Introduction

Subjectively reported sleep disturbances are common in IBS¹, as are psychological comorbidities². Whilst sleep and psychological disorders are clearly linked, it has been demonstrated that sleep disturbances amongst IBS patients appear to exist independently of psychological factors³, raising the potential for sleep as a novel intervention target in IBS. Developing our understanding of the role and associations of sleep within the disease experience of IBS patients could lead to better treatment.

Aims & Methods

We aimed to compare the characteristics of patients with IBS according to the quality of their sleep. Participants were recruited from the NIHR research register ContactME-IBS. We collected data for demographics, gastrointestinal symptoms^4,5,6, psychological health⁷, quality of life^8,9, and impact on work and daily activities¹⁰using validated questionnaires among adults with Rome IV IBS. We dichotomised the cohort according to whether they were good or poor sleepers, defined by a Pittsburgh sleep index score >5¹¹. We compared the characteristics of the two groups to explore significant associations.

Results

Of 341 respondents with Rome IV IBS, 287 (84.16%) were poor sleepers. A significantly higher proportion of poor sleepers had been diagnosed with IBS for 5 years or more (82.2% vs 66.7% p=0.009). A greater proportion of good sleepers had a university or postgraduate level of education (59.3% vs 41.1% p=0.014), though this did not meet our threshold for statistical significance. Poor sleepers had a significantly higher burden of severe somatisation, nearly fivefold that of good sleepers (60.3% vs 13% p=<0.001). Poor sleepers reported higher levels of anxiety and depression symptoms. Amongst the good sleepers, none had abnormal depression scores. Poor sleepers experienced greater impairment of their work activities, and were more adversely affected in their home and social activities (p=<0.001 across all analyses). Though not statistically significant, poor sleepers reported higher IBS symptom severity. There was no statistically significant difference between poor and good sleepers in relation to their IBS subtype.

Table 1. Characteristics of Individuals with Rome IV IBS according to the quality of their sleep.

Conclusion

Individuals with Rome IV IBS who report poor sleep have significantly higher levels of somatisation and psychological comorbidity and are more adversely affected in both their work and personal lives, compared with those who report good sleep. Our findings could support the potential of sleep as an intervention target in the management of IBS.

References

1. Tu Q et al. Neurogastroenterol Motil. 2017;29(3).
2. Zamani M et al. Alimentary pharmacology & therapeutics. 2019;50(2):132-43.
3. Koloski NA et al. Alimentary pharmacology & therapeutics. 2021;54(5):627-36.
4. Palsson OS et al. Gastroenterology. 2016:S0016-5085 (16) 00180.
5. Whitehead W et al. Rome III: The functional gastrointestinal disorders, 3rd editionVirginia: Degnon Associates Inc. 2006:835-53.
6. Labus JS et al. Alimentary pharmacology & therapeutics. 2004;20(1):89-97.
7. Spiller R et al. Alimentary pharmacology & therapeutics. 2010;32(6):811-20.
8. Patrick DL et al. Digestive diseases and sciences. 1998;43:400-11.
9. Drossman DA et al. Official journal of the American College of Gastroenterology| ACG. 2000;95(4):999-1007.
10. Reilly M et al. Alimentary pharmacology & therapeutics. 2004;20(4):459-67.
11. Buysse DJ et al. Psychiatry research. 1989;28(2):193-213

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

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.

Introduction

Seladelpar is a first-in-class delpar (selective PPAR-delta agonist) indicated for the treatment of primary biliary cholangitis in combination with ursodeoxycholic acid (UDCA) in patients (pts) with an inadequate response to UDCA or as monotherapy in pts unable to tolerate UDCA. RESPONSE was a Phase 3, randomised, placebo-controlled clinical trial of seladelpar in pts with inadequate response/intolerance to UDCA. Pts completing RESPONSE were eligible to roll over into ASSURE (NCT03301506), an ongoing, open-label, long-term, Phase 3 safety trial. Here, we describe data from month 18 (month 6 of ASSURE) in pts with or without prior use of fibrates or obeticholic acid (OCA) who rolled over from RESPONSE into ASSURE.

Aims & Methods

Pts received 10 mg seladelpar orally daily or placebo in RESPONSE; pts received open-label 10 mg seladelpar in ASSURE. Fibrates and OCA were prohibited during the study period and a 6-week washout was required prior to entry in RESPONSE. Data were described for pts in ASSURE with or without prior use of fibrates/OCA and based on whether they received seladelpar (continuous seladelpar pts) or placebo (crossover pts) in RESPONSE. Efficacy included the percentage of pts achieving a composite biochemical response (CBR; alkaline phosphatase [ALP] < 1.67 × upper limit of normal [ULN], ALP decrease ≥ 15%, and total bilirubin ≤ ULN). Safety assessments included adverse events (AEs) and laboratory parameters.

Results

Among pts who continued into ASSURE from RESPONSE (158), 16 continuous seladelpar and 11 crossover pts reported prior use of fibrates/OCA (total, n=27; 17%); 88 continuous seladelpar and 43 crossover pts reported no prior use of fibrates/OCA (total, n=131; 83%). At month 18, among continuous seladelpar pts, 9/15 (60%) pts with prior fibrate/OCA use achieved a CBR vs 54/87 (62%) pts without prior fibrate/OCA use. Among crossover pts, 7/11 (64%) pts with prior fibrate/OCA use vs 32/41 (78%) pts without prior fibrate/OCA use achieved a CBR at month 6 of ASSURE. From ASSURE initiation to month 6, incidence of AEs was similar across continuous seladelpar and crossover pts, regardless of prior OCA/fibrate use; no treatment-related serious AEs were reported.

Conclusion

In this interim analysis of continuous seladelpar and crossover pts from ASSURE, pts who reported prior use of fibrates/OCA achieved a similar sustained biochemical response with seladelpar compared with pts who reported no prior use. Seladelpar appeared safe and well tolerated in this subgroup.

Disclosure

AV reports receiving speaker fees from Intercept Pharmaceuticals and participation on an advisory board with Novartis. DP reports receiving consulting fees from Mediar Therapeutics. AEK reports receiving grants or contracts from Gilead Sciences, Inc., Intercept Pharmaceuticals and Roche; consulting fees from AbbVie; Advanz Pharma; Alentis Therapeutics; Alfasigma; Astellas; AstraZeneca; Attovia Therapeutics; Avior Bio; Bayer; Bristol Myers Squibb; Böhringer-Ingelheim; CymaBay Therapeutics; Escient Pharmaceuticals; Falk; Gilead Sciences, Inc.; GSK; Guidepoint; Intercept Pharmaceuticals; Ipsen; Merck Sharp & Dohme; Mirum Pharma; Novo Nordisk; Rectify Pharma; Roche; and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie; Advanz Pharma; AOP Orphan Pharmaceuticals; Bayer; Bristol Myers Squibb; CymaBay Therapeutics; Falk; Gilead Sciences, Inc.; GSK; Intercept Pharmaceuticals; Ipsen; Johnson & Johnson; Medscape; Merck Sharp & Dohme; Mirum Pharma; NewBridge Pharmaceuticals; Novartis; Roche; Vertex Pharmaceuticals; and Viofor; support for attending meetings and/or travel from Gilead Sciences, Inc.; participation on a data safety monitoring board with AbbVie; Advanz Pharma; Alentis Therapeutics; Alfasigma; AstraZeneca; Avior Bio; Bayer; Bristol Myers Squibb; CymaBay Therapeutics; Escient Pharmaceuticals; Falk; Gilead Sciences, Inc.; GSK; Guidepoint; Intercept Pharmaceuticals; Ipsen; Merck Sharp & Dohme; Mirum Pharma; Novo Nordisk; Roche; and Takeda; and a leadership or fiduciary role in other board, society, committee, or advocacy groups (paid or unpaid) with PBC Foundation, Swiss Association for the Study of the Liver (SASL), Swiss Gastroenterology Society (SGG), Swiss Hepa, and Swiss Transplant Society (STS). VC reports receiving speaker fees from AbbVie; Advanz Pharma; Echosens; Gilead Sciences, Inc.; Ipsen; and Roche; and participation on an advisory board with Advanz Pharma; Gilead Sciences, Inc.; Ipsen; and Roche. EGD reports receiving consulting fees from Ipsen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Ipsen; support for attending meetings and/or travel from Advanz Pharma; and participation on a data safety monitoring board or advisory board for GSK. CH, XQ, SP, WTB, and TRW are employees of Gilead Sciences, Inc., and may own stock in Gilead Sciences, Inc. SCG reports receiving grants or contracts from AbbVie, Arbutus Biopharma, CymaBay Therapeutics, GSK, Ipsen, and Mirum Pharma; and participation on a data safety monitoring board or advisory board with CymaBay Therapeutics, GSK, and Ipsen.