Introduction

Celiac disease (CeD) is triggered by gluten peptides that bind to HLA-DQ2 or -DQ8 in the small intestine leading to gluten specific Th1 T cell expansion and villous atrophy. The oral transglutaminase 2 inhibitor Zed1227 blocks the deamidation of gliadin peptides, a prerequisite for effective gliadin antigen presentation. The CEC-3 clinical trial demonstrated that Zed1227 effectively prevented mucosal damage in 160 CeD patients in remission challenged with 3 g gluten daily for 6 weeks (Schuppan D et al, NEJM 2021).

Aims & Methods

We analyzed regulatory T cell (Treg) gene expression pre and post gluten challenge in the 100 mg/d Zed1227 vs placebo treated patients using RNAseq from the patients’ small intestinal biopsies (Dotsenko V et al, Nat Immunol 2024). We focused on genes of Treg subtypes and related cells. Subanalysis was performed via different gene set enrichments for Treg subsets, regulatory pathways and cell types. Genes that were enhanced in favorable vs unfavorable villous height to crypt depth (V/C) ratio outcomes, also after placebo treatment, were analyzed. We further analyzed pre-disposing genes before challenge, favoring a beneficial or negative post challenge V/C outcome.

Results

93% of the top 100 most significant regulatory genes were upregulated in Zed1227-treated patients compared to those treated with a placebo. These regulatory genes included TGF-beta signaling genes such as Smad7 and MERTK, cholesterol- and fatty acid related genes, such as ACAT1 and NPC1L1, specific autophagy/apoptosis related genes such as VPS35, SQSTM1, BMF, and inhibitory genes like SOCS2. Zed1227 treated patient samples with a maintained post challenge V/C ratio showed evidence for upregulated iTreg genes. Interestingly, Treg genes from placebo-treated subjects were upregulated in correlation with better inflammatory control under gluten challenge compared to worse control.
Moreover, in pre-challenge duodenal samples we identified protective genes that help maintain tolerance during gluten challenge, as reflected by a better post challenge V/C ratio. Examples are ubiquitin ligase RNF167, BAD, FOXN3, BAG1 and CLAUDIN15, whereas other genes like IRF9, CD96 and HLA-/TAP1 were predictive of a more pronounced V/C ratio decline after gluten exposure.

Conclusion

Our data derived from superbly analyzed pre- and post challenge duodenal biopsies demonstrate an active anti-inflammatory immune modulation, largely Treg cell mediated, in CeD in patients prior to and during gluten challenge. Zed1227 treatment potently activates this regulatory response. The balance of several beneficial vs detrimental predisposing Treg-related genes may play a causative role in the variable sensitivity of CeD patients to gluten exposure. Our data support future Treg based therapies to attenuate inflammation in CeD and other (intestinal) autoimmune diseases.

References

Schuppan, D., Mäki, M., Lundin, K. E. A., Isola, J., Friesing-Sosnik, T., Taavela, J., Popp, A., Koskenpato, J., Langhorst, J., Hovde, Ø., Lähdeaho, M. L., Fusco, S., Schumann, M., Török, H. P., Kupcinskas, J., Zopf, Y., Lohse, A. W., Scheinin, M., Kull, K., Biedermann, L., … CEC-3 Trial Group (2021). A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease. The New England journal of medicine, 385(1), 35–45. https://doi.org/10.1056/NEJMoa2032441
Dotsenko, V., Tewes, B., Hils, M., Pasternack, R., Isola, J., Taavela, J., Popp, A., Sarin, J., Huhtala, H., Hiltunen, P., Zimmermann, T., Mohrbacher, R., Greinwald, R., Lundin, K. E. A., Schuppan, D., Mäki, M., Viiri, K., & CEC-3 Investigators (2024). Transcriptomic analysis of intestine following administration of a transglutaminase 2 inhibitor to prevent gluten-induced intestinal damage in celiac disease. Nature immunology, 25(7), 1218–1230. https://doi.org/10.1038/s41590-024-01867-0

Disclosure

V.D. and K.V. received funding from Dr. Falk Pharma to Tampere University to conduct the study. B.T., T.Z., R.M. and R.G. are employees of Dr. Falk Pharma. The data presented here are the subject of patent applications EP24173619.8 and EP24173615.6 filed by Dr. Falk Pharma, and B.T., T.Z., R.M., R.G., V.D. and K.V. are inventors on these applications. M.H. and R.P. are employees of Zedira. J.T. is a consultant for Jilab Oy and Dr. Falk Pharma. K.E.A.L. is a consultant for Amyra, Bioniz Pharmaceuticals, Chugai Pharmaceutical, Dr. Falk Pharma, Itrexon Actobios, TOPAS Therapeutics and Takeda California. D.S. is the data and safety monitor for Boehringer Ingelheim (Phil.) and is a consultant for the Dr. Falk Pharma, Takeda, Immunic, Sanofi and TOPAS Therapeutics. J.I. is the owner of Jilab Oy. M.M. is the founder, owner and Chair of the Board of Maki HealthTech (MHT). MHT receives Management/Advisory Affiliation fees from Dr. Falk Pharma and other funding not related to the research from Topas Therapeutics, Calypso Biotech, Vaccitech, ImmunogenX, Equillium and Immunic. MHT holds patents (patent number 7361480 (United States) and European Patent Office Number 1390753) licensed to Labsystems Diagnostics from where MHT receives royalties via Tampere University Hospital. All other authors declare no competing interests.

Introduction

Local excision (LE) is increasingly used to treat early rectal cancer (cT1-2N0M0), but its role in pT2 cancer remains controversial due to a reported 20–30% risk of lymph node metastasis (LNM). Since this risk is largely linked to adverse histological features, patients without these risk factors may safely avoid completion total mesorectal excision (cTME). We aimed to refine LNM risk in pT2 rectal cancer following LE to better guide decisions on rectal-preserving treatment strategies.

Aims & Methods

Patients with pT2 rectal cancer who underwent en bloc LE for cT1-2N0M0 lesions were retrospectivelly enrolled from seven international centres (2015-2025). Eligible patients received either cTME or active surveillance with MRI follow-up for at least two years. Exclusion criteria were positive resection margins (<0.1mm), synchronous or recurrent colorectal cancer and (neo)adjuvant therapy. LNM were confirmed through TME histology or considered absent when no suspicious lymph nodes appeared on follow-up MRI. A detailed histological review of LE specimens was conducted by specialised pathologists at each participating centre using a standardised protocol. Assessed risk factors included high-grade differentiation and/or mucinous subtype, lymphovascular invasion (small and/or large vessels), tumour budding grade 2-3 and/or poorly differentiated clusters grade 2-3, and perineural invasion. Primary endpoint was LNM rate in patients without histological risk factors. Secondary endpoints included the association between individual risk factors and LNM, as well as locoregional recurrences during active surveillance.

Results

A total of 103 patients (mean age 66 (SD 10), 56% male) with a median lesion size of 25mm (IQR 15) were included. Endoscopic LE was performed in 31 patients (30%) and surgical LE in 72 (70%). After LE, 76 patients (74%) underwent cTME while 27 (26%) opted for active surveillance. The overall LNM rate was 17.5% (18/103). Among the 36 patients (35%) without histological risk factors, the LNM rate was 5.6% (2/36; OR 0.19, 95% CI 0.04-0.87, p=0.032). Both LNM cases were detected in the cTME group. LNM rates per individual risk factor are presented in Table 1.
In the active surveillance group, no locoregional recurrences occurred in the ten patients without risk factors during a median follow-up of 53 months (IQR 26). Among patients with risk factors, two of 14 patients with one risk factor developed a locoregional recurrence and one of two patients with two risk factors. All recurrences occurred intramurally following prior surgical LE. The only patient with three risk factors had no locoregional recurrence but died from unrelated cause at 24 months.

Table 1. Univariate analyses of histological risk factors for lymph node metastasis

Conclusion

In this group of pT2 rectal cancer patients treated with LE, detailed histological analysis suggests a low LNM risk (5.6%) in patients without histological risk factors. No locoregional recurrences occurred in this low-risk group during active surveillance. As 35% of pT2 rectal cancers lacked histological risk factors, a risk-stratified approach could potentially allow a substantial proportion of patients to avoid cTME. Prospective validation in larger cohorts is needed before clinical implementation.

Introduction

Duvakitug, a human IgG1 monoclonal antibody, inhibits TL1A binding to death receptor 3 (DR3), which drives inflammation in Crohn’s disease (CD). The RELIEVE-UCCD trial (NCT05499130), a 14-week induction study, evaluated duvakitug in ulcerative colitis and CD. This was the first placebo-controlled study of an anti-TL1A in moderately to severely active CD. This subgroup analysis was performed to understand the impact of duvakitug in patients with moderate and severe endoscopic inflammation by assessing Week 14 outcomes in subgroups based on endoscopic disease severity at baseline.

Aims & Methods

Patients with CD (N=138) were randomized (1:1:1) to receive a subcutaneous (SC) loading dose (LD) of duvakitug 2250 mg followed by SC duvakitug 900 mg or duvakitug 450 mg every 2 weeks (q2w), or matching placebo LD followed by placebo q2w. Patients were required to have a simple endoscopic score for Crohn’s disease (SES-CD) ≥6 (≥4 for isolated ileal disease) for study eligibility. In this analysis, endoscopic and patient-reported clinical outcomes were assessed by baseline SES-CD scores of ≤15 (moderate) and >15 (severe).¹ Endpoints included response and remission based on endoscopic assessment (SES-CD) and clinical assessment [2-item Patient Reported Outcome assessment tool (PRO2)] at Week 14. Outcomes were analyzed using descriptive summary statistics.

Results

Among patients with severe endoscopic activity (SES-CD >15) at baseline, endoscopic response was achieved by 36% in the duvakitug 900 mg arm, and 18% in the duvakitug 450 mg arm compared to 8% in the placebo arm. In patients with moderate endoscopic activity (SES-CD ≤15) at baseline, endoscopic response was achieved by 51% in the duvakitug 900 mg arm, and 29% in the duvakitug 450 mg arm compared to 15% in the placebo arm (Table). Greater proportion of patients achieved endoscopic remission, clinical response and remission with both doses of duvakitug compared to placebo in the moderate and severe endoscopic subgroups (Table). The overall adverse event profile was similar across treatment arms by disease severity subgroups.

Table: Week 14 endoscopic and clinical response and remission in CD patients with moderate and severe endoscopic activity at baseline

Conclusion

In CD patients, duvakitug demonstrated efficacy in endoscopic and patient-reported clinical outcomes in both moderate and severe endoscopic activity subgroups in this Phase 2b study. Duvakitug was well tolerated across both subgroups. These findings support further development of duvakitug as a potential treatment option for moderately to severely active CD.

References

1. Moskovitz DN, Daperno M, Van Assche G. Defining and validating cut-offs for the Simple Endoscopic Score for Crohn's Disease. Gastroenterology 2007; 132:S1097.

Disclosure

W.R. has served as a speaker for AbbVie, Celltrion, Ferring, Janssen, Galapagos, Merck Sharp & Dohme, Roche, Pfizer, Sobi and Takeda; as a consultant for AbbVie, Amgen, AOP Orphan, Boehringer Ingelheim, Bristol Myers Squibb, Calyx, Celltrion, Eli Lilly, Galapagos, Gilead,
Index Pharma, Janssen, Medahead, Microbiotica, Pfizer, Teva and Takeda; as an advisory board member for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Galapagos, Janssen, Pfizer and Teva; and have received research funding from AbbVie, Janssen, Sandoz, Sanofi and Takeda.
V.J. has received consulting/advisory board fees from AbbVie, Alimentiv, AnaptyisBio, Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Enthera, Ensho, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Innomar, JAMP, Janssen, Merck, Metacrine, Mylan, MRM Health, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus Biosciences, Reistone Biopharma, Roche, Roivant, Sandoz, Second Genome, Sorriso, Spyre, Synedgen, Takeda, Teva, Ventyx and Vividion; and speaker’s fees from, Abbvie, Ferring, Bristol Myers Squibb, Eli Lilly, Fresenius Kabi, Janssen, Pfizer, Shire, Takeda and Tillotts.
B.S. has served as a consultant or received speaker’s fees from AbbVie, Abivax, Adiso Therapeutics, Alimentiv, Amgen, Arena Pharmaceuticals, Artizan Biosciences, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Celltrion Healthcare, ClostraBio, Connect Biopharm, Cytoki Pharma, Eli Lilly and Company, Entera, Evommune, Ferring, Fresenius Kabi, Galapagos, Gilead, Genentech, Glaxo SmithKline, Gossamer Bio, HMP Acquisition, Imhotex, Immunic, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido, Kalyope, Merck, MiroBio, Morphic Therapeutic, MRM Health, OSE Immunotherapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, RedHill Biopharma, Sun Pharma Global, Surrozen, Synlogic Operating Company, Takeda, Target RWE, Theravance Biopharma R&D, TLL Pharmaceutical, USWM Enterprises, Ventyx Biosciences, Viela Bio, and has stock options from Ventyx Biosciences.
S.D. reports consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring Pharmaceuticals, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB, and Vifor; and reports lecture fees from Abbvie, Amgen, Dr Falk Pharma, Ferring Pharmaceuticals, Gilead, Janssen, Mylan, Pfizer, and Takeda.
K.A., N.G., B.R-D. are employees of Teva Pharmaceutical Industries Ltd.
P.L. is an employee of Sanofi.
Duvakitug is being developed in partnership by Teva and Sanofi.