Abstract Background Guselkumab (GUS) is a selective dual-acting IL-23p19 subunit inhibitor that potently neutralises interleukin 23 (IL-23) and binds to CD64, a receptor on cells that produce IL-23.1 GUS is now approved in the United States for treatment of moderately to severely active ulcerative colitis (UC). GUS has demonstrated efficacy in UC based on the results of the QUASAR Phase 2/3 programme.2,3 Mechanistic data from the Phase 2b induction study demonstrated a restoration of intestinal homeostasis and initiation of epithelial repair.4 These findings were confirmed in the larger Phase 3 QUASAR induction study presented here. Methods At induction baseline, 701 patients with moderately to severely active UC were randomized 3:2 to receive GUS 200mg IV induction or placebo (PBO) and clinical efficacy was assessed at Week 12 (WK12). Molecular analysis of the randomised population was performed comparing induction WK12 to baseline (WK0). Transcriptional profiling of colonic biopsies from 593 patients was performed with bulk RNA sequencing and gene modules were evaluated for differential expression. Serum proteomic profiling of 648 patients was conducted using a targeted O-Link Inflammation panel and differential protein abundance was assessed. Results Significantly higher proportions of patients treated with GUS 200mg IV achieved clinical remission, endoscopic improvement, histologic-endoscopic mucosal improvement (HEMI), and endoscopic remission at WK12 compared with PBO. GUS IV induction demonstrated significant downregulation of inflammatory transcriptional modules in colon tissue at WK12, representing Th17, plasma cell, neutrophil and inflammatory fibroblast biology, and an upregulation of healthy epithelium-related gene modules including goblet cells and healthy epithelium (all false discovery rate [FDR]<0.05). This response correlated with changes observed in the GUS 200mg IV arm of the Phase 2b induction study (r=0.97, p<0.0001). GUS treated patients who achieved HEMI at WK12 demonstrated the most robust changes in gene module expression at WK12 (p<0.0001), nearing non-IBD control levels. Inflammatory serum proteins were reduced as early as WK4, and continued to decline through WK12 (IFNγ, IL-17A, OSM, and IL-6, FDR<0.05). Changes in serum proteins were consistent with those observed in the GUS 200mg arm of the Phase 2b induction study (r=0.96, p<0.0001) (Figure 1). Conclusion Mechanistic observations in response to GUS 200mg IV induction were validated in the Phase 3 QUASAR induction study. These data demonstrate GUS IV induction reduced inflammatory biology towards normal while also increasing the healthy epithelium in patients who achieved HEMI at WK12. References 1. Atreya R, Abreu MT, Krueger JG, et al. P165 Guselkumab binding to CD64+ IL-23–producing myeloid cells enhances potency for neutralizing IL-23 signaling. Journal of Crohn's and Colitis. 2024;18(Supplement_1):i470-i470. doi:10.1093/ecco-jcc/jjad212.0295 2. The Efficacy and Safety of Guselkumab as Maintenance Therapy in Patients With Moderately to Severely Active Ulcerative Colitis: Results From the Phase 3 QUASAR Maintenance Study. Gastroenterol Hepatol (N Y). Jul 2024;20(7 Suppl 6):8-9. 3. Peyrin-Biroulet L, Allegretti JR, Rubin DT, et al. Guselkumab in Patients With Moderately to Severely Active Ulcerative Colitis: QUASAR Phase 2b Induction Study. Gastroenterology. Sep 1 2023;doi:10.1053/j.gastro.2023.08.038 4. Sridhar S, Hart A, Venkat S, et al. OP23 Guselkumab induction restores intestinal immune homeostasis and promotes epithelial repair in moderately to severely active Ulcerative Colitis. Journal of Crohn's and Colitis. 2024;18(Supplement_1):i41-i41. doi:10.1093/ecco-jcc/jjad212.0023

Abstract Background Guselkumab (GUS) is a dual-acting IL-23p19 subunit inhibitor that potently neutralises interleukin 23 (IL-23) and binds to CD64, a receptor on cells that produce IL-23.1 The QUASAR Phase 2b/3 studies have demonstrated efficacy and safety in induction and maintenance phases.2,3 The cellular and molecular mechanism of action of GUS induction was also previously reported.4 Here, the molecular changes that occur with maintenance treatment are presented. Methods At maintenance baseline, clinical responders to GUS induction treatment (n=568) were randomized 1:1:1 to GUS SC 200mg q4w, GUS SC 100mg q8w, or placebo (PBO; GUS withdrawal). Molecular analysis of the randomised population was performed comparing maintenance baseline (M0) to Week 44 (M44). Transcriptional profiling of colonic biopsies from 396 patients was performed using RNA sequencing and gene modules were evaluated for differential expression. Serum proteins were evaluated from 430 patients using a targeted inflammation panel and differential protein abundance was assessed. Results Clinically, both GUS SC maintenance dose regimens were highly efficacious and achieved the primary endpoint of clinical remission and all major secondary endpoints at M44 compared with PBO.2 Molecular analysis demonstrated a further significant downregulation of key inflammatory gene modules from M0 to M44 (all false discovery rate [FDR]<0.05) from that previously observed during induction.4 Unique to maintenance, gene modules related to intestinal mesenchymal biology (pericytes, fibroblasts and endothelium) showed even greater changes in maintenance compared to induction. An upregulation of gene modules representing healthy epithelial biology (crypt, goblet cells, M-cells) was also observed at M44 (Figure 1). Importantly, patients who achieved clinical remission at M44 demonstrated the most significant changes and gene module expression levels at M44 approximated those observed in non-IBD healthy controls, consistent with the profile of healthy colonic tissue. Serum analysis showed continued reductions in inflammatory proteins (e.g. IL-17A, IL-8, FDR <0.05) and several chemokines from M0 to M44, including CCL11 that has been linked to mesenchymal biology. By M44, GUS withdrawal demonstrated a reversal in the anti-inflammatory effects achieved at the end of induction. Conclusion GUS maintenance therapy for UC mediated further improvements in the anti-inflammatory and pro-healing effects achieved during induction. Moreover, this work provides evidence supporting a role for mesenchymal biology in tissue remodeling during maintenance. Together, these data provide molecular evidence supporting the robust clinical benefit of GUS maintenance therapy. References 1.Atreya R, Abreu MT, Krueger JG, et al. P165 Guselkumab binding to CD64+ IL-23–producing myeloid cells enhances potency for neutralizing IL-23 signaling. Journal of Crohn's and Colitis. 2024;18(Supplement_1):i470-i470. doi:10.1093/ecco-jcc/jjad212.0295 2.The Efficacy and Safety of Guselkumab as Maintenance Therapy in Patients With Moderately to Severely Active Ulcerative Colitis: Results From the Phase 3 QUASAR Maintenance Study. Gastroenterol Hepatol (N Y). Jul 2024;20(7 Suppl 6):8-9. 3.Peyrin-Biroulet L, Allegretti JR, Rubin DT, et al. Guselkumab in Patients With Moderately to Severely Active Ulcerative Colitis: QUASAR Phase 2b Induction Study. Gastroenterology. Sep 1 2023;doi:10.1053/j.gastro.2023.08.038 4.Sridhar S, Hart A, Venkat S, et al. OP23 Guselkumab induction restores intestinal immune homeostasis and promotes epithelial repair in moderately to severely active Ulcerative Colitis. Journal of Crohn's and Colitis. 2024;18(Supplement_1):i41-i41. doi:10.1093/ecco-jcc/jjad212.0023

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

Objectives To evaluate the association between enthesitis resolution (ER) and dactylitis resolution (DR) and meaningful improvements in patient-reported outcomes (PROs) among biologic-naïve patients with PsA receiving guselkumab in the DISCOVER-2 study. Methods Enthesitis and dactylitis, characteristic lesions of PsA, were evaluated by independent assessors using the Leeds Enthesitis Index (range, 0–6) and Dactylitis Severity Score (range, 0–60). Proportions of patients with ER or DR (score = 0) among those with score > 0 at baseline were determined at weeks 24, 52, and 100. PROs included: fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-Fatigue]), pain (0–100 visual analog scale), physical function (Health Assessment Questionnaire-Disability Index [HAQ-DI]), and health-related quality of life (36-item Short-Form Health Survey physical/mental component summary [SF-36 PCS/MCS]). Meaningful responses were defined as: improvements of ≥ 4 for FACIT-Fatigue, ≥ 0.35 for HAQ-DI, and ≥ 5 for SF-36 PCS/MCS and absolute scores of ≤ 15 for minimal pain and ≤ 0.5 for normalized HAQ-DI. Associations between ER/DR status and PRO response status were tested using a Chi-square test. Results Guselkumab-treated patients with ER were more likely than those without ER to achieve minimal pain ( p < 0.001), normalized HAQ-DI ( p < 0.001), and PCS response ( p < 0.05) at weeks 24, 52, and 100. Patients with DR were more likely than those without DR to achieve FACIT-Fatigue response at week 24 and week 52 (both p ≤ 0.01) and minimal pain at week 24 and normalized HAQ-DI at week 52 (both p ≤ 0.03). Conclusion In biologic-naïve patients with active PsA treated with guselkumab, achieving ER or DR was associated with durable improvements in selected PROs, including those of high importance to patients. Trial registration ClinicalTrials.gov ( https://clinicaltrials.gov ) NCT03158285; Registered: May 16, 2017. Key Points • At week 100, 65% and 76% of guselkumab-treated patients achieved enthesitis and dactylitis resolution (ER/DR). • Achieving ER was associated with achieving DR and vice versa through the end of study. • Achieving ER or DR was associated with durable and meaningful improvements in selected patient-reported outcomes.

Background: Selective inhibition of interleukin-23 (IL-23) through antagonism of the IL-23p19 subunit has demonstrated clinical efficacy in inflammatory bowel disease, but the mechanism of action (MoA) has not been fully defined. Objectives: To provide a detailed evaluation of the cellular and molecular MoA of guselkumab (GUS), an IL-23p19 subunit antagonist, in patients with moderately to severely active ulcerative colitis (UC) from the QUASAR Phase 2b induction study (NCT04033445). Methods: Serum proteins were evaluated from 302 patients treated with intravenous GUS induction therapy or placebo (PBO) who had at least one paired sample at Weeks (WK) 0 and 4 or WK12. Matched colonic biopsies at WK0 and 12 were available for 255 patients. Transcriptional profiling was performed with bulk RNA sequencing (RNAseq). Transcriptional modules derived from public UC single cell RNAseq (scRNAseq) were evaluated with differential expression in the bulk RNAseq dataset. Flow cytometry and scRNAseq were performed on a subset of matched WK0 and WK12 cryopreserved biopsies from 60 patients. Results: Both GUS induction doses were effective vs PBO in achieving key endpoints including clinical remission, endoscopic and histologic outcomes. GUS reduced serum IL-22, IFNγ and IL-17A (P<1e-05) as early as WK4, which further declined through WK12. Unsupervised analysis of tissue transcriptomic modules (n=69) revealed 57 that were significantly changed with GUS at WK12. The top 6 downregulated modules represented Th17 cell (IL-23 pathway), neutrophil, IFNγ signaling, plasma cell and inflammatory epithelial and fibroblast cell states, while modules associated with epithelial cell populations and metabolism were upregulated (all false discovery rate [FDR]<0.05). Fc-γ receptor (CD64) expression was increased at baseline in all patients and reduced at WK12. Flow cytometry demonstrated reductions of CD45+ lymphocyte and CD66+ granulocyte populations (P<0.01). Parallel scRNAseq showed a reduction of inflammatory monocytes and fibroblasts in GUS responders at WK12 while pro-healing indicators were observed at WK12 including an increase in EpCam+ cells, BEST4+ enterocytes, and ADAMDEC1+ fibroblasts (P<0.01). Module analysis indicated an increase in goblet cells (FDR<0.05) which play a role in barrier integrity. Conclusion: GUS induction restored intestinal immune homeostasis in patients with UC who achieved key endpoints at WK12, demonstrated by resolution of inflammation associated with the IL-23 pathway and inflammatory myeloid, epithelial and fibroblast transcriptional states. GUS also promoted epithelial repair as evidenced by increases in epithelial cell population, consistent with endoscopic and histologic outcomes at WK12. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: Sunandini Sridhar Johnson & Johnson, Janssen, Amy Hart Johnson & Johnson, Janssen, Swati Venkat Johnson & Johnson, Janssen, Darren Ruane Johnson & Johnson, Janssen, Dan Horowitz Johnson & Johnson, Janssen, Tae Lee Johnson & Johnson, Janssen, Dawn Waterworth Johnson & Johnson, Janssen, Kuan-Hsiang G. Huang Johnson & Johnson, Janssen, Matthew Germinaro Johnson & Johnson, Janssen, Marion Vetter Johnson & Johnson, Janssen, Daniel Cua Johnson & Johnson, Janssen, Tom C. Freeman Johnson & Johnson, Janssen, Christopher Sisk Johnson & Johnson, Janssen, Bradford McRae Johnson & Johnson, Janssen, Bram Verstockt Abbvie, Biogen, Bristol Myers Squibb, Celltrion, Chiesi, Falk, Ferring, Galapagos, Janssen, Lily, MSD, Pfizer, R-Biopharm, Sandoz, Takeda, Tillots Pharma, Truvion, and Viatris, 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, AbbVie, Biora Therapeutics, Landos, Pfizer, Sossei Heptares and Takeda, David T. Rubin AbbVie, Altrubio, Allergan, Arena, Aslan, Athos, Bellatrix, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corp/Syneos, Connect, GalenPharma/Atlantica, Genentech/Roche, InDex, Ironwood, Iterative Scopes, Janssen, Eli Lilly, Pfizer, Prometheus, Reistone, Takeda, and Techlab; co-founder of Cornerstones Health, Takeda, Bruce E. Sands 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;, Ventyx Biosciences, 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;, Patrick Branigan Johnson & Johnson, Janssen.

Interleukin (IL)-23, an IL-12 cytokine family member, is a hierarchically dominant regulatory cytokine in a cluster of immune-mediated inflammatory diseases (IMIDs), including psoriasis, psoriatic arthritis, and inflammatory bowel disease. We review IL-23 biology, IL-23 signaling in IMIDs, and the effect of IL-23 inhibition in treating these diseases. We propose studies to advance IL-23 biology and unravel differences in response to anti–IL-23 therapy. Experimental evidence generated from these investigations could establish a novel molecular ontology centered around IL-23–driven diseases, improve upon current approaches to treating IMIDs with IL-23 inhibition, and ultimately facilitate optimal identification of patients and, thereby, outcomes.

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Background The combination treatment of golimumab (GOL), a tumor necrosis factor-alpha (TNFα) antagonist, and guselkumab (GUS), an interleukin (IL)-23 inhibitor was shown to induce higher rates of clinical remission, endoscopic improvement, and histologic remission than each monotherapy in a randomized phase 2 induction study in TNFα-naïve patients with moderate-to-severely active ulcerative colitis (UC) (VEGA; NCT03662542). Objectives To investigate the underlying mechanism of action of GOL, GUS, and the combination (GUS+GOL). Methods Colon biopsies were obtained at screening and at Week 12 in patients who received GOL (n=48), GUS (n=52), or GUS+GOL (n=50). Tissue transcriptional profiles were determined with RNA-seq. Differentially expressed genes were analyzed in the context of cell-type specific transcriptional modules by first defining a gene correlation network and unsupervised network clustering. We then developed a method to create a single-cell-derived co-expression network using published UC single-cell data to provide high-resolution gene modules associated with specific cell types and pathways. Gene set variation analysis (GSVA) was used to quantitatively assess changes in specific biologic modules in the context of responder and non-responder analyses. Results By Week 12, combination therapy induced a greater magnitude of transcriptional changes in the colon compared with each monotherapy (Table 1). These genes were associated with IL-23/Th17/myeloid-related processes, inflammation, and epithelial homeostasis. Significant changes were observed in Th17 cells and inflammatory epithelial cell modules in patients that achieved endoscopic improvement (subscore 0 or 1) at Week 12 compared with non-responders (Table 1). The magnitude of change relative to baseline was greater in the GUS monotherapy and GUS+GOL arms compared with GOL alone. These changes were consistent with a decrease in crypt destruction in responders at Week 12, as observed by histologic changes in the Geboes score. Genes modulated by GUS+GOL were indicative of greater suppression of inflammation, particularly myeloid cell activation and inflammatory fibroblast development. In contrast, genes modulated by either GUS or GUS+GOL were associated with increased epithelial normalization and decreased Th17 activity compared to GOL alone. Conclusion Combination induction with GOL+GUS for 12 weeks drove a greater reduction in inflammation and improvement in epithelial homeostasis compared to each monotherapy, demonstrating the differential and complementary mechanisms of action of TNFα and IL-23 blockade. Combination therapy drives a significant increase in the overall magnitude of response with marked improvement in the restoration of normal epithelium. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests Prerak Desai Employee of: Janssen Research & Development, LLC and may own stock or stock options in Johnson & Johnson., Patrick Branigan Employee of: Janssen Research & Development, LLC and may own stock or stock options in Johnson & Johnson., Dylan Richards Employee of: Janssen Research & Development, LLC and may own stock or stock options in Johnson & Johnson., Dennis McGonagle Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, and UCB, Marion Vetter Employee of: Janssen Research & Development, LLC and may own stock or stock options in Johnson & Johnson., Daniel Cua Employee of: Janssen Research & Development, LLC and may own stock or stock options in Johnson & Johnson., Thomas Freeman Employee of: Janssen Research & Development, LLC and may own stock or stock options in Johnson & Johnson.Table 1Differentially expressed genes at Week 12 compared with baseline pre-treatmentGolimumabGuselkumabCombinationNumber of genes up at Week 126334954,776Number of genes down at Week 127096134,867Th17 module: Responder vs Non-Responder Week 12 (p-value)<0.001<0.001<0.001Th17 module: Responder Week 12 vs Baseline (p-value)<0.05<0.001<0.001Th17 module: Non-Responder Week 12 vs Baseline (p-value)NS0.01<0.001Epithelial module: Responder vs Non-Responder Week 12 (p-value)<0.01<0.001<0.001Epithelial module: Responder Week 12 vs Baseline (p-value)<0.05<0.001<0.001Epithelial module: Non-Responder Week 12 vs Baseline (p-value)NS<0.01<0.001P-values associated with GSVA enrichment of biologic modules associated with endoscopic response and at Week 12.

Background Pain in patients (pts) with psoriatic arthritis (PsA) has multifaceted origins; sustained improvement is difficult to achieve. 1 Guselkumab (GUS), a fully human monoclonal antibody that selectively inhibits IL-23, is effective in treating multiple domains of PsA including joint, skin, and entheseal symptoms, and also elicits long-lasting improvements in pt-reported pain in the DISCOVER-1&2 trials of pts with active PsA. 2 Objectives These post hoc analyses were conducted to identify determinants of changes in pt-reported pain in PsA pts using pooled data through 1 year of DISCOVER-1&2. Methods Enrolled adult pts had active PsA despite standard therapies. DISCOVER-1 pts had ≥3 swollen and ≥3 tender joints and C-reactive protein (CRP) ≥0.3 mg/dL; DISCOVER-2 pts had ≥5 swollen and ≥5 tender joints and CRP ≥0.6 mg/dL. 31% of DISCOVER-1 pts received 1-2 prior tumor necrosis factor inhibitors; DISCOVER-2 pts were biologic-naïve. Pts were randomized 1:1:1 to GUS 100 mg every 4 weeks (wks) (Q4W); GUS 100 mg at W0, W4, then every 8 wks (Q8W); or placebo (PBO); PBO pts crossed over to GUS 100 mg Q4W at W24. Determinants with a statistically important effect (p<0.15) on pain (0-100 mm Visual Analogue Scale) in univariate Repeated Measures Generalized Linear Mixed Effects Models were included in a multivariate model employing backward stepwise selection (P out =0.1) to identify independent determinants of pain improvement over 24 wks; the model was then tested separately in pts treated with PBO (through W24) and with GUS (through W24 and through W52). Results GUS was associated with significantly greater improvement in pain compared to PBO as early as 2 wks post-treatment; there was a significant interaction between treatment group and time, with effect of GUS on pain continuously enhanced through W24. Higher baseline (BL) pain score, worse mental health (assessed with the Short-Form-36 Mental Component Summary [SF-36 MCS] score), and lower fatigue level and lower tender joint count [TJC] were also associated with significantly greater pain improvements at W24, while background use of NSAIDs was a negative predictor of pain improvement (Table 1). Treatment effect on pain was independent of PsA duration, gender, PsA subtype, prior TNFi exposure, BL skin disease, and BL swollen joint count (SJC). Continuous significant improvement from BL in pain with GUS extended through W52 even after adjustment for the identified determinants of pain improvement through W24 (Figure 1). At W52, predictors of change in pain remained significant with the exception of SF-36 MCS score (Table 1). Results did not exclude a small number of enrolled pts with fibromyalgia (FM: n GUS =8; n PBO =4). According to these exploratory findings, medical history of FM was associated with lower pain improvement through W24 (p=0.066); in the models run separately in pts with GUS and PBO, pts with FM treated with GUS had a mean (95% CI) pain improvement (-9.1 [-19.5, 1.2]) while pts treated with PBO had a mean worsening (0.7 [-12.5, 13.9]). Pain improvement through 52 wks was significant regardless of FM: pts with FM had a mean (95% CI) improvement of -14.7 Table 1. Significant Predictors of Change in Pain (W24 and W52 ) BL Determinant W24 W52 Estimate (95% CL) Estimate (95% CL) Pain score -0.62 (-0.69:-0.55) ‡ -0.75 (-0.83:-0.67) ‡ Fatigue -0.38 (-0.50:-0.27) ‡ -0.37 (-0.53:-0.22) ‡ SF-36 MCS 0.20 (0.11:0.30) ‡ 0.11 (-0.02:0.24) TJC 0.13 (0.06:0.19) † 0.12 (0.04:0.21) † NSAID use (Y vs N) 2.29 (0.62:3.96) † 2.76 (0.55:4.98) * * p <0.05; † p <0.01; ‡ p ≤0.0001 (-25.9, -3.6) comparable to non-FM pts at W24, while pain improvement in pts with no FM was -22.2 (-24.0, -20.4). Conclusion Early significant effects of GUS on pain were enhanced through 1 year. Significant predictors of change in pain were consistent at W24 and W52, with the exception of mental health measures. The impact of mental status on pt-reported pain and the potential for GUS to improve pain in pts with FM warrant further consideration. References [1]Gudu T et al. Expert Rev Clin Immunol 2018;14(5):405-17. [2]Nash P et al. ACR Convergence 2021;Nov 5-9 (Poster 21-1368). Disclosure of Interests Peter Nash Grant/research support from: Janssen, Abbvie, Pfizer, Novartis, Lilly, Gilead, Roche, Sandoz, Celgene, Sun, Boehringer, and Bristol Myers Squibb, Christopher T. Ritchlin Consultant of: UCB Pharma, Amgen, AbbVie, Lilly, Pfizer, Novartis, Gilead, Janssen, Grant/research support from: UCB Pharma, AbbVie, Amgen, Proton Rahman Consultant of: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, and UCB, Grant/research support from: Janssen and Novartis, May Shawi Shareholder of: Johnson & Johnson, Employee of: Janssen Pharmaceutical Companies of Johnson & Johnson, Emmanouil Rampakakis Consultant of: Janssen, Employee of: JSS Medical Research, YoungJa Lee Shareholder of: Johnson & Johnson, Employee of: Janssen Asia Pacific, Alexa Kollmeier Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Xie L Xu Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Jonathan Sherlock Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Daniel Cua Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Saakshi Khattri Speakers bureau: AbbVie, Eli Lilly, Glenmark, Ichnos Sciences, Janssen, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Eli Lilly, Glenmark, Ichnos Sciences, Janssen, Novartis, Pfizer, and UCB, Enrique Soriano Speakers bureau: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer, Roche, and UCB, Consultant of: AbbVie, Janssen, Novartis, and Roche, Grant/research support from: AbbVie, Janssen, Novartis, Pfizer, Roche, and UCB, Dennis McGonagle Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, and UCB