Introduction

GS-1427 is a novel selective small molecule inhibitor of the integrin receptor α4β7 in clinical development for once daily oral dosing in inflammatory bowel disease (IBD). Inhibition of α4β7 is an established efficacious therapeutic option for the treatment of Ulcerative Colitis (UC) and Crohn’s Disease, but current treatment requires intravenous or subcutaneous injection. A Phase 1 first-in-human study evaluated the pharmacokinetics, safety, tolerability, and exploratory biomarkers of GS-1427 in healthy subjects. The biomarker objectives in Phase 1 were to confirm preclinical findings of extended α4β7 receptor occupancy (RO) supporting once daily dosing, selectivity for α4β7 and to inform Phase 2 dose selection.

Aims & Methods

Biomarkers were evaluated before and after single (20mg-1000mg fasted, SAD) and multiple (20-500mg fed, once daily for 14 days, MAD) ascending doses GS-1427.
Using fluorescently labeled MAdCAM-1, α4β7 RO was assessed in fresh whole blood on CD4+CD45RO+β7+ memory T cells; α4β1 RO was evaluated on CD4+CD45RO+α4+β1+β7- memory T cells using fluorescently labeled tripeptide leucine aspartic acid valine (LDV). RO was calculated as a percent using the fluorescence intensity values measured post-dose and pre-dose. Changes in the frequency of β7+CD4+ memory T cells by flow cytometry and CCR9 gene expression by RNAseq in whole blood served to evaluate downstream functional α4β7 pharmacodynamics (PD); absolute lymphocyte counts (ALC) in fresh whole blood and frequencies of CD34+ Hematopoietic stem cells (HSC) in viably frozen PBMC were measured to estimate PD downstream of α4β1.

Results

α4β7 RO analyses post single and multiple once daily doses of GS-1427 demonstrated sustained and prolonged RO ≥95% confirming pre-clinical findings and supporting a once daily dosing regimen. Duration of α4β7 RO ≥95% post-dose was dose dependent. Doses ≥80mg GS-1427 demonstrated α4β7 RO ≥95% for 24 hours, starting with the first dose on Day 1 and persisted until Day 14. The highest dose group in the MAD demonstrated extended α4β7 RO ≥95% up to 72 hours in 100% of subjects after the last dose on Day 14. Corroborating α4β7 RO findings, analyses of %β7+CD4+ memory T cells demonstrated dose and time dependent significant increases from baseline compared to placebo, which reached 40% on average in the highest dose group in the MAD. Dose dependent significant increases of CCR9 mRNA expression levels compared to placebo were observed for doses ≥80mg GS-1427; up to ~2.5-fold increase on average were measured in the higher dose groups in the MAD. Unlike α4β7 RO, a4β1 RO was partial and transient across the doses tested, and RO levels returned to baseline within ~24 hours post-dose in both SAD and MAD. Individual values of α4β1 RO 24 hours post multiple doses GS-1427 on Day 14 were below the assay’s lower limit of quantification. The median maximum a4β1 RO at C_trough was estimated to be ~20% in the highest dose group. Supporting findings for a4β1 RO, percent change of ALC was transient and changes of CD34+ HSC frequencies were highly variable which was expected given the low frequency of this population and were within the natural variation across all GS-1427 doses tested.

Conclusion

In conclusion, the exploratory biomarker results in this Phase 1 study in healthy subjects demonstrating extended α4β7 RO and α4β7 selectivity together with the pharmacokinetics, safety, and tolerability data (abstract in preparation) support further development of GS-1427 with a once daily dosing regimen in a Phase 2 study in IBD.

Disclosure

All authors are employees and shareholders of Gilead Sciences.

Introduction

Among patients with celiac disease (CeD), following a gluten-free diet after diagnosis is expected to reduce symptom burden. Using a large US claims database, we compared symptoms in individuals with CeD pre- and post-diagnosis with those in matched individuals without CeD to evaluate the burden of CeD.

Aims & Methods

This case-control study was conducted among individuals of all ages enrolled in MarketScan from 2002 to 2023. CeD diagnosis (index date) was defined as ≥1 inpatient or ≥2 outpatient International Classification of Diseases (ICD)-9/-10 diagnostic codes; controls were matched (1:5 ratio) for age, sex, region, and diagnosis year. All individuals had continuous medical and pharmacy enrolment for 2 years pre- and post-index. Core CeD symptoms (abdominal pain, diarrhoea, joint pain, bloating, fatigue, and nausea) were defined as ≥1 inpatient or ≥2 outpatient ICD-9/-10 codes during each 2-year period. Unadjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated by logistic regression comparing CeD cases versus controls.

Results

During the 21 years of data coverage, we identified 39 814 patients with CeD and 198 961 matched individuals without CeD with similar age and sex distribution (mean age 41.6 years [standard deviation 20.1]; 70.5% female). The burden of CeD symptoms pre-diagnosis was significantly higher among patients with CeD versus controls, particularly for diarrhoea, bloating, and abdominal pain. The pre-diagnosis OR (95% CI) for abdominal pain was 5.37 (5.22, 5.52), joint pain 1.87 (1.81, 1.93), diarrhoea 11.64 (11.10, 12.20), bloating 8.64 (7.86, 9.51), fatigue 3.63 (3.48, 3.79), and nausea 5.78 (5.36, 6.24). As expected, symptom burden decreased post-diagnosis, however all symptoms (except joint pain) had an approximately twofold greater burden compared with controls, 2 years post-diagnosis: OR (95% CI) abdominal pain 2.43 (2.57, 2.30), joint pain 1.61 (1.51, 1.71), diarrhoea 2.47 (2.21, 2.76), bloating 2.47 (1.86, 3.27), fatigue 2.17 (1.98, 2.38), and nausea 2.24 (1.83, 2.74). When we evaluated symptoms only among individuals with CeD, on average symptom persistence 2 years after diagnosis occurred in 29.7% of patients while an average of 6.3% had new-onset symptoms (most commonly abdominal pain; 17.0%).

Conclusion

Claims databases were able to capture CeD symptom burden and demonstrated that patients with CeD continue to experience symptoms (including new-onset) post-diagnosis. Although a gluten-free diet might control some symptoms, there is still considerable remaining burden and some unresolved symptoms (e.g. joint pain and fatigue) or new-onset symptoms.

Disclosure

MA, SM, VG, SG, RS, DAL, IP, and NC are employees and shareholders of Takeda. BL has nothing to disclose. FZ served as a speaker for Werfen and a consultant for Takeda.

Introduction

Patients with inflammatory bowel diseases (IBD) exhibit distinct shifts in circulating metabolite levels that have been associated with clinical disease activity and disease phenotype. However, there are limited data on the impact of metabolomic changes on disease progression in IBD. In this study, we aimed to understand the association of circulating metabolite levels and related pathways with the risk of disease progression in patients with IBD. Furthermore, we aimed to predict disease progression in these patients using both clinical and metabolomic features.

Aims & Methods

We conducted an observational cohort study using the Mount Sinai Crohn’s and Colitis Registry (MSCCR). Patients were prospectively enrolled with baseline questionnaires and biospecimens that were then linked to longitudinal electronic health record data. A total of 1,456 serum metabolites were measured in 277 patients with UC and 375 patients with CD using untargeted metabolomics. Disease progression was defined as any new steroid or biological prescriptions, IBD-related hospitalizations, or surgery. Multivariable Cox proportional hazards regression (CoxPH) models, adjusted for age, sex, smoking, biologic use, and surgery were used to explore metabolite associations with risk of disease progression. Metabolite set enrichment analysis (MSEA) was performed to identify underlying metabolic pathways associated with disease progression. Prediction analyses were performed using L1-regularized CoxPH models with Random Survival Forests (RSF), and applied using different preceding feature selection approaches. Clinical parameters and metabolites were used as input features individually and in combination. Models were evaluated using Harrell’s C-index, the Brier Score, and the area under the curve (AUC) at 3-years follow-up time.

Results

During a median of 2-year follow-up (IQR 0.3-5.1 years), 375 patients (57.5%) had a disease progression event. Among CD, 151 metabolites significantly correlated with the composite outcome (FDR<0.1). Of these, 81 (53.6%) were linked to higher risk, mainly enriched in amino acids, purine, and pyrimidine metabolism, fibrinogen cleavage peptides, and bile acid pathways. Additionally, 70 (46.4%) metabolites associated with lower risk with enrichment in fatty acid metabolism, steroid biosynthesis, histidine, tryptophan, and antioxidant pathways. In CD, aspartate metabolism was most significantly associated with increased risk and linoleic metabolism with decreased risk. In UC, 84 metabolites were significantly associated with disease progression (FDR<0.1), with 29 (34.5%) associated with increased and 55 (65.5%) with decreased risk. Metabolic pathways linked to higher risk were sphingolipid, benzoate, hydrogen sulfide, polyamine, and tyrosine metabolism, while protective metabolites were enriched in branched-chain amino acid (BCAA), steroid biosynthesis, histidine, and phenylalanine pathways. In UC, sphingolipid metabolism was prominently associated with increased risk and BCAA metabolism with decreased risk. The combination of metabolomic and clinical features best predicted disease progression in both CD and UC, with 20 and 25 features robustly selected, respectively.

Conclusion

Specific metabolites and metabolic pathways are associated with risk of disease progression in patients with IBD, highlighting potential prognostic metabolite biomarkers and pathways that may be important in modulating risk of disease progression. ​Metabolomic features improve overall model performance ​when predicting disease progression in IBD, with distinct metabolites showing high predictive value.

Introduction

Disorders of gut-brain interaction (DGBI) and obesity are common and overlap between these two conditions has been reported in patient samples (1). However, the prevalence of DGBI among obese subjects in the general population is unknown.

Aims & Methods

Our aim was to assess the prevalence of DGBI among obese subjects in the general population in comparison with non-obese subjects, as well as exploring factors associated with DGBI in obesity in Europe.
We included subjects who completed the internet-based survey of the Rome Foundation Global Epidemiology study (2) in 11 European countries (Belgium, United Kingdom, France, Germany, Italy, Poland, Romania, Russia, Spain, Sweden, and the Netherlands). Obesity was defined as a BMI>30 and categorized to 3 classes: 1: BMI 30 to <35, 2: BMI 35 to <40, and 3: BMI 40 or higher. In the non-obese population, we included participants with normal BMI (between 18.5 and <25) and overweight (between 25 and <30), but excluded underweight participants (BMI<18.5, n=744). The prevalence of DGBI was determined, and then compared between obese and non-obese participants. Factors potentially associated with DGBI and obesity including demographics, psychological distress (PHQ-4), somatization (PHQ-15) and quality of life (PROMIS) were assessed.

Results

We included 20,117 participants in our analysis, and 2,023 patients were excluded because of missing BMI information. The prevalence of obesity was 17.8% (95%CI 17.3, 18.4), with 12.6%, 3.7% and 1.6% in obesity classes 1, 2 and 3, respectively. The prevalence of any DGBI was 44.2% in the obese group vs. 39.6% in the non-obese group (OR=1.20 (1.12, 1.30)). Most DGBI were more prevalent in the obese vs. non-obese group (table), with the exception of functional constipation where the opposite was seen. Female sex, higher level of psychological distress and somatization were found in the group with DGBI associated with obesity, as well as lower quality of life.

Table: Prevalence of any DGBI, by anatomical region and individual DGBI in obese and non-obese subjects

Conclusion

DGBI are common among obese subjects in the general population and linked with certain demographic and disease-related factors. This should be acknowledged in the management of patients with obesity.

References

1. Aasbrenn M, Høgestøl I, Eribe I, Kristinsson J, Lydersen S, Mala T, et al. Prevalence and predictors of irritable bowel syndrome in patients with morbid obesity: a cross-sectional study. BMC Obes. 2017;4:22.
2. Sperber AD, Bangdiwala SI, Drossman DA, Ghoshal UC, Simren M, Tack J, et al. Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study. Gastroenterology. 2021;160(1):99-114.e3.

Disclosure

C.M. has served as a consultant/advisory board member for Kyowa Kirin, Norgine, Biocodex, Mayoly Spindler, Tillots, Ipsen and Nestlé HealthScience.
OP has received salary support from Royal DSM and the Rome Foundation, consulting fees from iHealth, and royalties from MetaMe Health.
MS has received grants and personal fees from Glycom and Danone Nutricia Research; personal fees from Ironwood, Menarini, Biocodex, Adnovate, Arena, Tillotts, Kyowa Kirin, Takeda, Alimentary Health, AlfaSigma, and the Falk Foundation; and grants from Genetic Analysis.
J.T. has given scientific advice to Adare, AlfaWassermann, Allergan, Arena, Bayer, Christian Hansen, Clasado, Danone, Devintec, Falk, Grünenthal, Ironwood, Janssen, Kiowa Kirin, Menarini, Mylan, Neurogastrx, Neutec, Novartis, Noventure, Nutricia, Shionogi, Shire, Takeda, Theravance, Tramedico, Truvion, Tsumura, Zealand, and Zeria Pharmaceutical; received research support from Shire, Sofar, and Tsumura; and served on the Speakers Bureau for Abbott, Allergan, AstraZeneca, Janssen, Kyowa Kirin, Menarini, Mylan, Novartis, Shire, Takeda, Truvion, and Zeria Pharmaceutical, all outside the submitted work.
J.M.S. report personal fees from Biocodex, Kyowa Kirin, Norgine, Mayoly Spindler, Arko Pharma, and Tillots Pharma outside the submitted work.
J.P.H., J.K., Q.A., S.I.B., and A.S. have no conflict of interest.

Introduction

Stereotactic Body Radiation Therapy (SBRT) has proven to be a safe and effective therapy for patients with deep abdominal malignancies who are ineligible/suboptimal candidates for surgery^1,2. SBRT’s effectiveness is dependent on precise targeting, achieved through both bone imaging and implantation of small markers (fiducials) that are visible during imaging which delineate margins of the target lesion³. Fusion of computed tomography (CT) and magnetic resonance imaging (MRI) can provide enhanced soft tissue contrast and improved delineation of the tumor⁴, and is the preferred choice at our institution. Fiducials have traditionally been made of gold due to its bioinertness and visibility on CT imaging, however gold is not accurately detected on MRI⁵. Platinum fiducials have recently emerged as an attractive alternative⁵, considering their improved detectability on MRI imaging. Endoscopic ultrasound (EUS)-guided implantation techniques have largely supplanted percutaneous methods for deep abdominal targeting, due to improved access and visualization⁶.

Aims & Methods

The objective of this case series was to describe our novel platinum seed (PS) fiducials developed in house for EUS-guided fiducial SBRT application. We reviewed the adequacy of fiducial placement, quality of pre-treatment imaging, and migration rates of our fiducials.This single-center case series included patients diagnosed with cancers of the abdomen, including pancreas, adrenal, and liver, who were scheduled to undergo SBRT requiring EUS-guided fiducial implantation between January 2011-February2024. The cohort was derived from a prospectively collected EUS database at The Ottawa Hospital in Ottawa, Canada. Patient demographics (sex and age), procedure details (tumor site, number of fiducials implanted, complications), and radiologist’s interpretation of MRI/CT imaging were assessed using hospital records. Approximately 70% of patients received antibiotics ((either IV x 1 does or oral antibiotics for 5 days post-procedure (eg. Ciprofloxacin, 500mg)). Our PS fiducials are made from 0.75mm wire cut into 3mm seeds which are then autoclaved in-house. Fiducials were implanted using a 19g FNA needle and advanced using an ERCP guidewire using EUS and fluoroscopic guidance.

Results

55 patients underwent EUS implantation for a total of 176 fiducials. Preplanning CT/MRI imaging identified 166/176 (94.3%) fiducial signal voids. When evaluating fiducial placement adequacy, 52 of 55 (94.5%) patients had adequate placement for SBRT. Two patients required a repeat procedure with additional fiducial implantation. One case was due to suspected migration, and the second case was due to fiducials being placed too closely preventing adequate delineation. In a third case, no signal voids were visualized for an unknown reason, however, no repeat procedure was required as spine tracking was used. None of the patients developed post-procedure infection or other adverse events (AEs) in this case series (follow up at 1 month). Cost analysis revealed the fiducials made in-house were ~20-fold less expensive compared to commercially available solid gold, gold coil, or solid platinum fiducials.

Conclusion

Our platinum seed fiducials made in-house appear to have similar adequacy and no increased risk of AEs for EUS-implantation when compared to commercially available fiducials^7,8. For centres using fused CT-MRI imaging for SBRT planning, PS fiducials are recommended. Moreover, significant cost-saving can be achieved through in-house production.

References

1. Rwigema JM, et al. Stereotactic body radiation therapy for abdominal and pelvic oligometastases: Dosimetric targets for safe and effective local control. Pract Radiat Oncol. 2015;5(3):e183-e191.
2. Almaghrabi MY, et al. Stereotactic body radiation therapy for abdominal oligometastases: a biological and clinical review. Radiat Oncol. Aug 01 2012;7:126. doi:10.1186/1748-717X-7-126
3. Moskalenko M, et al. Fiducial Markers Allow Accurate and Reproducible Delivery of Liver Stereotactic Body Radiation Therapy. Curr Oncol. May 16 2023;30(5):5054-5061.
4. Bryant JM, et al. Stereotactic Magnetic Resonance-Guided Adaptive and Non-Adaptive Radiotherapy on Combination MR-Linear Accelerators: Current Practice and Future Directions. Cancers (Basel). Mar 30 2023;15(7).
5. Nair VJ, et al. Feasibility, detectability and clinical experience with platinum fiducial seeds for MRI/CT fusion and real-time tumor tracking during CyberKnife. J Radiosurg SBRT. 2015;3(4):315-323.
6. Pishvaian AC, et al. EUS-guided fiducial placement for CyberKnife radiotherapy of mediastinal and abdominal malignancies. Gastrointest Endosc. Sep 2006;64(3):412-7.
7. Choi JH, et al. Fiducial placement for stereotactic body radiation therapy under only endoscopic ultrasonography guidance in pancreatic and hepatic malignancy: practical feasibility and safety. Gut Liver. 2014;8(1):88-93.
8. Kataki K, et al. Prospective Evaluation Fiducial Migration after Placement for Liver SBRT and Influence on Treatment Delivery. International Journ of Rad Onc. 2019;105(1):E222.