D0389 - Differential and Combinatorial Mechanism of Action of Golimumab and Guselkumab in Ulcerative Colitis Induction Therapy: IL-23 Blockade Drives Restoration of Normal Epithelium and Mucosal Healing

Tuesday, October 25, 2022

10:00 AM – 12:00 PM ET

Location: Crown Ballroom

Has Audio

Presenting Author(s)

Dylan Richards, PhD

Janssen Research & Development, LLC
Spring House, PA

Prerak Desai, PhD, Patrick Branigan, PhD, Dylan Richards, PhD, Marion Vetter, MD, Daniel J. Cua, PhD, Thomas Freeman, PhD
Janssen Research & Development, LLC, Spring House, PA

Introduction: We studied the underlying mechanism of action of golimumab (GOL), a tumor necrosis factor alpha (TNFα) antagonist, guselkumab (GUS), an interleukin (IL)-23 inhibitor, and the combination (GUS+GOL) in a randomized Ph2 induction study in TNFα-naïve patients (pts) with moderately-severely active ulcerative colitis (UC) (VEGA; NCT03662542).

Methods: Colon biopsies were obtained at screening and at Wk12 in pts 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. A method to create a single-cell-derived co-expression network was developed 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 assess changes in specific biologic modules in the context of responder/non-responder analyses.

Results: By Wk12, 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 cell and inflammatory epithelial cell modules in pts achieving endoscopic improvement (subscore 0 or 1) at Wk12 compared with non-responders. Change from baseline was greater in the GUS monotherapy and GUS+GOL arms compared with GOL alone. Changes were consistent with a decrease in crypt destruction in responders at Wk12 as observed by histologic changes in the Geboes score. Genes modulated by GUS+GOL indicated greater suppression of inflammation, particularly myeloid cell activation and inflammatory fibroblast development. Genes modulated by either GUS or GUS+GOL were associated with increased epithelial normalization and decreased Th17 activity compared to GOL alone.

Discussion: Combination induction with GOL+GUS for 12 weeks drove a greater reduction in inflammation and improvement in epithelial homeostasis compared to each monotherapy, demonstrating 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.

	Golimumab	Guselkumab	Combination
Numbers of genes up at Week 12	633	495	4,776
Numbers of genes down at Week 12	709	613	4,867
Th17 module: Responder vs Non-Responder Week 12 (p-value)	< 0.001	< 0.001	< 0.001
Th17 module: Responder Week 12 vs Baseline (p-value)	< 0.05	< 0.001	< 0.001
Th17 module: Non-Responder Week 12 vs Baseline (p-value)	NS	0.01	< 0.001
Epithelial module: Responder vs Non-Responder Week 12 (p-value)	< 0.01	< 0.001	< 0.001
Epithelial module: Responder Week 12 vs Baseline (p-value)	< 0.05	< 0.001	< 0.001
Epithelial module: Non-Responder Week 12 vs Baseline (p-value)	NS	< 0.01	< 0.001

Table: Differentially Expressed Genes at Week 12 compared with baseline pre-treatment. P-values associated with GSVA enrichment of biologic modules associated with endoscopic response and at Week 12.

Disclosures:

Prerak Desai: Janssen Research & Development, LLC – Employee. Johnson & Johnson – Stock-publicly held company(excluding mutual/index funds).

Patrick Branigan: Janssen Research & Development, LLC – Employee. Johnson & Johnson – Stock-publicly held company(excluding mutual/index funds).

Dylan Richards: Janssen Research & Development, LLC – Employee. Johnson & Johnson – Stock-publicly held company(excluding mutual/index funds).

Marion Vetter: Janssen Research & Development – Employee. Johnson & Johnson – Stock-publicly held company(excluding mutual/index funds).

Daniel Cua: Janssen Research & Development, LLC – Employee. Johnson & Johnson – Stock-publicly held company(excluding mutual/index funds).

Thomas Freeman: Janssen Research & Development, LLC – Employee. Johnson & Johnson – Stock-publicly held company(excluding mutual/index funds).

Prerak Desai, PhD, Patrick Branigan, PhD, Dylan Richards, PhD, Marion Vetter, MD, Daniel J. Cua, PhD, Thomas Freeman, PhD. D0389 - Differential and Combinatorial Mechanism of Action of Golimumab and Guselkumab in Ulcerative Colitis Induction Therapy: IL-23 Blockade Drives Restoration of Normal Epithelium and Mucosal Healing, ACG 2022 Annual Scientific Meeting Abstracts. Charlotte, NC: American College of Gastroenterology.