Introduction

Currently, the only management option for patients with celiac disease (CeD) is lifelong adherence to a gluten-free diet (GFD). Here, we report the results of a phase 2 study of the computationally designed glutenase TAK-062 (zamaglutenase) for the treatment of CeD in patients on a GFD (NCT05353985).

Aims & Methods

Eligible patients were aged >18 years with ongoing CeD-related gastrointestinal (GI) symptoms and villous height to crypt depth ratio (Vh:Cd) <2.5, despite maintenance of a GFD for ≥1 year. Study phases were: (1) a 4-week screening period to confirm symptoms and perform endoscopy; (2) a 4-week single-blind placebo run-in, including 2 weeks receiving placebo simulated inadvertent gluten exposure (SIGE) bars (Weeks −4 to −2) and 2 weeks receiving SIGE bars containing approximately 500 mg of gluten 3× per week (TIW; Week −2 to Day 1); and (3) a 24-week treatment period with patients randomized to receive TAK-062 600 mg or placebo with meals 3× per day (TID), plus gluten-containing SIGE TIW, followed by an endoscopy. Symptoms were assessed daily using the 5-item Celiac Disease Symptom Diary v2.1 (CDSD), that evaluates the severity of CeD symptoms on a 5-point Likert scale.

The primary endpoint was change from baseline to Week 12 in mean weekly CDSD GI symptom severity scores, and the secondary endpoint was change from baseline to Week 24 in Vh:Cd. Safety was assessed throughout the study. Differences between groups were assessed using a mixed model for repeated measures (primary endpoint) and ANCOVA (secondary endpoint) at a 2-sided significance level of 0.05.

Results

A total of 153 patients were randomized (placebo: n = 76; TAK-062: n = 77); one patient in the TAK-062 arm did not receive treatment. Mean age was 46.0 years, 75.2% of patients were female, mean time since diagnosis was 8.7 years, and 24.2% were seropositive. Mean baseline Vh:Cd was 1.78 and mean baseline weekly CDSD GI symptom severity score was 0.93. There were no appreciable differences between groups in baseline characteristics.

There was no significant improvement in weekly CDSD GI symptom severity score from baseline to Week 12 in either arm, and no significant difference between groups; non-significant improvements of approximately 0.1 were observed in both arms (Table). Vh:Cd remained stable to Week 24 in the placebo arm, but significantly decreased by 0.34 (95% confidence interval: −0.53, −0.14) in the TAK-062 arm, with a significant difference between groups (Table). Similar results were observed in all subgroups assessed.

TAK-062 was clinically well tolerated despite the significant decrease in Vh:Cd, with comparable proportions of patients in both arms experiencing an adverse event (AE) (placebo: 64.5%; TAK-062: 73.7%) or serious AE (placebo: 5.3%; TAK-062: 1.3%). The most frequent AEs were GI-related and occurred at a similar frequency in both arms, with the exception of diarrhea (placebo: 2.6%; TAK-062: 17.1%).

Conclusion

TAK-062 did not demonstrate efficacy for improving symptoms or histology in patients with ongoing active CeD on a GFD. Vh:Cd significantly worsened in the TAK-062 arm, with a significant difference between groups; possible reasons for this are under investigation. Stable Vh:Cd in the placebo arm indicates that SIGE successfully mitigates trial-related disease improvements previously observed in similar cohorts.

Disclosure

LE has nothing to disclose. ML reports receiving consulting fees from Anokion, EllaOla, and Takeda, and research funding from Moderna (institution) and Takeda (institution). PR has nothing to disclose. CC has nothing to disclose. JS reports receiving consulting fees from Chugai, GIG, and Takeda, and research funding from Takeda. JAM reports grants from ImmusanT, National Institutes of Health, Department of Defense, Immunogenix, Takeda Pharmaceuticals, Allakos, Provention Bio, Oberkotter Foundation, and 9 Meters Biopharma; a contract (to institution) from Kanyos Bio (a wholly owned subsidiary of Anokion); consultancy fees from Johnson and Johnson, Bristol Myers Squibb, Intrexon Corporation, Dren Bio, Neoleukin Therapeutics, Reistone Biopharma, Immunic Therapeutics, Senda Biosciences, Brightseed Bio, Chugai Pharma, Alimentiv, Equillium, Interlude Biopharma, Ukko Inc., argenx; has received royalties from Torax Medical and Evelo Biosciences; and holds shares in Entero Healthcare and Minnesota Medical Technologies. DSS reports receiving honoraria and research funding from Takeda. HL, JRM, MZ, SG, and DAL are employees and shareholders of Takeda.

Introduction

Food related symptoms are frequently reported by patients with IBS and can occur within 30 minutes of a meal. The mechanisms underlying food-related symptoms likely involve local immunological reactions to food. To date, most research has focused on the distal GI tract and data on the proximal small intestine – the segment most exposed to food- is scarce.

Aims & Methods

Aim: To characterize the duodenal microenvironment, permeability and systemic inflammatory markers in patients with frequent food-related symptoms.
Methods: Cross-sectional study of a cohort of patients with IBS and age- and sex-matched healthy controls (HC). Symptoms were assessed using the Rome IV diagnostic questionnaire and daily symptoms were assessed daily using visual analog scales (reported as the mean of two weeks). Markers of systemic inflammation were assessed using Roche Cobas c502 (high-sensitivity C-reactive protein (hs-CRP)), Sysmex XN-9100 (white blood cell (WBC) count) and Thermo Fisher Phadia1000 (IgE and tryptase) on a Phadia 1000 platform. Small intestinal permeability was measured ex vivo in Ussing chambers, in vivo via the laculose/mannitol ratio in a 2-hour urine collection (LMR, 5g lactulose and 1g mannitol ) and by quantifying epithelial gaps using confocal laser endomicroscopy (CLE). Duodenal immune cell composition was quantified histologically and eosinophilic cationic peptide (ECP) and tryptase content were measured in mucosal lysates. Immune cell activity was assessed by quantifying the spontaneous release of tryptase and eosinophil-derived neurotoxin in biopsy supernatants. Assessed variables are presented in the table. Group-wise comparisons, correlation with daily symptoms and principal component analysis (PCA) were performed.

Results

Thirty-five patients with Rome IV IBS and 15 age- and sex-matched HC were included in this analysis. Patients with IBS had significantly higher tryptase content in the duodenal mucosa than HC (299 ng/mg total protein vs 143 ng/mg, p = 0.016) – none of the other variables were different between patients and HC. Based on the frequency of food-related pain, we subdivided patients with IBS into patients with frequent food-related pain (n = 22, overall ≥80% of abdominal pain episodes food-related) and patients with infrequent food-related pain. Using unsupervised PCA, patients with frequent and infrequent food-related symptoms did not cluster separately. There was no difference in duodenal eosinophil or mast cell counts between frequent and infrequent food-related pain. The proportion of patients with comorbid functional dyspepsia (FD) was not different between groups (45% vs 55%, p = 0.6). In the subgroup with frequent food-related symptoms, daily abdominal pain severity correlated significantly with LMR (r = 0.59, p = 0.02), hs-CRP (r = 0.69, p < 0.01) and WBC count (r = 0.55, p <0.01). In contrast, none of the duodenal variables correlated with pain severity.

Conclusion

The content of duodenal tryptase was significantly higher in patients with IBS than in HC. We found no differences in the duodenal micro-environment between patients with frequent and infrequent food-related symptoms. Among patients with IBS, the subgroup with the most frequent food-related symptoms showed significant correlations of daily pain severity and duration with hs-CRP, WBC and LMR, suggesting a possible pathophysiological role of systemic immune activation and small intestinal permeability. These preliminary findings warrant a larger-scale assessment.

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.