Histological Endpoints Research Articles

Dupilumab is efficacious for eosinophilic esophagitis irrespective of prior swallowed budesonide or fluticasone, or prior treatments used alongside swallowed topical corticosteroids: results from the phase 3, randomized, placebo-controlled, LIBERTY EoE TREET trial

ABSTRACT Background Standard treatments for eosinophilic esophagitis (EoE) may present adherence, tolerance, and efficacy challenges. Dupilumab 300 mg weekly is approved for the treatment of EoE in patients ≥ 1 year old, weighing ≥ 15 kg. This analysis aimed to evaluate dupilumab efficacy in patients from the LIBERTY EoE TREET trial (NCT03633617), with prior history of different EoE interventions. Research design and methods This analysis included patients from Parts B/B – C of LIBERTY EoE TREET. Dupilumab efficacy was analyzed according to prior swallowed budesonide or fluticasone use and in those patients with previously trialed food elimination diet, esophageal dilation, or baseline proton pump inhibitor use, as stratified by prior swallowed topical corticosteroid (STC) use or STC inadequate response/intolerance/contraindication. Results Dupilumab improved the proportion of patients achieving peak intraepithelial eosinophil count ≤ 6 eosinophils/high-power field, absolute change in Dysphagia Symptom Questionnaire score, and other histologic, symptomatic, and endoscopic endpoints vs. placebo at Week (W) 24, irrespective of prior swallowed budesonide/fluticasone use. Improvements were maintained at W52. Similar results were observed across the other subgroups. Conclusion Dupilumab was efficacious in patients with EoE irrespective of prior treatments/interventions. Clinical trial registration www.clinicaltrials.gov identifier is NCT03633617.

Small bowel magnetic compression anastomosis creation for bypass procedures in a porcine model.

Stapled and hand-sewn techniques dominate gastrointestinal anastomotic procedures. These techniques are effective but not without flaws. Retained foreign bodies, pathways from mucosa to serosa, and increased scar tissue are some of the drawbacks, and can lead to postoperative complications. The GI Windows Flexagon™ system utilizes self-forming magnets (SFM's) to create anastomoses by compression, sealing serosa to serosa, leaving no foreign bodies. Combining the Flexagon™ SFM with the OTOLoc™ device (implant with a central lumen which provides radial support to the enterotomies), enables immediate flow through the anastomosis and facilitates creation of enteral bypass procedures unique to this technology. We sought to compare the safety and efficacy of the GI Windows Flexagon™ and OTOLoc™ technologies against conventional stapling. A preclinical study was conducted on 14 Yorkshire swine to compare laparoscopic magnetic and stapled duodenoileostomies and jejunojejunostomies. Study endpoints included: adverse or serious adverse events, anastomotic burst pressure, adhesions, histopathology, and bacterial ingress. A Likert scale was used to assess the usability of the devices. All procedures were successfully completed via laparoscopic approach; no adverse or serious adverse events were observed at the 42-day endpoint. All SFM's were expelled in less than 20days. Average anastomotic burst pressure was 129.2mmHg for SFM compared to 79.4mmHg in stapled controls. Adhesion scores were similar between groups. Histopathology revealed that magnetic anastomoses have less intestinal wall distortion, fewer signs of chronic inflammation, and no bacterial ingress. The usability of all devices was reported as "Easy" or "Very Easy." GI Windows magnetic compression anastomoses creation in this porcine model revealed an overall ease of use, all while demonstrating procedural feasibility, safety, and clinical effectiveness. Surprisingly, in nearly all results assessed, SFM anastomoses were found to be comparable to the control stapled anastomoses in regard to structural, physiological, and histological endpoints.

P0257 Correlation of biochemical, endoscopic and histologic endpoints in vedolizumab-treated patients with ulcerative colitis: a post-hoc analysis from the VIEWS randomised controlled trial

Abstract Background Biochemical, endoscopic and histologic endpoints are commonly used to objectively define remission status in ulcerative colitis (UC). Little data exists on the correlation of these endpoints from prospectively collected samples based on a well-defined protocol. Also, optimal faecal calprotectin (FC) values that predict histo-endoscopic remission are lacking. Methods The phase IV Vedolizumab Immunomodulator Enforced Withdrawal Study (VIEWS) prospectively recruited 62 patients with UC on vedolizumab in steroid-free clinical remission. Treatment endpoints were assessed at week 0 and 48. Biopsies for histology were standardised using strict protocolised criteria. Definitions of remission using treatment endpoints were C-reactive protein (CRP)<5mg/L, FC<150µg/g, centrally-read Mayo endoscopic score (MES)=0, centrally-read Nancy Index (NI)=0, and histo-endoscopic remission (MES=0 and NI=0). Correlation was assessed using phi (ϕ) co-efficient analysis (value between -1 and 1 reflecting strength of correlation). Receiver operating characteristic (ROC) analysis was performed to determine optimal FC cutoffs to predict histo-endoscopic outcomes (IBM SPSS Statistics, version 30). Results A total of 124 datapoints were obtained from paired endpoints. From these, CRP remission was noted in 81%, FC remission 82%, endoscopic remission 66%, histologic remission 61% and histo-endoscopic remission in 54%. Strong correlations were found between endoscopy and histology (ϕ=0.447, P<0.001), and between FC and endoscopy (ϕ=0.395, P<0.001). FC had moderate correlation with histology (ϕ=0.204, P=0.03). CRP had weaker correlations with FC (ϕ=0.158, P=0.08), endoscopy (ϕ=0.111, P=0.24), and histology (ϕ=0.196, P=0.04) (Figure 1). A FC cut-off of 62.6 µg/g (sensitivity 78%, specificity 54%) predicted endoscopic remission (AUC 0.72 [95%CI: 0.61-0.84], P<0.001). A FC cut-off of 34.2µg/g (sensitivity 65%, specificity 60%) predicted histologic remission (AUC 0.66 [95%CI: 0.55-0.77], P=0.006). A FC cut-off of 23.7µg/g (sensitivity 60%, specificity 63%) predicted histo-endoscopic remission (AUC 0.65 [95%CI: 0.54-0.76], P=0.006) (Figure 2). Conclusion Endoscopic and histologic endpoints correlate strongly when standardised in a trial setting. FC values below 34.2µg/g and 23.7µg/g best predicted for histologic and histo-endoscopic remission respectively.

P0833 Trajectories of response in patients with moderately-to-severely active Crohn’s disease treated with mirikizumab or ustekinumab: Post hoc results from the VIVID-1 study

Abstract Background Mirikizumab (MIRI), an anti-IL-23p19 antibody, demonstrated robust efficacy in improving clinical and endoscopic endpoints with an acceptable safety profile1. In patients with moderate-to-severely active Crohn’s disease (CD), we explored the trajectory of response to MIRI or ustekinumab (USTE), an anti-IL-23p19p40 active comparator. Methods MIRI (N=572) and USTE (N=285) patients described previously1 were assessed via Growth Mixture Model to identify distinct clusters based on individual patient response trajectories. The Growth Mixture Model was first fit with MIRI only patient data with standardized beta link function to accommodate the non-Gaussian outcomes. Then the model was run with USTE only patient data based on the model parameter settings from the MIRI model to allow comparison. Change from baseline in Crohn’s Disease Activity Index (CDAI) total score was used in the Growth Mixture Model to identify trajectories. Week 52 clinical endpoints were assessed by trajectory group for MIRI and USTE. Modified baseline observation carried forward imputation used. Results There were four response trajectory clusters identified for MIRI, which were then compared to USTE: Super Responder (MIRI/USTE: 18.4%/10.9%), Responder (MIRI/USTE: 22.4%/13.0%), Delayed Responder (MIRI/USTE, 29.5%/31.2%), and Non/Incomplete Responder (MIRI/USTE, 29.7%/44.9%) (Figure 1). The proportion of Super Responders plus Responders was greater for MIRI vs USTE (40.7% vs 23.9%) and the proportion of Non/Incomplete Responders less (29.7% vs 44.9%). The proportion of patients achieving Week 52 clinical, endoscopic, and histologic endpoints was generally greatest for Super Responders followed by Responders and then Delayed Responders (Table 1). The proportion of patients achieving these endpoints for Super Responders + Responders was generally greater for MIRI vs USTE, in particular histologic response (70% vs 60%) and remission (36% vs 22%). Conclusion The overall response rate was 70.3% for MIRI and 55.1% for USTE. For the 4 MIRI symptom response trajectory groups – Super Responder, Responder, Delayed Responder, and Non/Incomplete Responder – the proportion of Super Responders plus Responders was greater for MIRI vs USTE and the proportion of Non/Incomplete Responders was less for MIRI vs USTE, while the proportion of patients achieving clinical endpoints for MIRI was generally numerically greater than USTE for Super Responders plus Responders.

DOP052 Etrasimod as induction and maintenance therapy in Asian patients with moderately to severely active Ulcerative Colitis: Results from the maintenance period of a randomised, double-blind, placebo-controlled, multi-centre Phase 3 study (ES101002)

Abstract Background Etrasimod (ETR) is an oral, once daily (qd), selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). ES101002 was a registrational Phase (Ph) 3 study evaluating the efficacy and safety of ETR in Asian patients (pts) with moderately to severely active UC (NCT04176588). ETR has shown significant benefit vs placebo (PBO) as induction and maintenance therapy in pts with UC, including in the 12-week (wk) induction period (IP) of ES101002.1–4 Here, we report results from the 40-wk maintenance period (MP) of ES101002. Methods The study comprised a 12-wk IP, 40-wk MP, and open-label (OL) period (up to 40 wks). Eligible pts were enrolled from the Chinese mainland, Taiwan, and South Korea, had confirmed moderately to severely active UC, and had failed ≥1 UC treatment (conventional and/or biologics/JAK inhibitors). Pts randomised 2:1 into the IP received ETR 2 mg qd or PBO for 12 wks. Clinical responders at wk 12 were re-randomised 1:1 into the MP and received ETR or PBO for 40 wks. In the MP, stratification factors were treatment in the IP, previous exposure to biologics/JAK inhibitors, and concomitant use of corticosteroids at IP baseline. IP non-responders or pts who experienced UC worsening in IP/MP were offered entrance into the OL period. The objectives for the MP of the study were to evaluate the efficacy and safety of ETR vs PBO. Results A total of 158 pts were randomised into the MP and received treatment (77 ETR; 81 PBO). Baseline pt demographics and disease characteristics, including mean age (43.8 years [yrs] ETR; 40.7 yrs PBO), proportion of female pts (45.5% ETR; 40.0% PBO), and mean baseline modified Mayo Score (6.0 ETR; 5.8 PBO), were balanced between groups. A higher proportion of pts receiving ETR (89.6%) vs PBO (51.9%) completed the 40-wk MP. All efficacy objectives in the 40-wk MP were achieved (Figure 1). A significantly greater proportion of pts receiving ETR vs PBO achieved clinical remission, clinical response, endoscopic improvement, endoscopic normalisation, mucosal healing, and symptomatic remission (P<.0001 each). Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity (Table 1). ETR vs PBO resulted in fewer Grade 3 TEAEs (ETR 10.4%, PBO 13.6%) and serious adverse events (ETR 7.8%, PBO 8.6%). In each group, there was a single treatment discontinuation due to a TEAE (UC worsening) with no Grade 4 TEAEs or deaths. Conclusion Consistent with previous studies, ETR resulted in clinically meaningful and statistically significant improvement of UC in Asian pts across clinical, endoscopic, and histologic endpoints, and was safe and well-tolerated.

DOP054 Early Histologic Response and Remission are Associated With Objective Control of Inflammation After One Year of Treatment With Mirikizumab in Moderately-to-Severely Active Crohn’s Disease

Abstract Background Histologic inflammation persists in up to 1/4 of patients with Crohn’s disease (CD) despite endoscopic mucosal healing. Histologic and combined endoscopic-histologic endpoints are evolving measures of treatment efficacy in CD; however, the impact of histologic healing on long-term outcomes and disease progression is unknown. Week (W) 52 data comparing mirikizumab (Miri) vs placebo (PBO) in the randomized, double-blind, placebo- and active-controlled, treat-through Phase 3 VIVID-1 trial in patients with moderately-to-severely active CD (NCT03926130) were reported previously.1 Methods The main objective was to evaluate the association of W12 histologic response and W12 histologic remission with W52 clinical and endoscopic outcomes in VIVID-1. Two biopsy specimens from each of 5 intestinal segments (1 ileal and 4 colonic) were obtained from the edge of the ulcers, or the most inflamed mucosa from randomized patients at screening, W12, and W52. All analyses were post hoc and among patients with active histologic disease (defined as a Robarts Histopathology Index >0 and a Global Histologic Disease Activity Score >0) at baseline. Results At W12, treatment with Miri resulted in statistically significantly higher rates of achieving histologic response and histologic remission vs. PBO (Figure). At W12, 62.1% of patients had agreement (k=0.27 [fair]) between histologic response and endoscopic response, with a greater percentage achieving histologic over endoscopic response (59.0% vs. 38.8%)*. Significantly greater proportions of patients who achieved histologic response at W12 also achieved histologic response, histologic remission, endoscopic response, endoscopic remission, combined CDAI (Crohn’s Disease Activity Index) remission and endoscopic response, and normalisation of faecal calprotectin levels ≤250 µg/g and ≤150 µg/g at W52 (Table). Similar associations were observed between W12 histologic remission and W52 outcomes. Conclusion Histologic response seems to be an early objective sign of anti-inflammatory response and was significantly associated with one-year endoscopic and histologic outcomes, as well as biomarker normalisation. *Observed data

P0853 Decrease in fecal calprotectin and C-reactive protein levels correlate with improved clinical outcomes in patients with moderately to severely active Crohn’s disease treated with mirikizumab

Abstract Background Mirikizumab (miri), an anti-IL-23p19 antibody, has shown efficacy in treatment of patients with moderately to severely active Crohn’s disease (CD) in a Phase 3 study VIVID-1 (NCT03926130). We evaluated the associations of inflammatory biomarkers, fecal calprotectin (FC) and C-reactive protein (CRP), with clinical, endoscopic, and histologic improvement in patients randomised to miri. Methods VIVID-1 achieved the primary and key secondary endpoints published previously1. The mean change from baseline in FC and CRP was compared between patients who achieved selected clinical, endoscopic, histologic, and combined endoscopic and histologic (endo-histo) endpoints versus those who did not achieve such endpoints who were randomised to miri using t-test. At week 12 (W12) and W52, clinical response by PRO (Patient Reported Outcome), clinical response by CDAI (Crohn’s Disease Activity Index), clinical remission by PRO, clinical remission by CDAI, endoscopic response, histologic response, and the composite of endo-histo response were evaluated. At W52, additional endpoints of endoscopic remission, histologic remission, and the composite of endo-histo remission were evaluated. Non-responder imputation (NRI) was used for binary missing data and modified baseline observation carried forward was used for continuous missing data. Results At W12, there was statistically greater improvement in both FC and CRP in all endpoints (Figure 1). Improvement in FC associated with endoscopic and histological improvement (p<0.001) more closely than CRP (p<0.05), while CRP associated more closely with clinical endpoints. At W52, change in FC and CRP from baseline were significantly associated with achieving clinical response by PRO, clinical response by CDAI, clinical remission by PRO, clinical remission by CDAI, endoscopic response and remission, histologic response and remission, and the composite of endo-histo response and remission (FC, p<0.001 for all endpoints; CRP, p<0.001 for all endpoints but histologic remission and endo-histo remission which have p<0.05) (Figure 2). Conclusion At W12 and W52, change from baseline of FC was better associated with endoscopic and histological improvement while decrease of CRP was better associated with clinical outcomes. These results further support non-invasive approaches to monitoring response of CD to treatment.

OP39 Treatment with RO7790121 induces and maintains histologic and histologic-endoscopic improvement and remission in moderately to severely active ulcerative colitis – Results from TUSCANY-2

Abstract Background Tumor necrosis factor-like ligand 1A (TL1A) is upregulated in inflammatory bowel disease, promoting inflammation and intestinal fibrosis. Targeting TL1A with the anti-TL1A antibody RO7790121 showed significant endoscopic improvement and favorable safety in the phase IIa TUSCANY trial1 and the subsequent phase IIb TUSCANY-2 trial (NCT04090411) in patients (pts) with moderately to severely active ulcerative colitis (UC). Here we report histologic and endoscopic improvement and remission data from the phase IIb TUSCANY-2. Methods Pts aged 18–75 years with moderately to severely active UC (total Mayo score ≥6, endoscopic subscore [ES] ≥2) were enrolled in this multicenter, randomized, double-blind, treat-through, dose-ranging study. Pts were randomized to receive subcutaneous (SC) RO7790121 50mg, 150mg, 450mg or matched placebo (PBO) monthly during the 12-week induction period, and SC RO7790121 50mg, 150mg or 450mg monthly during the 40-week, treat-through maintenance period. Histologic endpoints included histologic improvement (Geboes score [GS] ≤3.1) and remission (GS <2B.1), as well as histologic-endoscopic mucosal improvement (GS ≤3.1 and ES ≤1) and remission (GS <2B.1 and ES ≤1), assessed at Weeks 14 and 56. Results A total of 245 pts received ≥1 dose of RO7790121 or PBO; 228 pts completed the induction; 224 entered the maintenance period and 178 completed the maintenance period. At Week 14, the proportions of pts with histologic improvement (using Geboes histology score) were 40.0%, 39.6% and 32.9% with RO7790121 50mg, 150mg and 450mg, respectively, vs 12.2% with PBO, which were sustained through Week 56. Greater proportions of pts with histologic remission were also observed with any RO7790121 dose vs PBO at Week 14, sustained through Week 56 (Table). Additionally, 30.0%, 32.1% and 25.6% of pts treated with RO7790121 50mg, 150mg and 450mg, respectively, vs 4.9% with PBO experienced histologic-endoscopic mucosal improvement, which was sustained through Week 56. Greater histologic-endoscopic mucosal remission was also observed at any RO7790121 dose vs PBO at Week 14 and sustained through Week 56 (Table). Across the various endpoints, there was no apparent dose response. Conclusion Overall, higher rates of histologic improvement and remission were observed in pts treated with RO7790121 during induction, compared with PBO, and sustained through Week 56. Similarly, a higher proportion of pts treated with RO7790121 achieved histologic-endoscopic mucosal improvement and remission, sustained through Week 56. RO7790121 is currently being investigated in phase III studies (NCT06589986 and NCT06588855).

Integration of responses to lithium in mussels at different levels of biological complexity.

The increasing use of lithium (Li) in modern technology and medicine has raised up concerns in the scientific community due to the potential impact of this metal on the aquatic environment. Although several effects have been reported in different organisms, there is still scarce information concerning the mechanisms and chronic effects of Li toxicity in marine life. Our main objective is to determine biological effects of sub-lethal concentrations in Mytilus galloprovincialis at different biological organization levels using the biomarker approach. Mussels were exposed to environmental Li concentrations: 0.1, 1 and 10 mg/L. Samples of gills, muscle and digestive gland were taken at days 1, 7 and 21 for the assessment of biochemical, histochemical and histological endpoints. Results showed that exposure to Li caused greater impacts in a dose and time-dependent manner at different biological organization levels. Changes in acetylcholinesterase (AChE) activity were detected at day 1 (induction) and day 21 (inhibition) in accordance with increasing Li levels, indicating possible neurotoxic effects, while catalase (CAT) inhibition, and subsequent induction, was detected at day 1 in proportion to Li concentrations. Lysosomal biomarkers demonstrated a decreasing lysosomal membrane stability with higher Li doses after 21 days of exposure, whereas 10 mg Li/L provoked lysosomal size reduction from day 1. Finally, the integration of these biological responses into an IBR index indicated a clear effect of exposure after 21 days in a dose-dependent way, leading to cellular and tissue damage as consequence. Moreover, a time-course response was observed with an enhanced oxidative stress at day 1, and a neurotoxic effect, lysosomal membrane destabilization and histopathological alterations after 7 and 21 days of exposure to medium and high Li concentrations. Consequently, these findings provide valuable insights into Li's effects on marine life, emphasizing the need for further long-term studies across different biological organization levels.

Late-Life Alcohol Exposure Does Not Exacerbate Age-Dependent Reductions in Mouse Spatial Memory and Brain TFEB Activity.

Alcohol consumption is believed to affect Alzheimer's disease (AD) risk, but the contributing mechanisms are not well understood. A potential mediator of the proposed alcohol-AD connection is autophagy, a degradation pathway that maintains organelle and protein homeostasis. Autophagy is regulated through the activity of Transcription factor EB (TFEB), which promotes lysosome and autophagy-related gene expression. The purpose of this study is to explore whether chronic alcohol consumption worsens the age-related decline in TFEB-mediated lysosomal biogenesis in the brain and exacerbates cognitive decline associated with aging. To explore the effect of alcohol on brain TFEB and autophagy, we exposed young (3-month-old) and aged (23-month-old) mice to two alcohol-feeding paradigms and assessed biochemical, transcriptome, histology, and behavioral endpoints. In young mice, alcohol decreased hippocampal nuclear TFEB staining but increased SQSTM1/p62, LC3-II, ubiquitinated proteins, and phosphorylated Tau. Hippocampal TFEB activity was lower in aged mice than it was in young mice, and Gao-binge alcohol feeding did not worsen the age-related reduction in TFEB activity. Morris Water and Barnes Maze spatial memory tasks were used to characterize the effects of aging and chronic alcohol exposure (mice fed alcohol for 4 weeks). The aged mice showed worse spatial memory acquisition in both tests. Alcohol feeding slightly impaired spatial memory in the young mice, but had little effect or even slightly improved spatial memory acquisition in the aged mice. In conclusion, aging produces greater reductions in brain autophagy flux and impairment of spatial memory than alcohol consumption.

Network Meta-Analysis: Histologic and Histo-Endoscopic Improvement and Remission With Advanced Therapy in Ulcerative Colitis.

Histology has prognostic value in ulcerative colitis (UC). However, direct comparisons of histological endpoints are lacking. To perform a network meta-analysis (NMA) to compare histological endpoints with biologics and small molecules. We searched four databases up until July 2024 for randomised controlled trials (RCTs) on advanced therapies for moderate-to-severe UC reporting histological endpoints. Outcomes included histological improvement or remission, and histo-endoscopic improvement after induction or during maintenance. We used a random-effects frequentist model and have reported outcomes as relative risk and 95% confidence interval. We estimated relative drug efficacy with the P-score. We conducted subgroup analysis by trial phase and evaluated risk of bias and evidence certainty. We included 24 RCTs (15 therapies, 8874 patients). Nineteen provided data on induction and 10 on maintenance; outcome definitions were similar. Etrasimod 2 mg/day ranked highest in achieving histologic improvement (P-score 0.98) and remission (P-score 0.90) following induction. Globally, guselkumab 200-400 mg ranked first for histo-endoscopic improvement, while etrasimod 2 mg/day and upadacitinib 45 mg/day were superior in the subgroup analysis. During maintenance, upadacitinib 30 mg/day was superior in achieving histologic improvement and remission (P-score 0.88 for both) and histo-endoscopic improvement (P-score 0.94). Etrasimod 2 mg/day ranked second for histologic remission (P-score 0.70) and histo-endoscopic improvement (P-score 0.73), while mirikizumab 200 mg/month ranked second for histologic improvement. These results support the ability of small molecules to achieve stringent endpoints in moderate-to-severe UC. Histological outcome data for biologics was sparser, particularly during maintenance. Head-to-head RCTs are imperative to better inform clinical practice.

12380 Point Of Care Microscale Magnetic Resonance (µNMR) Effectively Monitors Mitigation Of Oxidative Stress By GLP-1 Treatment In A Preclinical Model Of Diabetic Nephropathy

Abstract Disclosure: A.T. Alves: ; co-founder. ; LarmorBio. S.S. Thamarath: ; co-founder. ; LarmorBio. S. Fjordside: Employee; Self; Novo Nordisk. S. Sassower, MS.EE: ; Co-founder. ; LarmorBio. R. Rohr: ; co-founder,CEO. ; LarmorBio. A.P. Chambers: Employee; Self; Novo Nordisk. Oxidative stress is a major driver in the pathogenesis of diabetes, obesity, and related (cardio-renal) disorders. Early detection and prevention of an oxidative stress overload can improve and potentially modify the long-term harmful outcomes associated with chronic hyperglycaemia. A novel assay was developed, that uses µNMR technology to directly monitor oxidative stress from 5 µL of plasma at the point of collection in less than 10 minutes. This assay is highly sensitive to redox changes in the blood microenvironment, including increased ferric iron (Fe3+), protein oxidation and lipid peroxidation. Here, we show the oxidative stress profiling of three groups of ZSF1 rats in a twelve week (11th -23rd week of age) observational study. Vehicle lean, vehicle obese, and glucagon-like-peptide-1 (GLP-1) treated obese ZSF1 rats (n = 8/group) were studied with the assay along with conventional diabetic/metabolic markers, blood glucose (BG), HbA1c, Albumin Creatinine Ratio (ACR). The kidney (immuno)histology studies, alpha-smooth muscle actin (aSMA) and leucocyte common antigen (CD45) were performed at the termination phase of the ZSF1 rats (23rd week of age). The results demonstrated that the assay distinguished obese rats from lean rats with statistical significance (P ≤ 0.01) independent of other in-life diabetic/metabolic markers. Significant correlations with urinary Albumin Creatinine Ratio (ACR, ρ = 0.64, P ≤ 0.0001) were established throughout the study. A positive quantitative association is highlighted with classic histological end points of organ damage, kidney fibrogenesis (aSMA, ρ = 0.23), and inflammation (CD45, ρ = 0.45). Moreover, the assay detected significantly reduced oxidative stress levels (e.g., P ≤ 0.01) in the GLP-1 drug treatment group at five weeks of follow-up. In summary, the µNMR assay effectively monitored oxidative stress and captured disease-modifying therapeutics. Presentation: 6/1/2024

Reproducible lung protective effects of a TGFβR1/ALK5 inhibitor in a bleomycin-induced and spirometry-confirmed model of IPF in male mice.

This study comprehensively validated the bleomycin (BLEO) induced mouse model of IPF for utility in preclinical drug discovery. To this end, the model was rigorously evaluated for reproducible phenotype and TGFβ-directed treatment outcomes. Lung disease was profiled longitudinally in male C57BL6/JRJ mice receiving a single intratracheal instillation of BLEO (n = 10-12 per group). A TGFβR1/ALK5 inhibitor (ALK5i) was profiled in six independent studies in BLEO-IPF mice, randomized/stratified to treatment according to baseline body weight and non-invasive whole-body plethysmography. ALK5i (60 mg/kg/day) or vehicle (n = 10-16 per study) was administered orally for 21 days, starting 7 days after intratracheal BLEO installation. BLEO-IPF mice recapitulated functional, histological and biochemical hallmarks of IPF, including declining expiratory/inspiratory capacity and inflammatory and fibrotic lung injury accompanied by markedly elevated TGFβ levels in bronchoalveolar lavage fluid and lung tissue. Pulmonary transcriptome signatures of inflammation and fibrosis in BLEO-IPF mice were comparable to reported data in IPF patients. ALK5i promoted reproducible and robust therapeutic outcomes on lung functional, biochemical and histological endpoints in BLEO-IPF mice. The robust lung fibrotic disease phenotype, along with the consistent and reproducible lung protective effects of ALK5i treatment, makes the spirometry-confirmed BLEO-IPF mouse model highly applicable for profiling novel drug candidates for IPF.

Current Progress and Challenges in the Development of Pharmacotherapy for Metabolic Dysfunction-Associated Steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH), a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD), poses a significant threat to global health. Despite extensive research efforts over the past decade, only one drug has received market approval under accelerated pathways. In this review, we summarise the pathogenesis of MASH and present a comprehensive overview of recent advances in phase 2-3 clinical trials targeting MASH. These trials have highlighted considerable challenges, including low response rates to drugs, limitations of current surrogate histological endpoints, and inadequacies in the design of MASH clinical trials, all of which hinder the progress of MASH pharmacotherapy. We also explored the potential of non-invasive tests to enhance clinical trial design. Furthermore, given the strong association between MASLD and cardiometabolic disorders, we advocate for an integrated approach to disease management to improve overall patient outcomes. Continued investigation into the mechanisms and pharmacology of combination therapies may offer valuable insights for developing innovative MASH treatments.

Surface engineering enhances the therapeutic potential of systemically delivered extracellular vesicles following acute myocardial infarction.

The objective of the study was to assess the therapeutic efficacy of targeting remote zone cardiomyocytes with cardiosphere-derived cell (CDC) extracellular vesicles (EVs) delivered via intramyocardial and intravenous routes following acute myocardial infarction (MI). Cardiomyocyte (CM) cell death plays a significant role in left ventricular (LV) remodeling and cardiac dysfunction following MI. While EVs secreted by CDCs have shown efficacy in promoting cardiac repair in preclinical models of MI, their translational potential is limited by their biodistribution and requirement for intramyocardial delivery. We hypothesized that engineering the surface of EVs to target cardiomyocytes would enhance their therapeutic efficacy following systemic delivery in a model of acute MI. CDC-derived EVs were engineered to express a CM-specific binding peptide (CMP) on their surface and characterized for size, morphology, and protein expression. Mice with acute MI underwent both intramyocardial and intravenous delivery of EVs, CMP-EVs and placebo in a double-blind study. LVEF was assessed by echo at 2- and 28-days post-MI and tissue samples processed for assessment of EV biodistribution and histological endpoints. CMP-EVs demonstrated superior cardiac targeting and retention when compared with unmodified EVs 24 h post-MI. Mice treated with IV delivered CMP-EVs demonstrated a significant improvement in LVEF and a significant reduction in remote zone cardiomyocyte apoptosis when compared with IV delivered non-targeted EVs at 28-day post-MI. Systemic administration of CMP-EVs improved cardiac function and reduced remote zone cardiomyocyte apoptosis compared with IV-administered unmodified EVs, demonstrating a strategy to optimize therapeutic EV delivery post-MI.

Health-related quality of life (HRQL) assessments in a 52-week, double-blind, randomized, placebo-controlled phase III study of resmetirom (MGL-3196) in patients with metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis.

Resmetirom, liver-directed thyroid-hormone receptor-β agonist, received approval for metabolic dysfunction-associated steatohepatitis (MASH) treatment. We assessed health-related quality of life (HRQL) in patients with MASH treated with resmetirom. Patients with MASH/NASH without cirrhosis and with confirmed/suspected fibrosis were enrolled in a 54-month double-blind randomized placebo-controlled phase III clinical trial with serial biopsy assessments at baseline and week 52 (MAESTRO-NASH, NCT03900429). HRQL was assessed using Chronic Liver Disease Questionnaire-NASH (CLDQ-NAFLD) and Liver Disease Quality of Life (LDQOL). Baseline HRQL score changes by treatment group (resmetirom 80mg, resmetirom 100mg, or placebo) and histological response (improvement of fibrosis without worsening of NAS or resolution of MASH/NASH without worsening of fibrosis) were compared after 52 weeks. Included were 966 intention-to-treat patients: 323 received resmetirom 100mg, 322 resmetirom 80mg, and 321 placebo. By weeks 24 and 52, patients receiving 80 or 100mg resmetirom experienced HRQL improvement in CLDQ-NAFLD Worry domain (mean +0.21 to +0.24, p < 0.05). At week 52, subjects who met histologic endpoints after treatment with resmetirom (100mg and 80mg pooled) experienced HRQL improvement in CLDQ-NAFLD Worry +0.46 (41% met minimal clinically important difference [MCID]), LDQOL domains: Role Emotional +3.0 (28% met MCID), Health Distress +8.1 (38% MCID), Stigma +3.5 (39% MCID), and total LDQOL +2.2 (35% MCID) (all p < 0.05). Similar improvements were noted in histologic responders from 100mg or 80mg resmetirom groups when separated-no improvements in placebo or nonresponders. Baseline F3 histologic responders had similar/more pronounced HRQL improvements. Patients with MASH/NASH with fibrosis improvement or the resolution of MASH with resmetirom experienced clinically meaningful and statistically significant HRQL improvements.

265. INITIAL RESULTS FROM RESOLVE, A PHASE 1B DOSE-ESCALATION STUDY OF EP-104GI (EXTENDED-RELEASE FLUTICASONE PROPIONATE INTRA-ESOPHAGEAL INJECTION) FOR EOSINOPHILIC ESOPHAGITIS

Abstract Background Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease characterized by inflammation, influx of eosinophils and esophageal remodeling. Therapy for EoE includes swallowed/topical corticosteroids, dupilumab, and dietary elimination; but these are not always effective. EP-104GI is an extended-release fluticasone propionate (FP) intra-esophageal injection being developed as a novel treatment for EoE. EP-104GI consists of coated FP crystals that release locally via diffusion at a pre-defined rate to reduce peak concentrations and prolong therapeutic window. RESOLVE (NCT05608681) is a Phase 1b, multicenter, open-label, dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, and efficacy of EP-104GI in patients with EoE. Methods The conservative starting dose of EP-104GI consisted of 1 mg injected at each of 4 sites in 4 quadrants over two ‘rings’ in the esophagus. Dose escalations increase the dose per site and/or number of sites; the second cohort received 1 mg at each of 8 sites. After a single administration of EP-104GI, participants are assessed for up to 24 weeks including adverse events (AEs) and laboratory tests. Efficacy assessments include histological endpoints and patient-reported symptom outcomes including the Straumann Dysphagia Index (SDI). Esophageal biopsies are collected at baseline, Week 4 and Week 12. Results All subjects demonstrated decreased symptom scores compared to baseline, with generally greater responses at the higher EP-104GI dose in Cohort 2 (Fig 1). Histologically, all Cohort 2 patients showed decreases in EoEHSS scores with 2/3 having ≈50% decrease in total grade score and ≈35% decrease in total stage score at Week 4, also, eosinophil counts were reduced by ≈35% at Week 4 and ≈40% at Week 12. Findings from Cohorts 1 and 2 of the ongoing trial include mild-moderate treatment-emergent AEs, the majority occurring on the day of treatment. No AEs were related to EP-104GI. Conclusions The initial results presented here indicate that the novel diffusion-based localized delivery of FP via EP-104GI injection into the esophagus is feasible and safe in patients with EoE and could avoid the side-effects typically associated with swallowed/topical corticosteroids. Efficacy data from the doses studied, although limited at this point, suggest a dose-response relationship with symptom outcomes and also show histologic improvements. These findings support the potential for an interval of at least 6 months between inter-esophageal injections, which may be further extended at the higher doses to be investigated in this study. Recruitment is ongoing.

Resmetirom and Metabolic Dysfunction-Associated Steatohepatitis: Perspectives on Multidisciplinary Management from Global Healthcare Professionals.

The approval of resmetirom brings great hope to patients with metabolic dysfunction-associated steatohepatitis (MASH). The purpose of this review is to explore its impact on the global health environment. The implementation of multidisciplinary management MASH is proposed. Resmetirom has benefits in the treatment of MASH, and its safety and effectiveness have been studied. The adverse events (AEs) need to be noticed. To improve patient outcomes, a multimodal approach with medication such as resmetirom, combined with metabolic and bariatric surgery (MBS) and lifestyle interventions can be conducted. MASH, a liver disease linked with obesity, is a challenging global healthcare burden compounded by the absence of any approved pharmacotherapy. The recent conditional approval by the Food and Drug Administration(FDA) in the United States of resmetirom, an oral, liver-directed, thyroid hormone receptor beta-selective agonist, marks a significant milestone, offering a treatment option for adults with non-cirrhotic MASH and who have moderate to advanced liver fibrosis. This narrative review discusses the efficacy and safety of resmetirom and its role in the therapeutic landscape of MASH treatment. Despite the promising hepatoprotective effect of resmetirom on histological liver endpoints, its use need further research, particularly regarding ethnic differences, effectiveness and cost-effectiveness, production scalability, social acceptance and accessibility. In addition, integrating resmetirom with other multidisciplinary therapeutic approaches, including lifestyle changes and MBS, might further improve clinical liver-related and cardiometabolic outcomes of individuals with MASH. This review highlights the importance of a comprehensive treatment strategy, supporting continued innovation and collaborative research to refine treatment guidelines and consensus for managing MASH, thereby improving clinical patient outcomes in the growing global epidemic of MASH. Studies done to date have been relatively short and ongoing, the course of the disease is highly variable, the conditions of various patients vary, and given this complex clinical phenotype, it may take many years of clinical trials to show long-term benefits.

Endoscopic, Histologic, and Composite Endpoints in Patients With Ulcerative Colitis Treated With Etrasimod

Histologic remission, a potentially important treatment target in ulcerative colitis (UC), is associated with favorable long-term outcomes. Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active UC. This post-hoc analysis of the ELEVATE UC program evaluated the efficacy of etrasimod according to histologic and composite (histologic/endoscopic/symptomatic) endpoints and examined their prognostic value. Patients with moderately to severely active UC were randomized 2:1 to once-daily oral etrasimod 2 mg or placebo. Histologic and composite endpoints, including disease clearance (endoscopic/histologic/symptomatic remission), were assessed at Weeks 12 (ELEVATE UC 52; ELEVATE UC 12) and 52 (ELEVATE UC 52). Logistic regressions examined associations between baseline and Week 12 histologic/composite endpoints and Week 52 outcomes. At Weeks 12 and 52, significant improvements with etrasimod vs placebo were observed in histologic/composite outcomes, including endoscopic improvement-histologic remission and disease clearance. The proportion of patients treated with etrasimod achieving clinical remission at Week 52 was higher among those with disease clearance at Week 12 vs those without disease clearance (73.9% [17/23] vs 28.3% [71/251]). Histologic improvement and endoscopic improvement at Week 12 were moderately and strongly associated with clinical remission at Week 52 (odds ratio [OR], 2.37; 95% confidence interval [CI], 1.27-4.41; and OR, 6.36; 95% CI, 3.47-11.64, respectively). Histologic remission and endoscopic improvement at Week 12 were strongly associated with endoscopic improvement-histologic remission at Week 52 (OR, 3.21; 95% CI, 1.70-6.06 and OR, 5.47; 95% CI, 2.89-10.36, respectively). Etrasimod was superior to placebo for achievement of stringent histologic and composite endpoints. gov, Number: NCT03945188; ClinicalTrials.gov, Number: NCT03996369.

Therapeutic inhibition of biomechanically-activated YAP-TAZ signaling prevents vein graft atherosclerosis

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Rembrandt Institute for Cardiovascular Sciences Background Venous bypass grafts may have limited patency due to excessive intimal hyperplasia and accelerated atherosclerosis. YAP-TAZ signaling regulates cellular responses to biomechanical cues, such as disturbed flow or vessel distention as seen in vein grafts. YAP activation leads to inflammation and angiogenesis, which both contribute to vein graft atherosclerosis. Inhibition of YAP-TAZ attenuates naive atherogenesis, but its potential to inhibit intraplaque angiogenesis and reduce vein graft atherosclerosis has not been explored. Methods Saphenous vein progenitor cells (SVPs) were subjected to mechanical strain in vitro to assess YAP activation. IHC to assess YAP-expression was performed on vein grafts from pigs as well as ex vivo cultured human saphenous veins. Furthermore, YAP-IHC was performed on murine vein grafts from hypercholesterolemic ApoE3*Leiden mice harvested at early, mid- and late-stage disease timepoints to assess optimal treatment window. In a separate experiment, mice (n=11-13/group) underwent bypass surgery and were treated with the FDA-approved YAP-TAZ inhibitor Verteporfin (50 mg/kg) or vehicle 3 times/week from day 10 until sacrifice (day 28). Ultrasound was used to longitudinally quantify vascular remodeling. Vein grafts were harvested and processed for morphometric and compositional analysis. Results Mechanical strain induced activation of YAP and its downstream targets (Ctgf, Cyr61) in SVPs, which was inhibited by Verteporfin (confirmed by WB, IP and qPCR). Moreover, YAP was abundantly expressed in pig vein graft lesions, whilst Verteporfin blocked YAP expression in ex vivo cultured human saphenous veins after exposure to disturbed flow. In addition, YAP was increasingly expressed during vein graft lesion development in mice, reaching its peak around day 14, which coincides with the initiation of intraplaque angiogenesis. Furthermore, YAP was predominantly expressed in luminal and adventitial endothelial cells. Analysis of ultrasound demonstrated that Verteporfin prevented vein graft thickening in mice over time. End-point histology revealed that the intima/media ratio was significantly decreased by Verteporfin treatment (37%, p=0.001). Intraplaque angiogenesis was also reduced (34%, p=0.002), whilst neovessel maturation was improved upon verteporfin treatment. The vessel wall ACTA2 content was reduced (42%, p=0.023), whilst collagen was not altered between both groups, indicating that Verteporfin diminished the fibroproliferative response without affecting vessel wall stability. Conclusion Verteporfin inhibited YAP-TAZ activation induced by mechanical strain in vitro (SVPs) as well as ex vivo (cultured human saphenous veins). In vivo, Verteporfin treatment resulted in a significant decrease of vein graft atherosclerosis and intraplaque angiogenesis. Therefore, therapeutic targeting of YAP-TAZ using Verteporfin might be a new candidate to improve vein graft patency.