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]. Additionally, up to 50% of patients experience a secondary loss of response (LOR) over time [1-3]. Considering the need for long-term management of IBD patients, it is a challenge to control patients with primary nonresponse and LOR to TNF antagonists. In UC, submucosal fibrosis directly links with severity of mucosal inflammation, and improvement of mucosal histology is difficult to achieve with conventional biological therapies [4-6]. High mucosal infiltration of neutrophils is associated with treatment resistance [7,8]. Thus, it is of interest to investigate whether new drugs with distinct MOA, such as anti-matrix remodeling agents, can impact mucosal inflammation and treatment responsiveness in UC patients with TNF antagonist-nonresponse.

Unique target

Our target matrix remodeling gene, carbohydrate sulfotransferase 15 (CHST15), is highly expressed in colonic mucosa of IBD patients with infliximab non-responders based on public database [9 (EMBL-EBI)]. And recently, 77 High Mayo Score-associated genes were identified based on public database [10]. Among the 77 genes, top 9 genes (BGN, CHST15, CYYR1, GPR137B, GPR4, ITGA5, LILRB1, SLFN11, ST3GAL2) were further identified as gene signatures of “UC exacerbation”. The expression levels of mucosal CHST15 mRNA in the Mayo Score High population were higher than those in the Mayo Score Moderate and Low populations [10]. Our Phase IIa data [11] also showed the significant correlation of the Mayo Score with % positive CHST15 area in the colon in patients with UC. These strongly suggest that CHST15 gene is the promising therapeutic target for oligonucleotide drug and reduced colonic CHST15 may correlate with reduced Mayo Score.

Distinct MOA

In UC, CHST15 is maily expressed by inflammtory neutrophils [mucosa] and fibroblasts [submucosa]. GUT-1 and GUT-2, RNA oligonucleoties that silences the CHST15 gene, thus directly act to these cells and repress neutrophil/fibroblast-mediated inflammation/fibrosis. The efficacy of CHST15 blockade is manifested as reduced inflammation in histology and improved stool consistency in symptom. Actually, induction of clinical remission by locally-injected GUT-1 was previously shown in 2 completed clincal studies for moderate-to-severe UC [11,12]:

Oral delivery

GUT-2 is a novel, chemically modified RNA oligonucleotide to CHST15 gene, having the equivalent active antisense sequence of GUT-1. Luminal difusion of GUT-2 into the colon tissue was demonstrated in vivo in mice after oral administration. In murine colitis, oral GUT-2 (QD) repressed colon CHST15, improved stool consistency and histological imflammation. Potentials of orally-formulated GUT-2 including enteric coated capsule to achive similar active mucosal drug concentration as GUT-1 are now shown in mice.

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.