Introduction

Ulcerative colitis (UC) represents the widespread inflammatory bowel disease (IBD) affecting millions of patients worldwide. UC usually begins at the onset of adulthood and progresses across the patient’s lifetime. Snail mucus has many hidden activities; many of them have been discovered in recent years. Scientific researchers have demonstrated that mucus-derivate drugs can be used in many therapies. For example, it is used in creams to ease skin abrasions and scars, to cure respiratory diseases and heartburn, and at last, scientists discovered unexpected and previously unknown properties. At the beginning of the twentieth century, a new interest in gastropods has grown up for their possible employment in medicine and industries.

Aims & Methods

This study aimed to investigate the possible therapeutic effect of mucus extracted from helix pomica snail in an experimental ulcerative colitis model induced by dextran sulphate sodium. Twenty-four mice were included and categorized into four groups. The 1^st group acted as a normal control group, whereas the 2^nd group acted as a pathological control group and ingested dextran sulphate sodium in drinking water. The 3^rd Group was treated orally with sulfasalazine and then ingested dextran sulphate sodium in drinking water. The 4^th group was treated orally with helix pomatia mucus and then ingested dextran sulphate sodium in drinking water. After seven days, the animals were euthanized, and the intestinal specimens were collected for pathological and biochemical assessment.

Results

Our results showed an improvement in histopathology with regression of the intestinal lesions in the 4th group compared to the pathological control group. The levels of nuclear-kappa B, and IL-1B decreased significantly after using helix pomatia mucus.

Conclusion

Helix pomatia mucus could be a potential therapy to protect against experimentally induced ulcerative colitis.

Introduction

Mirikizumab (miri), a p19-directed IL-23 antibody, showed efficacy in ulcerative colitis (UC)¹. Miri modulates transcripts associated with disease activity and anti-TNF resistance in UC and increases expression of transcripts associated with healthy mucosa². Here, we evaluate the transcription profile of patients with UC who respond to placebo (PBO, 20.6%) or miri 200mg treatment (59.7%) versus non-responders and build a model that can predict response in patients with UC.

Aims & Methods

In the phase 2 AMAC trial (NCT02589665), patients were randomized 1:1:1:1 to receive intravenous PBO (N=63), 50mg miri (N=63), or 200mg miri (n=62) with possible exposure-based dose increases or fixed 600mg miri (n=61) at Week (W)0, 4 and 8. Colonic biopsies were collected at baseline, W12, and W52. An Affymetrix HTA2.0 microarray measured gene expression. Limma comparing values at baseline and W12 determined differentially expressed genes (DEGs). DEGs maintaining their W12 expression level through W52 among responders in either the PBO and miri 200mg arms were designated as similarly expressed genes (DEGSEGs).
XGBoost models³ were trained to predict clinical response (decrease in 9-point Mayo subscore [rectal bleeding, stool frequency, endoscopy] of ≥2 points and ≥35% from baseline [BL] with either a decrease of RB subscore of ≥1 or an RB subscore of 0 or 1) using baseline levels of DEGSEGs and TNF biomarkers. Leave-one-out cross validation of the models using AMAC data and validation experiments by training on the PROTECT data⁴ then predicting in AMAC were used to evaluate our models.

Results

Miri 200mg responders were associated with 84 DEGSEGs, PBO responders were associated with 26 DEGSEGs, and 21 DEGSEGs were common to both. When using the PROTECT data as the training data and AMAC data as the validation cohort, we were able to achieve high ROC-AUC and PR-AUCs using the top 36 (FC > 1.5) miri DEGSEGs (PR-AUC=0.78), or combined (PR-AUC=0.93) gene sets as the features and found that the response prediction was significantly higher in AMAC responders vs. non-responders.

Conclusion

Baseline transcript features were predictive of clinical response in patients with UC treated with miri 200mg and our model distinguished responders from non-responders. Future studies are underway to validate this model.

References

1. Sandborn WJ, et al. Gastroenterology. 2020;158(3):537-549.e10.
2. Steere B, et al. J Crohns Colitis. 2020;S103-S104.
3. Chen T, et al. Proceedings of the 22^nd ACM SIGKDD International Conference. 2016;7285-794.
4. Hyams JS, et al. Lancet Gastroenterol Hepatol. 2017;2(12):855-868.

Disclosure

TJ and KH report no conflicts of interest. WR reports grant support and personal fees from Abbott Laboratories, AbbVie, Aesca, Centocor, Falk Pharma GmbH, Immundiagnostik, and Merck Sharp & Dohme, and personal fees from Aptalis, Celltrion, Danone Austria, Elan, Ferring, Mitsubishi Tanabe Pharma Corporation, Otsuka, PDL BioPharma, Pharmacosmos, Schering-Plough, Shire, Takeda, Therakos, Vifor, Yakult, Amgen, AM Pharma, Astellas, AstraZeneca, Avaxia, Bioclinica, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Covance, Galapagos, Genentech, Gilead Sciences, Grünenthal, ICON, Index Pharma, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millennium, Nestle, Novartis, Ocera, Pfizer, Procter & Gamble, Prometheus, Robarts Clinical Trial, Second Genome, SetPoint Medical, TiGenix, UCB, Zyngenia, and 4SC. BS, CH, NM, and VK are employees and shareholders of Eli Lilly and Company. CM is a former employee of Eli Lilly and Company. GD has served as an advisor for: AbbVie, Ablynx, Active Biotech, AgomAb Therapeutics, Allergan, AlphaBiomics, Amakem, Amgen, AM-Pharma, Applied Molecular Therapeutics, Arena Pharmaceuticals, AstraZeneca, Avaxia Biologics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, Celltrion, Cosmo Pharmaceuticals, Dr. Falk Pharma, DSM Pharmaceuticals, Echo Pharmaceuticals, Eli Lilly and Company, enGene, Exeliom Biosciences, Ferring Pharmaceuticals, Galapagos NV, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Immunic Therapeutics, Johnson & Johnson, Kintai Therapeutics, Lycera, Medimetrics, Medtronic, Merck Sharp & Dohme, Mitsubishi Pharma, Mundipharma, Nextbiotics, Novo Nordisk, Otsuka, Pfizer, PhotoPills, ProciseDx, ProDigest, Progenity, Prometheus Laboratories/Nestlé, Protagonist Therapeutics, RedHill Biopharma, Robarts Clinical Trials, Salix Pharmaceuticals, Samsung Bioepis, Sandoz, Seres Therapeutics/Nestec/Nestlé, Setpoint, Shire, Takeda, Teva, TiGenix, Tillotts Pharma AG, Topivert, Versant, and Vifor Pharma; and received speaker fees from: AbbVie, Biogen, Ferring Pharmaceuticals, Galapagos NV/Gilead Sciences, Johnson & Johnson, Merck Sharp & Dohme, Mundipharma, Norgine, Pfizer, Samsung Bioepis, Shire, Millenium/Takeda, Tillotts Pharma AG, and Vifor Pharma.