new safety concerns were identified.

References

1. Schuppan D, Maki M, Lundin KEA, Isola J, Friesing-Sosnik T, Taavela J, et al. A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease. N Engl J Med. 2021;385(1):35-45.

Disclosure

Sponsor of the trial: Dr. Falk Pharma GmbH
Acknowledgement: This research was supported by Takeda.

Introduction

Sigmoid volvulus is usually managed by endoscopic detorsion in the absence of complications, while surgery is reserved for severe cases. However, recurrence rates remain high, ranging from 18% to 90% (1). The guidelines from the American Society of Colon and Rectal Surgeons (1) recommend prophylactic surgery, although the optimal timing is not defined. In Europe, most cases are sporadic and affect elderly patients with comorbidities. However, large studies mainly originate from endemic regions, which limits their applicability to Western settings. Moreover, there is a lack of large-scale data focusing specifically on the endoscopic management of sigmoid volvulus.

Aims & Methods

The study aimed to evaluate the outcomes of patients with sigmoid volvulus managed by endoscopic detorsion during out-of-hours emergency endoscopy shifts across multiple centers.
We conducted a retrospective, multicenter study (8 centers), including all patients who underwent endoscopy for suspected sigmoid volvulus during on-call digestive endoscopy shifts between March 2016 and December 2023. Procedures were performed by the POET group (Parisian On-call Endoscopy Team), a mobile unit composed of an endoscopist and a nurse, covering urgent endoscopy during nights and weekends in Paris and suburbs (6.9 million inhabitants), using a portable system (2).

Results

A total of 404 patients were included. Median age was 72 years (IQR 59; 83), 69% were male, 19% institutionalized, 40% had neurocognitive disorders, 26% had anatomical abnormalities of the colon and 45% had constipation. The most common presenting symptoms were abdominal pain (53%), bowel obstruction (17%), and constipation (20%). Endoscopic detorsion was successful in 92% of cases, with a 2% perforation rate and 89% of clinical success. Predictors of technical failure included ischemia at endoscopy (OR 0,16 [0,07-0,37], p<0,0001) and history of abdominal surgery (OR=0,44 [0,2;0,99], p=0,0463). Ischemia was independently associated with initial CRP ≥ 27 mg/L (OR=2,24 [1,11-4,54], p=0,0253), time to endoscopy ≥ 10h (OR=2,38 [1,28-4,39], p=0,0058), and radiological signs of severity (OR=4,13 [1,82-9,36], p=0,0007). All 24 patients with colonic necrosis at endoscopy died without emergency surgery, regardless of the success of detorsion (58% in this subgroup). In 28% of cases, endoscopy was performed for recurrence. Among patients with a first episode, recurrence occurred in 40%, with 50% occurring within 12 days. Endoscopic success was associated with a higher risk of recurrence (OR=4,39 [1,18-16,32], p=0,0271). In-hospital and 30-day mortality was <10%; overall mortality at the latest follow-up was 31% (median follow-up : 9 months, IQR 2-31).

Conclusion

Emergency endoscopic detorsion is highly effective with low morbidity. However, in the presence of colonic necrosis, endoscopic treatment is ineffective and uniformly fatal without surgical intervention. Optimal patient selection is therefore critical, and relies on early identification of predictive factors for ischemia. Volvulus recurrence is frequent and early, highlighting the need for systematic prophylactic treatment following successful detorsion. Elective surgery during the same hospitalization should be considered whenever possible. For patients with surgical contraindications, endoscopic sigmoidopexy may offer a viable alternative.

References

1. Alavi K, Poylin V, Davids JS, Patel SV, Felder S, Valente MA, Paquette IM, Feingold DL; Prepared on behalf of the Clinical Practice Guidelines Committee of the American Society of Colon and Rectal Surgeons. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Colonic Volvulus and Acute Colonic Pseudo-Obstruction. Dis Colon Rectum. 2021 Sep 1;64(9):1046-1057. doi: 10.1097/DCR.0000000000002159. PMID: 34016826.
2. Camus M, Becq A, Jaïs B; Parisian On-Call Endoscopy Team; Dray X. Resource-sparing urgent endoscopies by a mobile on-call team in the Paris area during the COVID-19 outbreak. Gastrointest Endosc. 2020 Aug;92(2):447-448. doi: 10.1016/j.gie.2020.04.021. Epub 2020 Apr 16. PMID: 32305344; PMCID: PMC7161514.

Introduction

The achievement of histological remission (HR) is a key treatment goal in ulcerative colitis (UC), as it is suggestive of better disease management and predicts response to therapy.
The absence of neutrophils in epithelium and lamina is crucial to define HR. However, the role of neutrophil number and localisation remains unclear. We aimed to develop a novel artificial intelligence (AI)-driven system to automate neutrophil detection, localisation, and quantification, supporting assessment of HR and enable the prediction of response to therapy.

Aims & Methods

We developed an AI-driven system by integrating two deep learning models to (1) segment whole slide images (WSIs) into epithelium, crypts and lamina propria and to (2) detect and quantify neutrophils. Outputs from these models were combined to compute neutrophil densities in the lamina propria, epithelium, and overall tissue. The optimal neutrophil density cut-offs to assess disease activity (Geboes score >2B.0) in UC patients were identified in the AMAC phase 2 Mirikizumab trial, and subsequently validated in the multicentre prospective PICaSSO cohort study. Cut-offs to determine treatment response at weeks 12 and 52 (histological improvement [HI; Geboes score ≤3.1] and histological remission [HR; Geboes score ≤2B.0]), were also evaluated.

Results

Table 1 shows the system diagnostic performance in assessing disease activity and predicting response to therapy at W12 and W52 in the Mirikizumab cohort.
303 WSIs from active UC patients from the multicentre, randomised, double-blind, parallel-arm, placebo-controlled phase 2 clinical trial of Mirikizumab were analysed. The model yielded a DICE SØrensen of 0.57 for segmentation, precision of 82.3% and recall of 77.0% for neutrophil detection. The system identified an overall optimal neutrophil density cut-off (cells/mm²) predictive of disease activity of >21.7.0 (>10.1 and >30.4 for epithelium and lamina propria, respectively), with an accuracy of 86% (85% and 85%, respectively). Further validation in the multicenter PICaSSO cohort yielded to similar results.
Moreover, the overall optimal cut-off to predict histological remission at W52 was <20.8 (<10.4 and <27.9 for epithelium and lamina propria, respectively), with an accuracy of 82.0% (81% and 80%, respectively).

Conclusion

Our novel AI-based system demonstrates strong potential as an automated tool to detect, localise, and quantify neutrophils to assess histological activity and predict response to therapy in a clinical trial UC cohort and real-world settings. This framework could be applied in clinical trials and routine clinical practice, offering objective guidance for personalised management in UC patients.

References

[1] Santacroce G, Meseguer P, Zammarchi I, et al. P406 A novel active learning-based digital pathology protocol annotation for histologic assessment in Ulcerative Colitis using PICaSSO Histologic Remission Index (PHRI). Journal of Crohn's and Colitis, Volume 18, Issue Supplement_1, January 2024, Pages i843–i844
[2] Graham S, Vu QD, Jahanifar M, et al. CoNIC Challenge: Pushing the frontiers of nuclear detection, segmentation, classification and counting. Med Image Anal. 2024;92:103047.

Disclosure

MI received research grants and consultant fees from Olympus, Pentax, Eli Lilly, and Janssen. All other authors declare no competing interests.