P1082 - Impact of Subcutaneous Guselkumab Induction Therapy on Molecular Inflammation in Patients With Ulcerative Colitis: Results From the Phase 3 ASTRO Study

Swati Venkat, PhD¹, Sunandini Sridhar, PhD¹, Barbara Shaikh, BS¹, Klebea Sohn, PhD², Jared Liu, PhD³, Christopher Sisk, MS³, Bradford McRae, PhD², Yelinia Alvarez, MD, PhD³, Thomas Baker, MD⁴, Matthew Germinaro, MD⁴, Jessica R.. Allegretti, MD, MPH⁵, Millie D. Long, MD, FACG⁶, David T. Rubin, MD⁷, Laurent Peyrin-Biroulet, MD, PhD⁸, Amy Hart, PhD⁹, Patrick Branigan, BS⁴
1Janssen Research & Development, LLC, Spring House, PA; 2Janssen Research & Development, LLC, Spring House, PA, USA, Spring House, PA; 31Janssen Research & Development, LLC, Spring House, PA; 4Johnson & Johnson, Spring House, PA; 5Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; 6Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, Chapel Hill, NC; 7University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA, Chicago, IL; 8Department of Gastroenterology, CHRU Nancy, INSERM NGERE, Université de Lorraine, France, Vandœuvre-lès-Nancy, Lorraine, France; 9Janssen Research & Development, LLC,, Spring House, PA

Introduction: Guselkumab (GUS) is a dual-acting IL-23p19 subunit inhibitor that neutralizes interleukin 23 (IL-23) and binds to CD64, a receptor on cells that produce IL-23. GUS was effective and safe as intravenous (IV) induction and subcutaneous (SC) maintenance therapy in patients with moderately to severely active ulcerative colitis (UC) (QUASAR). Week 12 (WK12) results from the ASTRO phase 3 study demonstrated the efficacy of SC induction therapy with guselkumab in UC. Molecular changes occurring from induction baseline WK0 to WK12 evaluated in patients from the ASTRO study are presented here

Methods: Transcriptional profiling of biopsies from 339 patients from ASTRO was performed with RNA sequencing. Molecular analysis was performed comparing induction WK12 to baseline. A comparative analysis was performed with biopsy samples previously analyzed from 593 patients from the QUASAR Phase 3 induction study. Molecular changes were assessed in the context of clinical remission and combined histologic and endoscopic mucosal improvement (HEMI) at WK12. Serum IL-22 proteomic profiling of 355 patients was conducted using a high-sensitivity IL-22 assay and change in protein abundance was assessed.

Results: GUS SC induction demonstrated significant downregulation of inflammatory modules including Th17, IFNγ, inflamed epithelium, plasma cell, neutrophil and inflammatory fibroblast, and upregulation of goblet cell and healthy epithelium gene modules at WK12 (FDR]< 0.05). Significant correlation was observed with GUS 200mg IV induction in QUASAR (r=0.98, p< 0.0001). Patients who achieved clinical remission and HEMI at WK12 demonstrated the most changes in gene module expression from baseline (p< 0.0001), nearing non-IBD controls. Subgroup analyses defined by prior treatment history demonstrated similar magnitude of changes in both treatment-naïve and -resistant groups (R=0.93, p< 0.0001). Serum IL-22 was significantly decreased at WK12 (p < 0.05) with GUS SC induction, similar to IV induction. Patients who achieved clinical remission at WK12 demonstrated a robust decrease in Geboes total scores (p< 0.05) compared to non-remitters.

Discussion: Mechanistic observations confirm that GUS SC and IV induction show significant correlation, supporting the efficacy of both routes of administration in UC. These data demonstrate that GUS SC induction reduced inflammatory biology towards a normal state while upregulating genes associated with healthy epithelium in patients who achieved clinical remission or HEMI at WK12.

Disclosures:
Swati Venkat: Johnson and Johnson – Employee, Stock Options, Stock-publicly held company(excluding mutual/index funds).
Sunandini Sridhar: Johnson and Johnson – Employee, Stock Options, Stock-publicly held company(excluding mutual/index funds).
Barbara Shaikh: Johnson and Johnson – Employee, Stock Options, Stock-publicly held company(excluding mutual/index funds).
Klebea Sohn: Johnson and Johnson – Employee, Stock Options, Stock-publicly held company(excluding mutual/index funds).
Jared Liu: Johnson and Johnson – Employee, Stock Options, Stock-publicly held company(excluding mutual/index funds).
Christopher Sisk: Johnson and Johnson – Employee, Stock Options, Stock-publicly held company(excluding mutual/index funds).
Bradford McRae: Johnson and Johnson – Employee, Stock Options, Stock-publicly held company(excluding mutual/index funds).
Yelinia Alvarez: Johnson and Johnson – Employee, Stock Options, Stock-publicly held company(excluding mutual/index funds).
Thomas Baker: Johnson & Johnson – Employee, Stock Options, Stock-publicly held company(excluding mutual/index funds).
Matthew Germinaro: Johnson & Johnson – Employee, Stock Options, Stock-publicly held company(excluding mutual/index funds).
Jessica Allegretti: Abbvie – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Speaker, Speakers Bureau. Adiso – Consultant. Bristol Myer Squibb – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Speaker. Celltrion – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant. Ferring – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant. Finch – Consultant. Genentech – Advisory Committee/Board Member, Consultant. GlaxoSmithKline – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant. Iterative Scopes – Consultant. Janssen – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Speakers Bureau. Johnson & Johnson – Consultant, Grant/Research Support, Speaker. Merck – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Grant/Research Support. Pfizer – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Grant/Research Support. Roivant – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant. Roivant Adiso – Consultant. Seres Therapeutics – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant. Shattuck Labs – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant. TRXBio – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant. Vedanta – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant.
Millie Long: AbbVie – Consultant. Bristol Myers Squibb – Consultant. Celltrion – Consultant, Grant/Research Support. Intercept – Consultant. Johnson & Johnson – Consultant. Lilly – Consultant, Grant/Research Support. Merck – Consultant. Pfizer – Consultant, Grant/Research Support. Prometheus – Consultant. Roivant – Consultant. Sanofi – Consultant. Spyre – Consultant. Takeda – Consultant, Grant/Research Support. Target RWE – Consultant.
David Rubin: AbbVie – Advisory Committee/Board Member, Consultant, Speaker fees. Abivax SA – Consultant. Altrubio – Advisory Committee/Board Member, Consultant, Speaker feees, Stock Options. Avalo – Advisory Committee/Board Member, Consultant, Speaker fees. Bausch Health – Consultant. Bristol Myers Squibb – Advisory Committee/Board Member, Consultant, Speaker fees. Buhlmann Diagnostics – Advisory Committee/Board Member, Consultant, Speaker fees. Celltrion – Consultant. ClostraBio – Consultant. Connect BioPharma – Consultant. Cornerstones Health, Inc – Board of Directors membership. Douglas Pharmaceuticals – Consultant. Eli Lilly & Co. – Consultant. Foresee, Genentech (Roche) Inc. – Consultant. Image Analysis Group – Consultant. InDex Pharmaceutical – Consultant. Intouch Group – Advisory Committee/Board Member, Consultant, Speaker fees. Iterative Health – Advisory Committee/Board Member, Consultant, Speaker fees. Iterative Health – Stock Options. Janssen Pharmaceuticals – Consultant. Lilly – Advisory Committee/Board Member, Consultant, Speaker fees. Odyssey Therapeutics – Consultant. Pfizer – Advisory Committee/Board Member, Consultant, Speaker fees. Sanofi – Consultant. Takeda – Advisory Committee/Board Member, Consultant, Grant/Research Support, Speaker fees. Throne – Consultant. Vedanta – Consultant.
Laurent Peyrin-Biroulet: AbbVie – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria, meeting attendance/travel support, Speakers Bureau. Abivax – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Adacyte – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant. Alfasigma – Speakers Bureau. Alimentiv – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Amgen – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria, meeting attendance/travel support, Speakers Bureau. Applied Molecular Transport – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Arena – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria, Speakers Bureau. Banook – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Biogen – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria, Speakers Bureau. Bristol Myers Squibb – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Celltrion – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Grant/Research Support, Honoraria, meeting attendance/travel support, Speakers Bureau. Connect Biopharm – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria, meeting attendance/travel support. Cytoki Pharma – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Eli Lilly – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria, meeting attendance/travel support, Speakers Bureau. Enthera – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. F. Hoffmann-La Roche Ltd – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Ferring – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria, meeting attendance/travel support, Speakers Bureau. Fresenius Kabi – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Grant/Research Support, Honoraria. Galapagos – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria, meeting attendance/travel support, Speakers Bureau. Genentech – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria, meeting attendance/travel support, Speakers Bureau. Gilead – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria, meeting attendance/travel support, Speakers Bureau. Gossamer Bio – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria, meeting attendance/travel support. GSK – Advisory Committee/Board Member, Consultant. IAC Image Analysis – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Index Pharmaceuticals – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Inotrem – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Janssen – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Speakers Bureau. Johnson & Johnson – Advisory Committee/Board Member, Consultant, Honoraria, meeting attendance/travel support. Medac – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Grant/Research Support, Honoraria, meeting attendance/travel support, Speakers Bureau. Mopac – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Morphic – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria, meeting attendance/travel support. MSD – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Grant/Research Support, Honoraria, meeting attendance/travel support, Speakers Bureau. Nordic Pharma – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria, Speakers Bureau. Novartis – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Oncodesign Precision Medicine – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. ONO Pharma – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. OSE Immunotherapeutics – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Pandion Therapeutics – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Par' Immune – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Pfizer – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria, meeting attendance/travel support, Speakers Bureau. Prometheus – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Protagonist – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Samsung – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Sandoz – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria, meeting attendance/travel support, Speakers Bureau. Sanofi – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Satisfay – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Takeda – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Grant/Research Support, Honoraria, meeting attendance/travel support, Speakers Bureau. Telavant – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Theravance – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Thermo Fischer – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria, meeting attendance/travel support. Tigenix – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Tillots – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria, meeting attendance/travel support, Speakers Bureau. Vectivbio – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Ventyx – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria. Viatris – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria, Speakers Bureau. Ysopia – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Honoraria.
Amy Hart: Johnson and Johnson – Employee, Stock Options, Stock-publicly held company(excluding mutual/index funds).
Patrick Branigan: Johnson & Johnson – Employee, Stock-publicly held company(excluding mutual/index funds).

Swati Venkat, PhD¹, Sunandini Sridhar, PhD¹, Barbara Shaikh, BS¹, Klebea Sohn, PhD², Jared Liu, PhD³, Christopher Sisk, MS³, Bradford McRae, PhD², Yelinia Alvarez, MD, PhD³, Thomas Baker, MD⁴, Matthew Germinaro, MD⁴, Jessica R.. Allegretti, MD, MPH⁵, Millie D. Long, MD, FACG⁶, David T. Rubin, MD⁷, Laurent Peyrin-Biroulet, MD, PhD⁸, Amy Hart, PhD⁹, Patrick Branigan, BS⁴. P1082 - Impact of Subcutaneous Guselkumab Induction Therapy on Molecular Inflammation in Patients With Ulcerative Colitis: Results From the Phase 3 ASTRO Study, ACG 2025 Annual Scientific Meeting Abstracts. Phoenix, AZ: American College of Gastroenterology.