Objective Selective inhibition of interleukin (IL)-23 through antagonism of the IL-23p19 subunit has demonstrated clinical efficacy in inflammatory bowel disease, but the molecular changes underlying the efficacy outcomes have not yet been described. Here, we provide a detailed evaluation of the cellular and molecular changes associated with guselkumab treatment in patients with moderately to severely active ulcerative colitis (UC) from the QUASAR Phase IIb induction study.Methods In this double-blind, placebo-controlled, dose-ranging induction study, patients (n=313) were randomised (1:1:1) to receive intravenous guselkumab 200 or 400 mg or placebo at weeks 0, 4, and 8. Colon biopsy samples were collected at weeks 0 and 12, enabling molecular profiling by bulk RNA sequencing (RNA-seq, n=257), single-cell RNA sequencing (n=52), and flow cytometry (n=30). Serum proteomic profiling was also performed at weeks 0, 4, and 12 (n=302).Results Guselkumab treatment significantly reduced pro-inflammatory serum proteins by week 4 with continued decline through week 12, compared with placebo. Unsupervised analysis of tissue gene modules revealed significant changes in transcriptional states related to pro-inflammatory and epithelial repair pathways, which were most pronounced in patients who achieved histological-endoscopic mucosal improvement (HEMI) at week 12, an important tissue-based end point. Single-cell analyses supported a decrease in the cellular abundance of pro-inflammatory and an increase in mucosal cell types in tissue following treatment.Conclusion This analysis of guselkumab in UC demonstrated changes in key pathways and cell types that are associated with achieving important clinical end points including HEMI at week 12.Trial registration number NCT04033445.

BackgroundThere is a need to identify peripheral biomarkers reflective of defined disease associated fibroblasts in Ulcerative Colitis (UC), with the aim of enabling clinical development approaches for novel-stromal-targeted therapeutics for individuals at risk for fibrostenotic complications. Additionally, longitudinal non-invasive biomarkers of tissue remodelling, fibroblast biology and pharmacodynamic measurements are needed in the clinic to facilitate risk stratification.AimTo identify novel blood protein biomarkers associated with defined fibroblast subsets, tissue remodelling and treatment response/non-response in UC.MethodsWe performed data analysis on matched serum and tissue transcriptomics from the UNIFI trial at weeks 0 and 8 in clinical responders and non-responders. Detailed gene correlation analysis was performed on 97 colonic biopsies from 50 patients pre- and post-treatment, to construct detailed cell-type mapping associated with clinical parameters. Detailed serum-based proteomics analysis was performed using matched serum and tissue sample sets to evaluate specific correlations between defined tissue cellular subsets and unique peripheral proteins, reflective of defined tissue transcriptional subsets and clinical parameters.ResultsEvaluation of the UNIFI clinical study, revealed a significant association between intestinal-inflammatory activated fibroblasts (IIAF) and various clinical parameters, including Geboes scores. These findings were unique to IIAFs and were confirmed using spatial tissue transcriptomics. Evaluation of novel peripheral proteomics revealed a significant correlation between selective serum collagen biomarkers, including Pro-Collagen 22, Collagen 1M, CTX-III, ELP-3, and the IIAF tissue module. These serum collagen biomarkers were unique to IIAFs, as other broad proteomics methodologies failed to demonstrate significant correlations with known UC serum markers. Ustekinumab endoscopic responders had a significant decrease in IIAFs, which was associated with decreases in these IIAF associated serum proteins. Furthermore, C1M and ELP-3 demonstrated predictive value to enable characterisation of UC patients with IIAF driven disease.ConclusionsThese serum biomarkers were correlated with tissue levels of IIAFs, identifying unique peripheral markers of tissue associated cell types correlated with fibrosis. Given the association of IIAFs and treatment response, this highlights the utility of these triaged collagen biomarkers for anti-stromal therapeutic development and patient stratification in UC and beyond.

BACKGROUNDIcotrokinra is the first and only targeted oral peptide that selectively binds the IL-23 receptor with high affinity to precisely inhibit IL-23 signaling. Icotrokinra demonstrated high rates of complete skin clearance and durable disease control in the phase IIb trial, FRONTIER-1, and its long-term extension, FRONTIER-2, in participants with moderate-to-severe plaque psoriasis. This study evaluated systemic and skin pharmacodynamic response of icotrokinra and its relationship to clinical response in FRONTIER participants.METHODSFRONTIER-1 participants received icotrokinra or placebo for 16 weeks. FRONTIER-2 followed participants for up to 1 year of treatment; placebo participants transitioned to icotrokinra after week 16. Systemic pharmacodynamic changes were assessed in serum through week 52. Skin pharmacodynamic changes were assessed using transcriptomic analysis of skin biopsies and protein quantification in tape-strip samples through week 16.RESULTSIcotrokinra dose-dependently reduced serum levels of the IL-23/IL-17 axis and psoriasis disease biomarkers through week 52, with maximal reductions observed with the highest 100 mg twice-daily dose. Proteomic analyses showed icotrokinra selectively blocked IL-23-driven inflammation without broader impacts on circulating proteins, including serum IL-23 levels. Sixteen weeks of icotrokinra, but not placebo, reduced expression of psoriasis-associated genes in lesional skin. Icotrokinra treatment also reduced psoriasis-relevant proteins in week 16 lesional skin tape-strips to levels comparable to nonlesional samples.CONCLUSIONIcotrokinra induced a dose-dependent pharmacodynamic response, with early (week 4) and sustained (week 52) reductions in biomarkers of IL-23 pathway activation and psoriasis disease severity, which correlated with clinical response.TRIAL REGISTRATIONClinicalTrials.gov: NCT05223868, NCT05364554.FUNDINGJohnson & Johnson.

Celiac disease is a chronic autoimmune disorder affecting 0.5%-1% of the population. Here, we assembled the most comprehensive single-cell RNA sequencing (scRNA-seq) dataset in celiac disease (CeD) to date, including 203,555 cells across 21 active CeD and 11 control duodenal samples. CeD was characterized by single-cell differential changes in abundance, gene expression, and cell-cell interactions across cellular compartments versus control. Epithelial changes included increased stem/crypt and secretory epithelial cells in CeD and decreased absorptive enterocytes, reflecting crypt hyperplasia and villus atrophy. Distinct changes in stromal populations correlated with epithelial changes, particularly increased abundance and transcriptional activity of NRG1 and SMOC2 fibroblasts. Cell-cell interaction analysis proposed a distinct increased role of fibroblasts to support epithelial reprogramming of the increased stem/crypt epithelial fraction in CeD, mediated by myeloid derived interleukin-1β (IL-1β) and lymphoid-derived interferon γ (IFN-γ). This dataset reveals a role for T-myeloid-stromal-epithelial cell communication in CeD, highlighting key mechanisms of the tissue-level cellular dynamics in response to gluten ingestion.

Abstract Background Guselkumab (GUS) is a selective dual-acting IL-23p19 subunit inhibitor that potently blocks IL-23 and binds to CD64 demonstrated efficacy with intravenous (IV) induction in patients with moderately to severely active Crohn’s disease (CD) in the GALAXI trials.1 Subcutaneous (SC) induction with GUS evaluated in the Ph3 GRAVITI trial was also efficacious in treating patients with CD.2 Here we present a comparison of the pharmacodynamic and mechanistic response of GUS SC and GUS IV induction therapy in CD. Methods Serum proteins were evaluated from 290 GRAVITI patients randomised to PBO or GUS 400mg SC q4w, and a subset of 292 GALAXI patients randomised to PBO or GUS 200mg IV q4w at Weeks 0 and 12 using a 92-analyte inflammatory protein panel. Transcriptional profiling from each of the five anatomic segments in GRAVITI was conducted with samples from 277 patients at WK0 and WK12 using RNA sequencing. A tissue inflammation score (bMIS3) was used to assess segmental molecular inflammation which correlated with segmental histology scores defined by Global Histologic Activity Score (GHAS), endoscopic scores and subscores defined by Simple Endoscopic Score for CD (SES-CD).3 Analysis of treatment effect was performed using molecularly inflamed samples (defined as bMIS >0) from segments with SES-CD >0 at baseline. Transcriptional gene modules were evaluated for differential expression. Results In serum, protein changes observed with GUS 400mg SC q4w induction at WK12 were highly correlated with those observed with GUS 200mg IV q4w induction at WK12 (R=0.96, p<0.05), including similar reduction of IFNγ, IL-17A, CRP and fecal calprotectin (p<0.05; Figure 1). In tissue, segmental molecular inflammation assessed by bMIS correlated with segmental histological and endoscopic subscores (percent affected tissue and ulceration severity). In each anatomic segment, GUS SC induction reduced key cellular and inflammatory transcriptional modules at WK12 including plasma cell, inflammatory epithelial, neutrophil, and IL-23/Th17 biology consistent with molecular analysis from GUS IV induction in GALAXI Ph2b.4 The decrease in molecular inflammation in 5 anatomic segments corresponded to the segmental endoscopic improvement observed in isolated ileal, ileocolonic and colonic patient subgroups. Conclusion Following SC induction, the protein changes observed in serum at WK12 in GRAVITI were highly correlated with those seen with GUS IV induction from GALAXI Ph3. These data demonstrate similar molecular effects of GUS SC and IV induction doses and are aligned with previously reported similar efficacy results, supporting the flexible choice for patients and healthcare professionals between GUS SC and IV to treat patients with CD. References 1.Panaccione R, Danese S, Feagan BE, et al. Efficacy and safety of guselkumab therapy in patients with moderately to severely active Crohn’s disease: results of the GALAXI 2 & 3 phase 3 studies. Gastroenterology. 2024; 5 (Supplement): p1057b. 2.Panaccione R, Hart A, Steinwurz F et al. Efficacy and Safety of Subcutaneous Guselkumab Induction Therapy in Patients with Moderately to Severely Active Crohn’s Disease: Results Through Week 48 From the Phase 3 GRAVITI Study. ACG 2024. 3.C Argmann, et al. Biopsy and blood-based molecular biomarker of inflammation in IBD. Gut. 2022; 0:1-17. 4.Richards D, Venkat S, Ruane D, et al. Guselkumab Decreases Key Cellular Inflammatory Processes Across Ileum and Colon Tissue in Crohn’s Disease. P0950 ACG 2024.

Abstract Background Crohn’s disease (CD) is characterized by significant heterogeneity in disease location and other clinical factors, making it challenging to define the underlying molecular mechanisms associated with disease. Here, we provide a detailed molecular characterization of baseline ileal and colonic tissue from patients enrolled in the GALAXI Ph2b study of guselkumab in CD (NCT03466411) and explore the association of regional molecular profiles with endoscopic and histologic severity. Methods Baseline biopsies from 241 patients were obtained from rectum (R), splenic flexure (SF), and terminal ileum (TI). Paired biopsies within a region were processed for histology and RNA sequencing (RNAseq). Cell-type specific transcriptional modules were used to evaluate differential expression and to create a disease severity axis. Principal component analysis (PCA) was applied to modules with the highest correlation with paired Global Histologic Activity Scores (GHAS) per region and the resulting PC1 was used to define an objective tissue-based molecular activity score (MAS) to identify inflamed and uninflamed tissue. Inflamed tissue was used to assess regional molecular profiles which were correlated with paired regional histology scores defined by GHAS and endoscopic severity defined by Simple Endoscopic Score for CD (SES-CD). Results Modules specific to inflammatory myeloid and epithelial transcriptional states, and IL-23 and interferon response pathways, were highly correlated with paired GHAS. Applying this subset of modules as a MAS revealed a bimodal distribution of inflamed and non-inflamed biopsies. MAS identified 114/241 (47.3%), 85/229 (37.1%) and 114/229 (49.8%) inflamed biopsies in the R, SF, and TI, respectively. Regional molecular profiles of inflamed biopsies demonstrated increased mRNA expression of IL-23p19 (IL23A) and Fc-γ receptor 1 (CD64) (p<0.001), and enrichment of inflammatory modules across locations. Local MAS per region showed highest correlations with paired baseline GHAS, followed by SES-CD in the segment (Figure 1 and Table 1). Notably MAS provides higher resolution to identify representative biopsies for affected regions. Conclusion Application of the MAS to identify inflamed tissue enabled identification of key immune and inflammatory related processes across the ileum and colon that were associated with the IL-23 pathway, and baseline regional endoscopic and histologic severity. By identifying inflamed baseline samples, molecular changes associated with treatment can be more accurately defined in future analyses to better understand regional heterogeneity in CD.

Background: Combination induction therapy with guselkumab (GUS), an interleukin (IL)-23p19 subunit antagonist, and golimumab (GOL), a tumor necrosis factor (TNFα) antagonist, induced higher rates of clinical remission, endoscopic, and histologic outcomes than either monotherapy at Week (WK)12 in patients with ulcerative colitis (VEGA NCT03662542). Data through WK38 suggested the continued benefit of combination induction even after a transition to GUS monotherapy at WK12. Objectives: To explore early molecular changes in colon tissue in a subset of patients at WK4 to define mechanistic contributions of each monotherapy and combination; these parameters were evaluated again at WK38 to assess potential carry-over of efficacy. Methods: Colon biopsies were obtained at baseline (n=195), WK4 (n=42 substudy), and WK38 (n=172). Transcriptional profiles were generated with RNA sequencing (RNAseq). Gene correlation network analysis was applied in conjunction with publicly available single cell RNAseq data to define biologically relevant bulk and cell type-specific transcriptional modules associated with molecular features of disease. Gene set variation analysis (GSVA) was used to quantitatively assess changes in biologic modules with treatment. Results: At WK4, combination induction (n=10) showed significant (p<0.05) decreases in molecular features compared to GUS (n=19) and GOL (n=13), including transcriptomic modules representing the IL-23 pathway, interferon response, and inflammatory epithelial and myeloid transcriptional states associated with endoscopic improvement at WK4 (Mayo endoscopy subscore of 0 or 1) (combination 5/11, GOL 1/13; GUS 2/19). Reduction (p<0.05) in inflammatory modules persisted through WK38 with combination vs monotherapy induction. Module changes between treatments at WK4 indicated a stronger correlation between GUS and combination (R=0.8; p=2.2e-16) than GOL and combination (R=0.52; p=4.1e-12), with processes associated with epithelial and stromal biology, and mucosal inflammation (Figure 1). In contrast, the combination effect on specific neutrophil/myeloid biology at WK4 was more similar to GOL than GUS, supporting the early role of GOL in targeting innate inflammation. Conclusion: Combination induction with GUS and GOL showed significant reductions in major inflammatory features of disease as early as WK4 which persisted through WK38 with GUS maintenance. Correlative analysis supports the role of GUS as the primary driver of tissue healing, with GOL further contributing to innate inflammatory activity, which demonstrate differential and complementary mechanisms of action of TNFα and IL-23p19 subunit blockade. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: Dylan Richards Stock options in Johnson & Johnson, Employee of Janssen, Marion Vetter Stock options in Johnson & Johnson, Employee of Janssen, Matthew Germinaro Stock options in Johnson & Johnson, Employee of Janssen, Bram Verstockt Consultant fees from Abbvie, Alimentiv, Applied Strategic, Atheneum, BenevolentAI, Biora Therapeutics, Bristol Myers Squibb, Galapagos, Guidepont, Landos, Lily, Mylan, Inotrem, Ipsos, Janssen, Pfizer, Progenity, Sandoz, Santa Ana Bio, Sosei Heptares, Takeda, Tillots Pharma, and Viatris, Grant/research support from AbbVie, Biora Therapeutics, Landos, Pfizer, Sossei Heptares, and Takeda; speaker's fees from Abbvie, Biogen, Bristol Myers Squibb, Celltrion, Chiesi, Falk, Ferring, Galapagos, Janssen, Lily, MSD, Pfizer, R-Biopharm, Sandoz, Takeda, Tillots Pharma, Truvion, and Viatris, Raja Atreya Speakers for AbbVie, Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Cellgene, Celltrion Healthcare, DrFalk Pharma, Galapagos, Gilead, InDex Pharmaceuticals, Janssen-Cilag, Lilly, MSD Sharp & Dohme, Novartis, Pandion Therapeutics, Pfizer, Roche Pharma, Samsung Bioepis, Takeda Pharma, and Viatris, Consultant for AbbVie, Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Cellgene, Celltrion Healthcare, DrFalk Pharma, Galapagos, Gilead, InDex Pharmaceuticals, Janssen-Cilag, Lilly, MSD Sharp & Dohme, Novartis, Pandion Therapeutics, Pfizer, Roche Pharma, Samsung Bioepis, Takeda Pharma, and Viatris, Grant/research support from AbbVie, Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Cellgene, Celltrion Healthcare, DrFalk Pharma, Galapagos, Gilead, InDex Pharmaceuticals, Janssen-Cilag, Lilly, MSD Sharp & Dohme, Novartis, Pandion Therapeutics, Pfizer, Roche Pharma, Samsung Bioepis, Takeda Pharma, and Viatris, Julian Panes Payment for lectures including service on speakers bureaus from Abbott and Janssen, Consultant for Abbvie, Arena, Athos, Atomwise, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Galapagos, Genentech - Roche, GlaxoSmithKline, Janssen, Mirum, Morphic, Origo, Pandion, Pfizer, Progenity, Protagonist Therapeutics Inc., Revolo, Robarts, Takeda, Theravance, and Wassermann; Data Safety Monitoring Board or Advisory Board from Alimentive and Sanofi; Support for travel to meetings from Abbvie and Takeda during the conduct of the study, Grants from Abbvie and Pfizer; support for travel to meetings from Abbvie and Takeda during the conduct of the study, Bruce E. Sands Speaker's fees from AbbVie, Abivax, Adiso Therapeutics, AgomAb, Alimentiv, Amgen, Arena Pharmaceuticals, Artizan Biosciences, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Celltrion, ClostraBio, Connect Biopharm, Cytoki Pharma, Eli Lilly and Company, Enthera, Evommune, Ferring, Fresenius Kabi, Galapagos, Gilead Sciences, Genentech, Glaxo SmithKline, Gossamer Bio, HMP Acquisition, Imhotex, Immunic, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido, Kalyope, Merck, MiroBio, Morphic Therapeutic, MRM Health, OSE Immunotherapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, RedHill Biopharma, Sun Pharma Global, Surrozen, Synlogic Operating Company, Takeda, Target RWE, Theravance Biopharma R&D, TLL Pharmaceutical, USWM Enterprises, Ventyx Biosciences, and Viela Bio, Stock options in Ventyx Biosciences, Consultant for AbbVie, Abivax, Adiso Therapeutics, AgomAb, Alimentiv, Amgen, Arena Pharmaceuticals, Artizan Biosciences, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Celltrion, ClostraBio, Connect Biopharm, Cytoki Pharma, Eli Lilly and Company, Enthera, Evommune, Ferring, Fresenius Kabi, Galapagos, Gilead Sciences, Genentech, Glaxo SmithKline, Gossamer Bio, HMP Acquisition, Imhotex, Immunic, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido, Kalyope, Merck, MiroBio, Morphic Therapeutic, MRM Health, OSE Immunotherapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, RedHill Biopharma, Sun Pharma Global, Surrozen, Synlogic Operating Company, Takeda, Target RWE, Theravance Biopharma R&D, TLL Pharmaceutical, USWM Enterprises, Ventyx Biosciences, and Viela Bio, Brian Feagan A member of the speakers bureau for Abbvie, Janssen, Takeda, and BI; payment for expert testimony from Morgan Lewis and Lenczner Slaght; support for attending meetings and/or travel from Abbvie, Janssen, Pfizer, Takeda, and BI, Stock options in Gossamer, Consultant fees from AbbVie, AbolerIS, AgomAB, Allianthera, Amgen, AnaptysBio, Applied Molecular Transport Inc, Arena, Avoro Capital Advisors, Atomwise, BioJamp, Biora, Boehringer-Ingelheim, Boxer, Celsius, Celgene/Bristol Myers Squibb, Connect BioPharma, Cytoki, Disc Medicine, Duality, EcoR1, Eli Lilly, Equillium, Ermium, First Wave, First Word Group, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, Gossamer, GlaxoSmithKline, Hinge Bio, Hot Spot, Index, Imhotex, Immunic, JAKAcademy, Janssen, Japan Tobacco Inc., Kaleido, Landos, Leadiant, L.E.K. Consulting, LifeSci Capital, Lument AB, Millennium, MiroBio, Morphic, Mylan, OM Pharma, Origo, Orphagen, Pandion, Pendopharm, Pfizer, Prometheus, Play to Know AG, Progenity, Protagonist, PTM Therapeutics, Q32 Bio, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres, Silverback, Surrozen Inc., Takeda, Teva, Thelium, Tigenix, Tillotts, Ventyx Biosciences, VHSquared Ltd., Viatris, Ysios, Ysopia, and Zealand Pharma; Safety Monitoring Board or Advisory Board from AbbVie, Amgen, AMT, AnaptysBio, Axio, Boehringer-Ingelheim, Celgene/Bristol Myers Squibb, Ecor1Capital, Eli Lilly, Genentech/Roche, GlaxoSmithKline, Index, Janssen, MiroBio, Morphic, Origo BioPharma, Pfizer, Progenity, Prometheus, RedX, Sanofi, Takeda, Tillotts, and Teva, Bradford McRae Stock options in Johnson & Johnson, Employee of Janssen, Daniel Cua Stock options in Johnson & Johnson, Employee of Janssen, Patrick Branigan Stock options in Johnson & Johnson, Employee of Janssen, Tom C. Freeman Stock options in Johnson & Johnson, Employee of Janssen

Introduction: JNJ-77242113, a first-in-class oral IL-23R antagonist peptide, demonstrated significantly greater efficacy vs placebo (PBO) for moderate-to-severe plaque psoriasis in FRONTIER-1. Objective: To evaluate the pharmacodynamic (PD) response to JNJ-77242113 and its relationship to clinical efficacy. Methods: FRONTIER-1 was a randomized, double-blind, PBO-controlled, dose-ranging, phase 2 study of JNJ-77242113 in moderate-to-severe plaque psoriasis. Patients were randomized 1:1:1:1:1:1 to receive JNJ-77242113 25mg daily (QD), 50mg QD, 25mg twice daily (BID), 100mg QD, 100mg BID, or PBO through Week (W)16. Clinically validated therapeutics that target the IL-23 pathway in psoriasis drive systemic PD changes in the serum levels of beta-defensin-2 (BD-2), IL-22, IL-17A, and IL-17F relative to baseline. We analyzed serum levels of these disease biomarkers in FRONTIER-1 patients who received PBO or JNJ-77242113. A linear mixed effect model was used to analyze the data. Results: All doses of JNJ-77242113 significantly decreased serum levels of biomarkers relevant to psoriasis disease pathophysiology (BD-2, IL-22, IL-17A, IL-17F), with the fold reduction relative to baseline significantly distinguished from PBO (p<0.05 for all doses vs PBO). Interestingly, as previously observed with therapeutic blockade of the IL-23 pathway in psoriasis, reduction of these systemic biomarkers by JNJ-77242113 showed a strong correlation with clinical response. Importantly, JNJ-77242113 treatment did not increase serum levels of IL-23 in psoriasis patients as seen with some other cytokine receptor antagonist therapeutics. Conclusion: We show for the first time that specific targeting of the IL-23 pathway through inhibition of IL-23R signaling with JNJ-77242113 induces a strong systemic PD response in psoriasis patients that is significantly distinguished from PBO. JNJ-77242113 PD response is comparable to other clinically validated therapeutics targeting IL-23 in psoriasis, and it corroborates the observed clinical efficacy of JNJ-77242113. Taken together, consistent with its mechanism of action, JNJ-77242113 dampens objective biomarkers of IL-23 pathway activation and psoriasis disease severity.

Abstract Background Ustekinumab (UST) is a monoclonal antibody specific for the p40 subunit of interleukin (IL)-12 and IL-23. In a randomised phase 3 trial (UNIFI; NCT02407236) in patients with moderate-to-severe ulcerative colitis (UC), UST was shown to be more effective for inducing and maintaining clinical remission than placebo. There has yet to be a mechanistic understanding of p40 blockade in inflammatory bowel disease. Here, we investigated the underlying molecular mechanism of action of UST in UC. Methods Paired colon biopsies for transcriptomic analysis were obtained at screening and week 8 in patients who received a single intravenous induction treatment of placebo (n=145 subjects), UST 130 mg (n=155 subjects), or a weight-range-based dose (approximated to UST 6 mg/kg of body weight; n=171 subjects). Tissue transcriptional profiles were determined using Affymetrix microarrays. Transcriptional changes were analysed in the context of cell type-specific co-expression modules derived from single cell UC data. Gene set variation analysis (GSVA) was used to quantitatively assess changes in specific biologic modules in the context of endoscopic and histologic-endoscopic mucosal improvement (HEMI) responder and non-responder analyses. Nichenet, which predicts ligand–target gene links, was used with single cell UC data to identify ligands that are predicted to be associated with our cell type-specific modules. Results By week 8, both UST treatment arms induced a greater magnitude of transcriptional changes associated with Th17, Th1 cytotoxicity, myeloid inflammatory, epithelial inflammatory, and inflammatory fibroblast modules compared with placebo. Ligand-target gene predictions indicate IL-12 and IL-23 are associated with changes in the Th1 cytotoxicity and Th17 module expression, respectively. Population level molecular changes in both UST treatment arms are consistent with endoscopic and HEMI response at week 8. When evaluating sub-groups stratified by endoscopic improvement or HEMI status, significant changes were observed in transcriptional modules in both UST responders and UST non-responders identifying mechanistic processes associated with dual blockade of IL-12 and IL-23 following exposure to UST. Placebo non-responders showed no significant changes. Conclusion Molecular analysis of colon biopsies from UC patients after UST induction revealed IL-12 and IL-23-related transcriptional changes associated with Th1 cytotoxicity and Th17 biology. By leveraging UC single cell derived transcriptional modules, we have identified key disease-relevant processes that significantly changed with UST treatment, regardless of response status and have extended the mechanistic understanding of p40 blockade in UC.

Human cardiac organoids hold remarkable potential for cardiovascular disease modeling and human pluripotent stem cell–derived cardiomyocyte (hPSC-CM) transplantation. Here, we show cardiac organoids engineered with electrically conductive silicon nanowires (e-SiNWs) significantly enhance the therapeutic efficacy of hPSC-CMs to treat infarcted hearts. We first demonstrated the biocompatibility of e-SiNWs and their capacity to improve cardiac microtissue engraftment in healthy rat myocardium. Nanowired human cardiac organoids were then engineered with hPSC-CMs, nonmyocyte supporting cells, and e-SiNWs. Nonmyocyte supporting cells promoted greater ischemia tolerance of cardiac organoids, and e-SiNWs significantly improved electrical pacing capacity. After transplantation into ischemia/reperfusion–injured rat hearts, nanowired cardiac organoids significantly improved contractile development of engrafted hPSC-CMs, induced potent cardiac functional recovery, and reduced maladaptive left ventricular remodeling. Compared to contemporary studies with an identical injury model, greater functional recovery was achieved with a 20-fold lower dose of hPSC-CMs, revealing therapeutic synergy between conductive nanomaterials and human cardiac organoids for efficient heart repair.

Abstract Introduction Motion-based wearable sensors, typically on wrist, have long been used for free-living sleep detection and quantification. However, it is hard to differentiate sleep from sedentary awake time by immobility alone. Vital signs, like heart rate and respiration rate, can greatly enhance determination of wake-sleep state, and are easily monitored with newer wearable sensors. Deep learning techniques are particularly adept at learning labeled physiological states. By combining movement plus vital signs in a deep neural network algorithm, improved sleep detection, fragmentation and sleep staging should be possible compared to activity alone. We report on performance of a deep learning sleep detection and REM/NREM algorithm providing 24-hour evaluation with high specificity using data from a torso-wearable patch sensor as compared to polysomnography (PSG). Methods Twenty-six healthy adults (mean age 53.7 years, 81% female) contributed 150 nights of PSG during laboratory visits, during which participants simultaneously wore a multi-day skin-adherent patch with continuous single-lead ECG and 3-axis accelerometer streams, as well as a wrist activity monitor. A pre-trained deep neural network algorithm generated epoch-level Wake/REM/NREM classification (Sleep equals REM plus NREM) using vital signs and movement derived from the patch sensor ECG and accelerometer waveforms and was then compared to expert human staging of PSGs. The wrist actigraphy sleep-wake determinations (Actiware) were also compared to PSG. Results Data includes 900 hours sleeping and 139 hours awake, of which 195 hours of sleep were in REM state. Using patch data, the deep neural net algorithm achieved 92% sensitivity and 85% specificity to detect sleep as compared to PSG; REM was detected with 85% sensitivity and 97% specificity. By comparison, the wrist motion-based algorithm only exhibited 33% specificity and 95% sensitivity, essentially overcalling immobile wake as sleep. Conclusion Sleep evaluation in free-living environments with wearable sensors can be greatly improved over conventional motion-based wrist sensors by leveraging continuous vital signs. Deep learning-trained neural network algorithms are particularly effective for use with such data, as demonstrated with this algorithm. Support (if any) R01 HL140580 and P01 AG011412