P0061 Guselkumab induction therapy results in molecular resolution of inflammation in moderately to severely active Ulcerative Colitis: results from the Phase 3 QUASAR induction study
Authors: Sridhar S , Hart A , Venkat S , Huang K H G , Yarandi S , Germinaro M , Vetter M , 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 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]&lt;0.05). This response correlated with changes observed in the GUS 200mg IV arm of the Phase 2b induction study (r=0.97, p&lt;0.0001). GUS treated patients who achieved HEMI at WK12 demonstrated the most robust changes in gene module expression at WK12 (p&lt;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&lt;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&lt;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