Gut Inc.

Research and Development

New challenges in the era of multiple biologics

Approximately 10-40% of patients with IBD exhibit a primary non-response to TNF antagonists [1-3], while up to 50% experience a secondary loss of response (LOR) over time [1-3]. Overcoming this treatment resistance remains a critical challenge in the long-term management of IBD. In UC, submucosal fibrosis is directly linked to the severity of mucosal inflammation, and conventional biological therapies struggle to achieve profound mucosal histology improvement [4-6]. Furthermore, high mucosal infiltration of neutrophils is strongly associated with this treatment resistance [7,8]. Therefore, introducing a novel “pathology changer” with a distinct MOA-such as an anti-matrix remodeling agent-holds immense potential to reverse fibrosis, resolve underlying mucosal inflammation, and restore treatment responsiveness in patients refractory to biologics.

Unique target

Our target matrix remodeling gene, carbohydrate sulfotransferase 15 (CHST15), is highly expressed in the colonic mucosa of IBD patients who are infliximab non-responders, as validated by public databases [9 (EMBL-EBI)]. Furthermore, an analysis of 77 genes associated with high Mayo Scores identified the top 9 genes-including CHST15-as core signatures of “UC exacerbation” [10]. The mucosal expression levels of CHST15 mRNA in the High Mayo Score population were significantly elevated compared to the Moderate and Low groups [10]. Crucially, our Phase IIa clinical data [11] demonstrated a strong correlation between the Mayo Score and the percentage of CHST15-positive areas in the colons of UC patients. These findings establish CHST15 as a highly promising therapeutic target for oligonucleotide intervention, where suppressing colonic CHST15 directly correlates with clinical improvement.

Distinct MOA

In UC, CHST15 is mainly expressed by inflammatory neutrophils in the mucosa and fibroblasts in the submucosa. GUT-1 and GUT-2, RNA oligonucleotides designed to silence the CHST15 gene, directly target these cell populations to suppress neutrophil-driven inflammation and fibroblast-mediated fibrosis. The clinical efficacy of this CHST15 blockade translates into robust histological healing and symptomatic relief, including improved stool consistency. In fact, the induction of clinical remission by locally administered GUT-1 has already been demonstrated in two completed clinical studies for moderate-to-severe UC [11, 12].

Oral delivery

GUT-2, our nominated Development Candidate, is a novel, chemically modified RNA oligonucleotide targeting the CHST15 gene. It utilizes the identical active antisense sequence as GUT-1, thereby building upon the clinically validated mechanism of action described above. By highly optimizing the core formulation within an enteric-coated capsule, we have successfully established an oral delivery system that achieves active mucosal drug concentrations equivalent to local administration. In murine colitis models, this definitive oral formulation demonstrated targeted distribution to Vimentin⁺ fibroblasts in the inflamed mucosa. Consequently, oral GUT-2 strongly repressed colonic CHST15 expression, resolved underlying histological inflammation, and improved stool consistency, establishing its readiness to advance into IND-enabling studies.

References:

  1. Roda G, Jharap B, Neeraj N, et al. Loss of Response to Anti-TNFs: Definition, Epidemiology, and Management. Clin Transl Gastroenterol. 2016; 7: e135.
  2. Atreya R, Neurath MF, Siegmund B. Personalizing Treatment in IBD: Hype or Reality in 2020? Can We Predict Response to Anti-TNF? Front Med (Lausanne). 2020; 7: 517.
  3. Marsal J, Barreiro-de Acosta M, Blumenstein I, et al. Management of Non-response and Loss of Response to Anti-tumor Necrosis Factor Therapy in Inflammatory Bowel Disease. Front Med (Lausanne). 2022; 9: 897936.
  4. Arijs I, De Hertogh G, Lemmens B, et al. Effect of vedolizumab (anti-α4β7-integrin) therapy on histological healing and mucosal gene expression in patients with UC. Gut. 2018; 67: 43-52.
  5. Gundersen MD, Goll R, Fenton CG, et al. Fibrosis Mediators in the Colonic Mucosa of Acute and Healed Ulcerative Colitis. Clin Transl Gastroenterol. 2019 Oct;10(10): e00082.
  6. Gordon IO, Agrawal N, Willis E, et al. Fibrosis in ulcerative colitis is directly linked to severity and chronicity of mucosal inflammation. Aliment Pharmacol Ther. 2018 Apr;47(7):922-939.
  7. Markus F Neurath. Targeting immune cell circuits and trafficking in inflammatory bowel disease. Nat Immunol. 2019 Aug;20(8):970-979.
  8. Friedrich M, Pohin M, Jackson MA, et al. IL-1-driven stromal-neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies. Nat Med. 2021 Nov;27(11):1970-1981.
  9. EMBL-EBI, Expression Atlas (https://www.ebi.ac.uk/gxa/home).
  10. Wang Y, Zhuang H, Jiang XH, et al. Unveiling the key genes, environmental toxins, and drug exposures in modulating the severity of ulcerative colitis: a comprehensive analysis. Front Immunol. 2023 Jul 19;14:1162458.
  11. Atreya R, Kühbacher T, Waldner MJ, et al. Submucosal Injection of the RNA Oligonucleotide GUT-1 in Active Ulcerative Colitis Patients: A Randomized, Double-Blind, Placebo-Controlled Phase 2a Induction Trial. J Crohns Colitis. 2024 Mar 1;18(3):406-415.
  12. Suzuki K, Sameshima Y, Yokoyama J, et al. Add-on multiple submucosal injections of the RNA oligonucleotide GUT-1 to anti-TNF antibody treatment in patients with moderate-to-severe ulcerative colitis: an open-label, proof-of concept study. Inflamm Regen. 2024 Apr 25;44(1):22.