AB1381 GUSELKUMAB AND GOLIMUMAB COMBINATION INDUCTION THERAPY IN ULCERATIVE COLITIS RESULTS IN EARLY LOCAL TISSUE HEALING THAT IS SUSTAINED THROUGH GUSELKUMAB MAINTENANCE THERAPY
Authors: D. Richards, M. Vetter, M. Germinaro, B. Verstockt, R. Atreya, J. Panes, B. E. Sands, B. Feagan, B. Mcrae, D. Cua, P. Branigan, T. C. Freeman
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> 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. <h3>Objectives:</h3> 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. <h3>Methods:</h3> 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. <h3>Results:</h3> At WK4, combination induction (n=10) showed significant (p&lt;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&lt;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 (<b>Figure 1</b>). 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. <h3>Conclusion:</h3> 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. <b>REFERENCES: NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> Dylan Richards Stock options in Johnson &amp; Johnson, Employee of Janssen, Marion Vetter Stock options in Johnson &amp; Johnson, Employee of Janssen, Matthew Germinaro Stock options in Johnson &amp; 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 &amp; 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 &amp; 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 &amp; 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 &amp; 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&amp;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 &amp; 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&amp;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 &amp; Johnson, Employee of Janssen, Daniel Cua Stock options in Johnson &amp; Johnson, Employee of Janssen, Patrick Branigan Stock options in Johnson &amp; Johnson, Employee of Janssen, Tom C. Freeman Stock options in Johnson &amp; Johnson, Employee of Janssen