Introduction

Extended mesenteric resection has recently been proposed to improve clinical outcomes after an ileocolic resection (ICR) for Crohn’s disease (CD).

Aims & Methods

The aim of this study was to analyse the clinical relevance of an extended mesenteric resection, up to the level of the ileocolic trunk (intervention group), when compared to conventional mesenteric sparing resection (control group) with respect to postoperative outcomes in patients undergoing primary ICR for CD. In a multicentre international RCT, patients ≥16 years, undergoing elective surgery, were assigned 1:1 to either the intervention- or the control-group. The anastomotic technique was standardised (side-to-side stapled). To demonstrate a relevant decrease of 25% in postoperative endoscopic recurrence ((ER), according to local scoring; modified Rutgeerts score ≥i2b) at 6 months, a minimum of 62 evaluable patients per arm were required. Secondary outcome parameters were postoperative morbidity and the need to (re-)start medication within 6 months following surgery. The last patient (n=139) was included in April 2023 and the final analyses will be available from October 2023.

Results

Currently, the primary endpoint is available in 90/139 included patients: 47 in the intervention group, and 43 in the control group. Overall, there were 41 (46%) men with a median age of 39 (IQR 25 – 55). There were no statistically significant differences in baseline characteristics between the two groups, although numerically more patients received postoperative medical prophylaxis in the intervention group (30% vs 16%, Table 1: baseline characteristics). ER was observed in 19/47 (40%) of patients in the intervention group and in 22/43 (51%) in the control group (p=0.3). In the control group, more patients (re-)started medication after endoscopy (intervention group 23% vs control group 35%). This resulted in an overall comparable number of patients in both groups being on Crohn’s medication after six months. There was no significant difference in length of resection-specimens between groups (median length coecum/colon 7 cm; ileum 24.5 cm). A trend was seen towards more active inflammation in the distal resection margin in the control group when compared to the intervention group (23% vs 7%). Overall, a postoperative complication was reported in 28 patients (31%), with 4 suffering from an anastomotic leak. There were no significant differences between the groups.

Conclusion

This is the first RCT presenting data on the effect of an extended mesenteric resection during ICR for CD. Preliminary results on the first 90 out of 139 included patients do not demonstrate the hypothesized reduction in endoscopic recurrence, which suggests that final analysis of the primary outcome in October 2023 will not be able to demonstrate superiority of this surgical technique.

Disclosure

none to declare

Introduction

Oncostatin M (OSM) is a pleiotropic cytokine belonging to the interleukin (IL)-6 family that acts on a large variety of cells involving two distinct heterodimeric receptor complexes: leukemia inhibitory factor receptor beta (LIFRβ) and OSM receptor beta (OSMRβ) that is the receptor able to mediate the most relevant biological effects of OSM in mice. OSM has been proposed to contribute to the progression of chronic liver diseases, hepatocellular carcinoma (HCC) development and metastasis. High levels of OSM were found in cirrhotic patients with different etiology carrying HCC. In particular we observed that OSM serum levels are significantly higher in patients carrying non-alcoholic steatohepatitis (NASH)-related HCC, as compared to those whit viral etiologies, and their increase paralleles the disease progression from simple steatosis to HCC. Noteworthy, OSM serum levels are significantly higher in patients with intermediate/advanced HCC and correlate with poor survival.

Aims & Methods

This work discusses the role of OSM in relation to the development of HCC in a NASH background. We investigated the role of OSM taking advantage of: a) cohort of NASH patients with HCC; b) human THP1 macrophage cell lines exposed to human recombinant OSM (hrOSM); c) Wild type (wt) mice fed with a control diet (CSAA) or a lipogenic diet (CDAA) for 24 weeks in order to reproduce the non-alcoholic fatty acid disease (NAFLD)/NASH pathogenic phenotype (CSAA-CDAA protocol); d) Wild type (wt) and OSMRβ knock out (OSMRβ^-/-) mice treated with a protocol of NASH-related liver carcinogenesis (DEN/CDAA protocol).

Results

In patients with NASH-related HCC, OSM is expressed in cancer cells and its expression increases with patient tumor grade. In in vitro experiments, conducted on human THP1 macrophages exposed to hrOSM, we found that OSM is able to promote an M2 pro-tumorigenic phenotype, which is due to the activation of STAT3 and PI-3K/Akt signaling pathways. Accordingly, OSM expression, which was found increased in NASH-related liver tumours of wt mice during the progression of NAFLD/NASH towards HCC, correlates with F4/80 gene expression. This data suggests an interplay between OSM and macrophages recruitment/functions in the tumor microenvironment. In particular, wt mice treated with the DEN-CDAA protocol show a stronger promotion of the M2 phenotype compared with the M1 and in these mice OSM transcript levels correlate better with M2 macrophage polarization markers. As OSMRβ is fundamental for the activation of the OSM-related STAT3 and PI-3K/Akt signaling pathways, the OSMRβ^-/- murine model was employed to exploit the role of OSM in this regard. In this respect, the data obtained in the OSMRβ^-/- murine models shows that the livers of these animals develop smaller tumours. This event appears to be due to: i) a decreased amount of M2 Tumor Associated Macrophages (TAMs) in the nodules as revealed by the reduction of transcription levels of CD163, PDL1, ARG1, CCL2 and CCR2 compared with wt mice; ii) a impairment of the angiogenic process as shown by lower transcript levels of VE-cadherin, VEGFR2 and CD105 compared with wt mice; iii) a reduction of tumor growth demonstrated by decreased levels of proliferation markers (PCNA, Ki67).

Conclusion

Experimental data highlight a pro-carcinogenic contribution for OSM in NASH, by promoting pro-tumorigenic inflammation, suggesting a possible role for the OSM/OSMRβ axis as therapeutic target for NASH-related HCC.

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.