Y-ECCO Literature Review: Lushen Pillay

Lushen Pillay

Submucosal injection of the RNA nucleotide GUT-1 in active ulcerative colitis patients: A randomized, double-blind, placebo-controlled phase 2a induction trial.

Atreya R, Kuhbacher T, Waldner M, et al.

J Crohns Colitis 2023. doi: 10.1093/ecco-jcc/jjad162. Online ahead of print.

Lushen Pillay
© Lushen Pillay


Despite an increasing number of therapeutic options for Ulcerative Colitis (UC), many patients still have disease which progresses over time, and there has been renewed interest in and improved understanding of the chronic fibrosis and remodelling that occurs in UC [1–3]. In particular, there has been a growing appreciation of both the importance of the extracellular matrix (ECM) for remodelling in UC and the potential to target the ECM with new therapeutic agents [4]. One such target is carbohydrate sulphotransferase 15 (CHST15). This is a type II transmembrane Golgi protein that biosynthesises highly sulphated disaccharide units (E-units) of chondroitin sulphate, which binds to various functional proteins and pathogenic microorganisms. Targeting this molecule in mouse models has previously been shown to offer promising signals for ameliorating colitis [5]. Based on this promising pre-clinical data, blockade of CHST15 has emerged as a potentially promising therapeutic target, and such blockade can be achieved by a silencing RNA oligonucleotide molecule called GUT-1 (previously called STNM01). A prior phase I clinical trial demonstrated the safety of GUT-1 in patients with Crohn’s Disease [6]. Accordingly, Atreya and colleagues now sought to evaluate the safety, as well as the efficacy and mode of action, of GUT-1 in patients with UC as part of a phase IIa placebo-controlled, clinical trial.

Methods and key findings

1. Adults with left-sided UC enrolled and submucosal injections administered

Adult patients aged 18–65 years with moderate-to-severe left-sided UC were recruited from five centres around Germany. Twenty-eight patients were screened and of these 24 were randomised in a 1:1:1 fashion to receive a single dose of 250 nM GUT-1, 25 nM GUT-1 or placebo. These doses were determined on the basis of the previously published phase I clinical trial in Crohn’s Disease, in which silencing efficacy from saturation of messenger RNA (mRNA) levels was achieved at 250 nM. The treatment was administered as submucosal injections during one endoscopy procedure. As regards the injections themselves, 2 mL was injected at each site with two further injections made on the opposite side of the bowel wall, at distances of 35 cm, 25 cm, 15 cm and 5 cm from the anal verge. Therefore in total there were eight injections. Patients and investigators were blinded to treatment allocation and the primary outcome measure was endoscopic improvement of disease at week 2 or week 4.

2. Higher-dose GUT-1, but not lower-dose GUT-1, shows promising signs of endoscopic improvement even in patients previously exposed to advanced therapies

Of the 24 patients randomised, 21 were included in the final efficacy analysis. Patients in the three study arms were similar with regard to demographic data and concomitant medication, with at least 50% anti-TNF-exposed patients in each group. All patients who received vedolizumab had had prior anti-TNF treatment and were also demonstrated to be refractory to the subsequent vedolizumab therapy. Endoscopic improvement was achieved in 71.4% of patients in the 250 nM GUT-1 arm, 0% of patients in the 25 nM GUT-1 arm and 28.6% of patients in the placebo arm. The mean baseline endoscopic subscores in the evaluable population (n=7 in each arm) were 2.5 (95% CI 1.9–2.9) in the 250 nM GUT-1 arm, 2.6 (95% CI 2.1–3.1) in the 25 nM GUT-1 arm and 2.5 (95% CI 1.9–2.9) in the placebo arm. The placebo response rates in this trial were higher than those reported from many other UC trials in recent years [7]. One reason for this may be the fact that although central reading took place, for logistical reasons this was central reading of images taken at endoscopy and not central reading of video-recorded procedures, which has typically been considered the gold standard approach to central reading in UC. However, perhaps even more striking than the placebo response was the 0% endoscopic response seen in the lower-dose GUT-1 arm, which was in stark contrast to the high levels of endoscopic response reported in the higher-dose GUT-1 arm. The authors highlight that although the lower dose of GUT-1 did not meet the criteria for endoscopic response based on Mayo endoscopic scoring, qualitative endoscopic findings in colonoscopy reports by local investigators showed that the numbers and sizes of ulcerated lesions were reduced in five patients who received 25 nM GUT-1. This does highlight an ongoing issue in clinical trial assessments, namely that the number and size of ulcers as well as the condition of bleeding are not reflected by the Mayo endoscopic score [8], and demonstrates that there remains a need for more detailed and granular endoscopic criteria in clinical trials for UC.

3. GUT-1 also shows promising signs of early histological improvement

Histological improvement/response was evaluated using the Geboes score [9] and the Nancy histological index [10]. Histological improvement was defined as the composite of neutrophil infiltration in less than 5% of crypts (Grade 3 Geboes Index score of 0 or 1) and no crypt destruction, erosions, ulcerations, or granulation tissue (Grade 4 Geboes Index score of 0 and Grade 5 Geboes Index score of 0) at week 2 or week 4. Histological response was also evaluated by changes in the NHI, showing that the mean baseline NHI in the evaluable population (n=7 in each arm) was 3.6 (95% CI 2.8–4.3) in the 250 nM GUT-1 arm, 3.9 (95% CI 3.5–4.2) in the 25 nM GUT-1 arm and 3.6 (95% CI 3.5–4.2) in the placebo arm. The mean changes at the end of the induction study (at week 2 or week 4) from baseline were -1.71 (95% CI -2.60 to -0.83) in the 250 nM GUT-1 arm, -0.86 (95% CI -1.85 to 0.13) in the 25 nM GUT-1 arm and -0.43 (95% CI -0.92 to 0.07) in the placebo arm.

4. GUT-1 mechanistic work shows evidence of target engagement

Immunohistochemical analyses were then performed to investigate changes in CHST15 expression. The mean percentage positive areas of CHST15 in the 250 nM GUT-1 arm were 19.7% (95% CI 17.0%–22.5%) at baseline, 11.5% (95% CI 6.5%–16.5%) at week 2 and 8.4% (95% CI 3.1%–13.7%) at week 4, suggesting good target engagement with a >50% drop in expression from baseline to week 4. The values in the 25 nM GUT-1 arm were 19.6% (95% CI 15.2%–24.1%) at baseline, 14.7% (95% CI 10.6%–18.7%) at week 2 and 14.0% (95% CI 7.7%–20.2%) at week 4, suggesting an element of target engagement with the lower dose of GUT-1 although this was seemingly insufficient to enact an effect on the outcome measures described above. Finally, values in the placebo arm were 16.3% (95% CI 14.6%–18.0%) at baseline, 18.8% (95% CI 16.1%–21.4%) at week 2 and 18.8% (95% CI 15.3%–22.2%) at week 4, demonstrating, as expected, a lack of target engagement from placebo. At two hours after injection, the plasma concentration of GUT-1 was below the lower limit of quantification (LLOQ 0.5 ng/ml) in all treatment groups, and both lower and higher doses of GUT-1 were generally well tolerated.


Despite the growing number of therapeutic options in UC, there remains a large area of unmet need for patients and therefore further therapies, and in particular those using novel modes of action and with a fast onset of action, are very welcome. Atreya and colleagues should be congratulated for conducting this trial, which provides promising evidence of safety, efficacy and target engagement for GUT-1, a selective RNA oligonucleotide molecule in patients with left-sided UC. Important steps going forward will be to determine whether this treatment can also be used in pancolitis and proctitis and to further elucidate the biological basis as part of mechanistic work in future clinical trial phases.


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    6. Suzuki K, Yokoyama J, Kawauchi Y, et al. Phase 1 clinical study of siRNA targeting carbohydrate sulphotransferase 15 in Crohn’s disease patients with active mucosal lesions. J Crohns Colitis 2017;11:221–8. https://doi.org/10.1093/ecco-jcc/jjw143.
    7. Sedano R, Hogan M, Nguyen TM, et al. Systematic review and meta-analysis: Clinical, endoscopic, histological and safety placebo rates in induction and maintenance trials of ulcerative colitis. J Crohns Colitis 2022;16:224–43. https://doi.org/10.1093/ecco-jcc/jjab135.
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    10. Marchal-Bressenot A, Salleron J, Boulagnon-Rombi C, et al. Development and validation of the Nancy histological index for UC. Gut 2017;66:43–9. https://doi.org/10.1136/gutjnl-2015-310187.

Lushen Pillay - Short Biography

Lushen Pillay is undertaking an Advanced Training Programme (ATP) fellowship in IBD at Cambridge University Hospitals in Cambridge, United Kingdom. He has a particular interest in advanced endoscopy and applying more advanced endoscopic techniques to help with the management of patients living with IBD.

Posted in ECCO News, Y-ECCO Literature Reviews, Committee News, Volume 18, Issue 4, Y-ECCO