Introduction

Current treatment options for IBD are limited by low clinical remission rates and loss of response. Most therapies target single pathogenic pathways and while combinations of biologics targeting different pathogenic cytokines can increase clinical remission rates, dosing schedules are inconvenient. JAK inhibitors, target multiple cytokine pathways, but are limited by safety concerns.
Salt-inducible kinases (SIKs) are a subfamily of serine/threonine kinases in the AMP-activated protein kinase (AMPK) family and act as key regulators of immune cell signaling. SIK inhibitors have been shown to target multiple cytokine pathways.
Three SIK isoforms exist: SIK1, SIK2 and SIK3. SIK inhibitors targeting multiple isoforms have been investigated in clinical trials. Although there have been signals of activity in patients with ulcerative colitis and psoriasis, limited efficacy and safety concerns related to SIK1 and 2 inhibition have hampered their development.

Aims & Methods

We performed structure based drug design to identify highly potent and selective SIK3 inhibitors that could offerbest in class efficacy and safety for the treatment of various auto-immune diseases. Our effort led to to the discovery of 100s of compounds spanning SIK3 binding sites. Compounds were tested in protein and cell-based assays to evaluate potency and selectivity against SIK3 and in a phenotypic human whole blood TNFα assay. Lead optimization involving rigorous testing in safety and pharmacology panels, resulted in the selection of lead candidates that were tested in a variety of translational models to identify the most efficacious compounds. Human PK predictions were performed using non-clinical in vivo PK assessments and allometric scaling leading to the selection of the drug candidate, which entered GLP toxicology studies.

Results

O3R-5671 is a highly potent and specific SIK3 inhibitor with sub-nanomolar potency for SIK3 and low activity against SIK1 and 2 and over all human kinases. It demonstrated potent activity in a panel of human primary phenotypic cell assays inhibiting TNFα, IL-12, and IL-23 release in LPS-stimulated myeloid cells, and inhibiting TNFa release in LPS-stimulated human whole blood. O3R-5671 also inhibited activation of TCR-stimulated human primary T cells and induced IL-10 secretion from myeloid cells.
In vivo, O3R-5671 demonstrated dose-dependent activity in a mouse LPS challenge model, dose-dependent efficacy in two distinct mouse models of IBD, and dose-dependent efficacy in mouse models of IL-23-induced psoriasis and psoriatic arthritis. Cross-species PK and allometric scaling were used to predict O3R-5671’s human PK profile- which is expected to be conducive to potent SIK3 inhibition and clinical efficacy in patients with IBD.
O3R-5671 demonstrated a highly attractive profile in ADME and in vitro safety panels. Six-week GLP toxicity studies in rats and dogs established no observed adverse effect levels (NOAELs) which support dosing in humans with doses that are predicted to be pharmacologically active with a large safety margin.

Conclusion

O3R-5671 is a highly specific and potent SIK3 inhibitor that is predicted to have a flat PK profile in humans. These properties should allow O3R-5671 to apply strong drug pressure on SIK3 while sparing SIK1 and 2. This is expected to result in the inhibition of multiple pathogenic cytokines including TNFa and IL-23, both of which have been validated as IBD targets. A clinical trial is ongoing to establish the safety and PK profile of O3R-5671 and understand its effect on pharmacodynamic biomarkers.

Disclosure

All authors were employed by Galapagos who discovered O3R-5671 or Novalix, a CRO that was employed by Galapagos. Some authors are employed by Onco3R therapeutics, who are currently developing O3R-5671

Introduction

Few studies have examined esophageal motility disorders in patients with type 2 diabetes operated with sleeve gastrectomy (SG) or gastric bypass (RYGB).

Aims & Methods

We have recently reported overall prevalence of gastroesophageal reflux disease (GERD) in this group of patients (1) and now aimed to investigate potential differences between the two surgical methods regarding the prevalence of dysmotility 5 years after surgery. Furthermore, we also aimed to analyse and report on the available GERD-data in detail.
In the Oseberg study (January 2013 – December 2022), 125 patients with BMI ≥ 35 kg/m² and type 2 diabetes were screened, sixteen patients were excluded or withdrew consent, leaving 109 patients allocated to SG (n=55) or RYGB (n=54). To assess reflux symptoms, GerdQ (Gastroesophageal reflux disease questionnaire) was completed. Gastroscopy and 24-hour pH monitoring were used to examine GERD. High-resolution manometry with the Chicago classification v3.0 was used to assess esophageal motility.

Results

At inclusion the average age was 47.7 years (SD 9.6), BMI was 42.3 kg/m2 (5.3), and 66% were women. At the 5-year follow-up, 29 (53%) patients in SG-group and 32 (59%) in RYGB-group underwent gastroscopy, 22 (40%) vs. 25 (46%) underwent 24-hour pH monitoring, 23 (42%) vs. 26 (48%) underwent manometry, and 42 (76%) vs. 42 (78%) completed GerdQ. The proportion of patients with GERD symptoms (GerdQ ≥8) was low in both groups, with a slightly lower prevalence after RYGB (2%) than after SG (14%). There was no difference in the prevalence of erosive esophagitis between the groups (38% in SG and 41% in RYGB), all findings with less advanced esophagitis (Los Angeles grades A and B), but one patient in each group had new onset Barrett's esophagus. The proportion of patients with pH<4 for more than 6% of the recording (Acid exposure time, AET) was significantly higher after SG compared with RYGB (59% versus 8%, p < 0.0001). Esophageal dysmotility was diagnosed in 14 (61%) after SG compared with 19 (73%) patients after RYGB. Most of these patients (n=22) had hypertensive or hypotensive lower esophageal sphincter (LES), with no difference between groups. The remaining 11 patients had ineffective esophageal motility (IEM) or elevated distal contractile integral (DCI). None of the patients with dysmotility reported swallowing difficulties or chest pain with food intake.

Conclusion

The Oseberg study demonstrates a high prevalence of asymptomatic esophageal dysmotility after SG or RYGB with uncertain clinical relevance. Furthermore, a seven times higher prevalence of pathological acid reflux after SG compared with RYGB was demonstrated, but the prevalences of erosive esophagitis and esophageal dysmotility were approximately similar between groups. Few of the examined patients reported GERD symptoms, hence objective assessment of GERD should be included in long-term follow-up after SG to detect and prevent the development of Barrett's esophagus, dysplasia, and adenocarcinoma.

References

1. Hauge JW et al., Effect of gastric bypass versus sleeve gastrectomy on the remission of type 2 diabetes, weight loss, and cardiovascular risk factors at 5 years (Oseberg): secondary outcomes of a single-centre, triple-blind, randomised controlled trial. Lancet Diabetes Endocrinol. 2025 Apr 1:S2213-8587(24)00396-6

Introduction

Endoscopic submucosal dissection (ESD) is an effective treatment for superficial esophageal cancer, but postoperative stenosis remains a significant concern. Particularly, probability of the stenosis is less investigated in cases with a 50%-75% circumferential mucosal defect.

Aims & Methods

This study aimed to identify influential factors for postoperative stenosis after the moderate circumferential resection in esophageal ESD. This multi-center retrospective observational study analyzed data from 513 patients across 19 institutions who underwent esophageal ESD from April 2018 to March 2022 and showed 50% to 75% of the circumferential mucosal defect. We firstly overviewed the current status on the postoperative stenosis, the steroid use, and postoperative adverse events in these patients. Subsequently, we identified influential factors for postoperative stenosis. Patients were categorized into stenosis and no stenosis groups, and univariate and multivariate analyses were performed for each parameter. We further investigated influential factors of stenosis in two cohorts: steroid and no steroid groups. Finally, the parameters were compared between the steroid and no steroid groups to assess the tendency of the steroid use in general practice.

Results

Postoperative stenosis was observed in 28 cases (5%). Univariate analysis comparing the stenosis group (n = 28) and no stenosis group (n = 485) revealed significant differences in the prior endoscopic treatment near the lesion (p = 0.02), cervical esophageal location (p = 0.04), defect circumference (p =0.01), and procedure duration (p = 0.02). There was no significant difference in the steroid use between two groups. Multivariate analyses identified history of prior endoscopic treatment close to the lesion (p = 0.01, odds ratio [OR], 5.10), cervical esophageal lesions (p = 0.03, OR, 3.97), large circumferential defect (p <0.01, OR, 3.78), and longer procedure duration (p <0.01, OR, 3.83) as independent risk factors for stenosis formation. Among the steroid group, significant associations of the postoperative stenosis were revealed with the prior endoscopic treatment near the lesion (p = 0.02), cervical esophageal location (p = 0.04), and >5/8 of defect circumference (p = 0.02). In the no steroid group, only the procedure duration (p = 0.01) showed a significant difference between the stenosis and non-stenosis groups. Comparison between the steroid (n = 223) and no steroid groups (n = 290) revealed significant differences in the prior endoscopic treatment near the lesion (p <0.01), cervical esophageal lesions (p <0.01), and resected specimen dimensions (p <0.01). The stenosis rates were 7% in the steroid group and 4% in the no steroid group, without a significant difference. No significant difference in adverse events was observed between the two groups.

Conclusion

In esophageal ESD with a 50%-75% circumferential mucosal defect, the steroid was used in over 40% of patients, and postoperative stenosis still occurred in 5%. Because wider circumference, location of the cervical esophagus, prior endoscopic treatment close to the lesion, and prolonged operative time were identified as independent risk factors on the stenosis, steroid therapy should be preferred in these cases. Particularly, lesions with a history of endoscopic treatment, on cervical esophagus, and with >5/8 of defect circumference should require more aggressive countermeasures than currently applied.