DOP069 Guselkumab maintenance therapy mediates further improvements in intestinal immune homeostasis and mucosal healing in patients with ulcerative colitis
Authors: Hart A , Sridhar S , Venkat S , Huang K H G , Yarandi S , Germinaro M , Vetter M L , Rubin D T , Dignass A , Cua D , Freeman T , Waterworth D , McRae B , Verstockt B , Branigan P 
Published: January 2025

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]&lt;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 &lt;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