P0197 Comparison of pharmacodynamic and mechanistic response of guselkumab intravenous and subcutaneous induction in moderately to severely active Crohn’s disease: molecular analysis of the GRAVITI and GALAXI Phase 3 studies
Authors: Richards D , Patel R , Sohn K , Hart A , Lee T , Liu J , Sisk C , Olurinde M , Terry N , McRae B , Reinisch W , Feagan B , Steinwurz F , Panaccione R , D’Haens G , Branigan P 
Published: January 2025

Abstract

Background
Guselkumab (GUS) is a selective dual-acting IL-23p19 subunit inhibitor that potently blocks IL-23 and binds to CD64 demonstrated efficacy with intravenous (IV) induction in patients with moderately to severely active Crohn’s disease (CD) in the GALAXI trials.1 Subcutaneous (SC) induction with GUS evaluated in the Ph3 GRAVITI trial was also efficacious in treating patients with CD.2 Here we present a comparison of the pharmacodynamic and mechanistic response of GUS SC and GUS IV induction therapy in CD.

Methods
Serum proteins were evaluated from 290 GRAVITI patients randomised to PBO or GUS 400mg SC q4w, and a subset of 292 GALAXI patients randomised to PBO or GUS 200mg IV q4w at Weeks 0 and 12 using a 92-analyte inflammatory protein panel. Transcriptional profiling from each of the five anatomic segments in GRAVITI was conducted with samples from 277 patients at WK0 and WK12 using RNA sequencing. A tissue inflammation score (bMIS3) was used to assess segmental molecular inflammation which correlated with segmental histology scores defined by Global Histologic Activity Score (GHAS), endoscopic scores and subscores defined by Simple Endoscopic Score for CD (SES-CD).3 Analysis of treatment effect was performed using molecularly inflamed samples (defined as bMIS &gt;0) from segments with SES-CD &gt;0 at baseline. Transcriptional gene modules were evaluated for differential expression.

Results
In serum, protein changes observed with GUS 400mg SC q4w induction at WK12 were highly correlated with those observed with GUS 200mg IV q4w induction at WK12 (R=0.96, p&lt;0.05), including similar reduction of IFNγ, IL-17A, CRP and fecal calprotectin (p&lt;0.05; Figure 1). In tissue, segmental molecular inflammation assessed by bMIS correlated with segmental histological and endoscopic subscores (percent affected tissue and ulceration severity). In each anatomic segment, GUS SC induction reduced key cellular and inflammatory transcriptional modules at WK12 including plasma cell, inflammatory epithelial, neutrophil, and IL-23/Th17 biology consistent with molecular analysis from GUS IV induction in GALAXI Ph2b.4 The decrease in molecular inflammation in 5 anatomic segments corresponded to the segmental endoscopic improvement observed in isolated ileal, ileocolonic and colonic patient subgroups.

Conclusion
Following SC induction, the protein changes observed in serum at WK12 in GRAVITI were highly correlated with those seen with GUS IV induction from GALAXI Ph3. These data demonstrate similar molecular effects of GUS SC and IV induction doses and are aligned with previously reported similar efficacy results, supporting the flexible choice for patients and healthcare professionals between GUS SC and IV to treat patients with CD.

References
1.Panaccione R, Danese S, Feagan BE, et al. Efficacy and safety of guselkumab therapy in patients with moderately to severely active Crohn’s disease: results of the GALAXI 2 & 3 phase 3 studies. Gastroenterology. 2024; 5 (Supplement): p1057b.
2.Panaccione R, Hart A, Steinwurz F et al. Efficacy and Safety of Subcutaneous Guselkumab Induction Therapy in Patients with Moderately to Severely Active Crohn’s Disease: Results Through Week 48 From the Phase 3 GRAVITI Study. ACG 2024.
3.C Argmann, et al. Biopsy and blood-based molecular biomarker of inflammation in IBD. Gut. 2022; 0:1-17.
4.Richards D, Venkat S, Ruane D, et al. Guselkumab Decreases Key Cellular Inflammatory Processes Across Ileum and Colon Tissue in Crohn’s Disease. P0950 ACG 2024.