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.

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

Immune checkpoint inhibitors (ICIs) have marked a breakthrough in the management of a wide range of cancer types, leading to increased overall survival. However, this treatment is frequently associated with the onset of various immune-related adverse events (irAEs), including ICI-related diarrhea and colitis.¹ Current recommendations for patients with diarrhea or colitis grade 2 or higher (graded via CTCAE)² include the discontinuation of ICI and administration of immune suppressants (e.g. steroids or biologics), which may lead to worse outcomes in these patients.³ Therefore, alternative therapeutic strategies to manage irAEs are needed. The gut microbiota plays a pivotal role in the onset of gastrointestinal irAEs, but the role of its therapeutic modulation on these disorders is mostly unknown. ^4,5

Aims & Methods

Our aim was to evaluate the efficacy and safety of therapeutic microbiome modulation for gastrointestinal irAEs in cancer patients. We enrolled cancer patients affected by ICI-related diarrhea/colitis referred to our Microbiome Clinic from January 2023 to March 2025. After clinical evaluation, patients were stratified according to severity of diarrhea (graded via CTCAE)² and then received a microbiome-modulating therapy. Patients were followed-up for at least 8 week after the initiation of therapy. We collected data about patient demographics (age and gender), patient’s overall health status as assessed by the the Charlson Comorbidity Index (CCI)⁶, type of cancer, oncological therapy and its suspension, time in weeks from initiation of cancer therapy to onset of diarrhea, severity of diarrhea (graded via CTCAE)², time in weeks until resolution of diarrhea and resumption of oncological therapy

Results

We enrolled 42 patients in the study period (8 males, 34 females, mean age 58,3 years-old, mean CCI-index 5.8). All patients were treated with ICI (Pembrolizumab: n=25 , Dostarlimab: n=4, Nivolumab: n=4; Atezolizumab: n=3; Novulumab and Ipilumab: n=2, Cemiplimab: n=2; Mogamulizumab: n=1; Pertuzumab: n=1). Ten patients experienced G1 diarrhea (23,8%), 16 (38,1) G2, 15 (35,7%) G3 and one G4 (2,4%). As indicated by current European Guidelines³, 30 patients (71,4%) had to interrupt ICI due to diarrhea. Multi-strain probiotics were administered to 27 (64.3% ) patients, rifaximin to 22 (52,4%). Overall, 21 patients (50%) needed therapy with systemic steroids. Seven patients who experienced ICI-related colitis refractory to steroids and biologics were successfully treated with FMT. Twenty-eight patients (66.7% ) had a resolution of the diarrhea (G0) and 11 patients (26.2%) had diarrhea G1 at a mean time of 8 weeks. Upon resolution of diarrhea, nine of the 30 patients who had interrupted ICI (30%) were able to resume the treatment. None of the patients experienced any adverse event related to gut microbiota modulation as defined by CTCAE².

Conclusion

Therapeutic modulation of gut microbiota appears to be a promising safe and effective approach for treating ICI-related diarrhea and colitis. However, these preliminary findings need confirmation through more consolidated and well-designed studies.

References

1. Dougan M, Wang Y, Rubio-Tapia A, Lim JK. AGA Clinical Practice Update on Diagnosis and Management of Immune Checkpoint Inhibitor Colitis and Hepatitis: Expert Review. Gastroenterology. 2021;160(4):1384-1393. doi:10.1053/j.gastro.2020.08.063
2. Freites-Martinez A, Santana N, Arias-Santiago S, Viera A. Using the Common Terminology Criteria for Adverse Events (CTCAE - Version 5.0) to Evaluate the Severity of Adverse Events of Anticancer Therapies. Actas Dermosifiliogr. 2021;112(1):90-92. doi:10.1016/j.ad.2019.05.009
3. Haanen J, Obeid M, Spain L, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(12):1217-1238. doi:10.1016/j.annonc.2022.10.001
4. Wang Y, Wiesnoski DH, Helmink BA, et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat Med. 2018;24(12):1804-1808. doi:10.1038/s41591-018-0238-9
5. Wang T, Zheng N, Luo Q, et al. Probiotics Lactobacillus reuteri Abrogates Immune Checkpoint Blockade-Associated Colitis by Inhibiting Group 3 Innate Lymphoid Cells. Front Immunol. 2019;10. doi:10.3389/fimmu.2019.01235
6. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis. 1987;40(5):373-383. doi:10.1016/0021-9681(87)90171-8

Disclosure

G.I. has received personal fees for acting as speaker for Biocodex, Danone, Sofar, Malesci, Metagenics and Tillotts Pharma, and for acting as consultant and/or advisor for Ferring Therapeutics, Giuliani, Malesci and Tillotts Pharma. A.G. reports personal fees for consultancy from Eisai Srl, 3PSolutions, Real Time Meeting, Fondazione Istituto Danone, SinergieSrl, Board MRGE and Sanofi SpA personal fees for acting as a speaker for Takeda SpA, AbbVie and Sandoz SpA and personal fees for acting on advisory boards for VSL3 and Eisai. G.C. has received personal fees for acting as advisor for Ferring Therapeutics. All other authors have no conflicts of interest to disclose.

Introduction

Corpus atrophic gastritis (CAG) requires endoscopic-histological surveillance due to the risk of developing gastric neoplastic lesions (GNL). This study aimed to identify variables associated with GNL development at long-term follow-up using a feature ranking method based on a novel One-Class Support Vector Machine (SVM) model.

Aims & Methods

A dataset containing clinical, endoscopic, and histological variables from consecutive CAG patients (2001-2023) adhering to a surveillance program was considered. GNL presence at the longest available follow-up was recorded. Gastric biopsies and histological evaluations were conducted according to the updated Sydney system. CAG patients with any missing data or a GNL diagnosis at the baseline gastroscopy were excluded from the final analysis. A Fisher score-based feature ranking method and One-Class SVM were used to select the optimal subset of baseline variables associated with GNL development, aiming to achieve average sensitivity (Se) and specificity (Sp) above 80%.

Results

Overall, 355 CAG patients were initially considered. Of these, 36 were excluded due to the presence of GNL at baseline gastroscopy, and 216 for missing data. Thus, a total of 103 patients were considered and grouped into: CAG patients with [22 patients (F 68.1%), median age 68 (35-83) years] and without GNL at follow-up [81 patients (F 72.8%), median age 59(26-84) years]. After a median follow-up of 60 (12-192) months, 13 epithelial GNL (gastric adenocarcinoma or high/low-grade dysplasia) and nine type-1 gastric-neuroendocrine-tumors (T1gNET) were recorded. Parietal-cell-antibodies and pepsinogen-I < 30 μg/l were associated with both epithelial GNL and T1gNET. Antral inflammation and age > 60 were linked to epithelial GNL, while anti-thyroperoxidase-antibodies, smoking, and dyspeptic symptoms at CAG diagnosis were linked to T1gNET. Low-dose aspirin and H. pylori eradication therapy showed inverse associations with epithelial GNL and T1gNET, respectively.

Conclusion

This is the first study in which an AI model simultaneously considers clinical, endoscopic, and histological characteristics from a dataset of CAG patients, showing good sensitivity and specificity in identifying those variables associated with developing GNL. Nonetheless, we acknowledge the need for improved variable standardization and data balancing between groups to enhance model performance further.

Introduction

Spasmolytic polypeptide expressing metaplasia (SPEM) is a cell repair lineage and is a very important phenotype of gastric mucosal injury and precancerous lesion.
Previously, parietal cells loss is considered as the first step and followed with chief cells transdiffernation to induce SPEM. But whether chief cells initial loss cause SPEM
needs to be further investigation. Acidic mammalian chitinase (CHIA) belongs to the 18 glycosidase family and is highly expressed in the chief cells. Our previous study showed that CHIA deficiency in the chief cells is the key event to induce SPME to progress to gastric cancer (Liu et al., DDW 2023 and 2024). However, the molecular role of CHIA in the development of SPEM is need further investigated.

Aims & Methods

Electron microscopy, qRT-PCR and single-cell sequencing (scRNA-seq) technology, as well as histopathological and immunofluorescence (IF) stainning with specific markers were performed in chief cells specific CHIA knockout mouse model (CHIA^rox/rox-GIF-Dre) and wild-type mice(CHIA^rox/rox), and in CHIA over - expression mice (CHIA ^rox/rox - GIF - Dre + rAAv - CHIA) and the control group (CHIA ^rox/rox - GIF - Dre + rAAv - control).

Results

Compared with CHIA^rox/rox mice, histological analysis and scRNA-seq technology data showed that loss of chief cells with increased M2 macrophage infiltration and final SPEM formation, but remaining of parietal cells in CHIA^rox/rox-GIF-Dre mice. Electron microscopy showed CHIA deficiency in mice resulted in endoplasmic reticulum was dilated and swollen, as well as the mitochondrial membrane was discontinuous of chief cells, followed with the accumulation of endoplasmic reticulum stress marker, including PERK, XBP-1, eIF2α/P-eIF2α, and GRP78, together with upregulation of pyroptosis-related marker, including NLRP3, ACS, GSDMD, NEK7, Caspase1, Caspase11, IL-1β, and IL-18, which was detected by qRT-PCR. These data indicating that target CHIA deletion caused chief cells pyroptosis. Furthermore, qRT-PCR analysis showed that CHIA deficiency caused the activation of IL33/IL-13 circuit in the mucosa of mice. Moreover, double immunofluorescence staining confirmed that upregulation and colocalization of IL-33 induced M2 macrophage polarization markers, including F4/80 and CD163⁺ with NLRP3 in the base of gastric mucosal of CHIA^rox/rox-GIF-Dre mice when compared with CHIA^rox/rox mice.Notably, CHIA ^rox/rox - GIF - Dre + rAvv - CHIA mice reversed the above process compared with controls.

Conclusion

Chief cells specific CHIA deficiency resulted in endoplasmic reticulum stress mediate NLRP3 inflammasome activation to induce chief cells proptosis.
Chief cells initial loss is sufficient and the key step to activate IL-33/ST2-M2 macrophage polarization axis to induce SPEM, which is independent of parietal cells loss.

Introduction

Pathological esophageal acid exposure may persist in patients with Barrett’s esophagus (BE) despite standard proton pump inhibitor (PPI) therapy and symptom control, although current guidelines recommend at least standard-dose PPI for all patients with BE.¹

Aims & Methods

Aim was to evaluate the role of esophageal function testing in assessing acid exposure in BE patients on PPI therapy and in predicting neoplastic progression. We conducted a multicenter retrospective study including asymptomatic BE patients (defined by GerdQ total score <8 and a score of 0 on the first GerdQ item) who underwent high-resolution manometry and 24-hour pH impedance monitoring while on various PPI regimens. Maximal PPI therapy included esomeprazole 40 mg, pantoprazole 40 mg, rabeprazole 20 mg, or lansoprazole 30 mg, all administered twice daily. All other regimens were considered standard dosing. Index upper endoscopy with biopsies was performed under the same therapeutic regimen. Histologically, presence and degree of neoplasia (all confirmed by a second pathologist) was recorded. Acid exposure time (AET) <4% was defined as adequate acid control; AET >6% as pathological reflux. Predictors of pathological reflux and neoplasia were assessed using logistic regression analysis.

Results

A total of 135 patients (2016-2025) were included (mean age 58 ± 15 years; 73% male). Median BE length was C1 (range 0–3 cm) and M2 (range 1–5 cm), with 41% (n=56) classified as having long-segment BE. Sixty-seven patients (50%) were on standard-dose PPI. Pathological reflux was identified in 37 patients (27%), of whom 25 (67%) were on standard-dose therapy. Fourteen patients (10%) had borderline AET values (4–6%). Among the 84 patients (62%) with adequate acid control, 33 (39%) were taking standard-dose PPI. On multivariable analysis, standard-dose PPI (OR 3.04; 95% CI 1.34–6.89; p=0.008) and type III esophagogastric junction morphology (OR 2.52; 95% CI 1.01–5.01; p=0.047), consistent with manometric hiatal hernia, were independently associated with pathological reflux. Non-dysplastic BE was found in 112 patients, while 13 (10%) had neoplasia at index endoscopy (8 low-grade dysplasia, 3 high-grade dysplasia, 2 intramucosal adenocarcinoma). Pathological reflux was the only independent predictor of neoplasia (OR 10.41; 95% CI 2.65–41.26; p<0.001).

Table 1. Logistic regression analysis for factors associated with neoplasia on index endoscopy.

Conclusion

Nearly one-third of asymptomatic BE patients exhibit pathological reflux on pH-monitoring despite PPI treatment, predominantly among those on standard-dose and with manometric hiatal hernia. Nonetheless, adequate acid control is achieved in over one-third of patients on standard PPI therapy. Pathological reflux is associated with a 10-fold increased risk of neoplasia.

References

1. Shaheen NJ, Falk GW, Iyer PG, et al. Diagnosis and Management of Barrett's Esophagus: An Updated ACG Guideline. Am J Gastroenterol. 2022;117(4):559-587.