Crohn’s disease and Pouchitis (IBD)
The prevalence of Inflammatory Bowel Diseases (IBD) patients has witnessed a staggering rise in diagnoses over recent decades in Denmark with recent studies showing that numbers has reached 58.000. A development that has been in progress during the past decades. From 1995 to 2016, incidences of Crohn’s disease tripled, while Ulcerative Colitis surged by approximately 33% [1]. This development underscores the urgency of awareness, support, and effective management for those impacted. Crohn’s disease and Ulcerative Colitis, are both chronic and autoimmune, and bring forth a myriad of challenges to individuals‘ lives. IBD’s are often intertwined with other autoimmune conditions and various Co-morbidities.
Benthe Bertelsen, Deputy Chairman of the Danish Colitis-Crohn’s Association, rightly emphasizes the pressing need for attention to this patient group and their associated disease burden. ‘The escalating prevalence of chronic diseases compounds an already delicate healthcare system, necessitating a focused approach to address the multifaceted needs of those affected. The economic ramifications of IBD in Denmark are significant, with recent studies revealing an annual cost of approximately DKK 4 billion [1]. Within this, around DKK 1.9 billion accounts for sick days, increased social benefits, and lost tax revenue.’
What is IBD?
Inflammatory Bowel Disease (IBD) refers to a group of chronic conditions causing inflammation in the digestive tract, including Crohn’s disease and Ulcerative Colitis. These conditions result from an abnormal immune response. Inflammatory Bowel Disease (IBD) patients experience intense abdominal pain, diarrhea, fatigue, fever, and occasional bleeding due to inflammation. Additionally, these conditions are often linked with other co-morbidities like respiratory issues, colon cancer, depression, anxiety, heart problems, arthritis, and dental deterioration. These factors collectively impact their quality of life, restricting enjoyment of specific foods or activities due to the urgency of frequent restroom visits.
Drug candidate RNX - 041
What is the innovation behind the drug candidate.
The drug being developed by Reponex for treating Inflammatory Bowel Diseases (IBD), particularly Crohn’s Disease and Pouchitis, comprises three active substances: GM-CSF, Metronidazole, and Fosfomycin. This innovative combination is designed with a dual effect targeting specific bacteria associated with progressive disease alongside GM-CSF’s immunomodulatory action to improve healing. The treatment is applied topically as an in-situ formed gel under endoscopic supervision directly at the inflamed area.
Metronidazole and Fosfomycin (Antibiotics): These antibiotics target anaerobic and aerobic bacteria directly linked to the inflammation in Crohn’s Disease and Pouchitis. By targeting these specific bacterial strains, Metronidazole and Fosfomycin aim to reduce the microbial load and subsequent inflammatory response within the gut.
GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor – Immunomodulator): GM-CSF plays a crucial role in fortifying the immune system by augmenting the population of macrophages and other essential phagocytic cells in the intestine [2]. Macrophages are pivotal in maintaining the intestinal barrier, as they clear invading microbes and prevent the onset of larger-scale adaptive immune reactions[3]. In Crohn’s Disease, a breach in the mucosal barrier function is observed, often accompanied by macrophage hypo-responsiveness [4]. This leads to inefficient clearance of invading bacteria and an inadequate inflammatory reaction, culminating in the disease’s manifestations [5].
GM-CSF deficiency can impair the mucosal barrier function and trigger inflammation, as evidenced in animal models of Crohn’s Disease. Moreover, defects in GM-CSF signaling have been documented in Crohn’s Disease patients, leading to decreased effectiveness of the growth factor on target cells [2].
Crohn's disease
One of the Inflammatory bowel diseases that Reponex focuses on is Crohn’s disease. Crohn’s disease is an immune-mediated condition, meaning the body’s immune system mistakenly attacks healthy cells in the gastrointestinal tract, leading to ongoing inflammation and damage. This inflammation can occur anywhere in the gut (including in the mouth. But most commonly Crohn’s disease affects the small intestine. Damage caused by the body’s own immune system leads to intestinal narrowing and abscess formation causing abdominal pain, diarrhoea, fatigue, weight loss, and fever. Despite the introduction of biologics, 20-30% [6] of patients with Crohn’s Disease fail to respond or the treatment loses effect over time. Thus, there is a continuing need for the development of new treatment.
Pouchitis
Pouchitis is a condition that develops in patients with Ulcerative Colitis. When medical treatment for patients with Ulcerative Colitis is no longer effective in relieving symptoms or to treat complication of the disease, many patients undergo a surgical procedure referred to as “J-Pouch surgery”. This surgery involves removing the entire colon and forming an internal pouch shaped as a ‘J’, using the end of the small bowel, avoiding the need for an ileostomy, (figure 1). An estimated 5000 patients undergo J Pouch surgery in the United States each year.
Pouchitis is a condition where the patient experience inflammation after the creation of the J-Pouch [7]. Up to 80% of patients will suffer from pouchitis or pouchitis like symptoms and need treatment at some point after creation of the J-Pouch.7 Approximately 50 % of patients [8] develop pouchitis within the first 2 years of J pouch surgery, and approximately 20% suffer with recurrent pouchitis. Pouchitis symptoms include painful and frequent toilet visits with bloody diarrhoea, , which significantly impacts quality of life. Occasionally, patients with pouchitis becomes too severe and can’t be treated with medicine and the last resort is to close to rectum and create an ileostomy for the rest of the patient’s life.
Figure 1: The surgical procedure commonly chosen for the treatment-resistant ulcerative colitis is proctocolectomy. This is an operation in which the colon and rectum are removed (Image A). Subsequently, a new intestinal connection is created with a temporary ileostomy and a ‘pouch’ formed from the ileum, a part of the small intestine (Image B). Finally, the temporary stoma is removed, and bowel movements can once again occur through the anus (Image C).
Drug Development and Clinical trials
Reponex’s drug candidate, RNX-41, is presently undergoing clinical trials at Zealand University Hospital. The study aims to assess the safety and potential benefits of administering RNX-041, topically in the J-pouch to patients with Pouchitis. The clinical trial is divided into two parts.
The first phase focuses on evaluating the safety and tolerability of the drug following administration of a single dose. The second phase assesses safety and effectiveness of once daily treatment over 7 days. Data from this clinical trial is expected in 2024.
Below graphic illustrates the clinical pipeline for Drug Candidate RNX-041.
List of sources
1.Politik-katalog CCF, 2023 – Patientforeningen for tarmsyge
2. Däbritz Granulocyte macrophage colony-stimulating factor and the intestinal innate immune cell homeostasis in Crohn’s disease. Am J Physiol Gastrointest Liver Physiol. 2014;306(6):G455-465. doi:10.1152/ajpgi.00409.2013
3. Ruder, B., & Becker, C. (2020). At the Forefront of the Mucosal Barrier: The Role of Macrophages in the Intestine. Cells, 9(10), 2162. https://doi.org/10.3390/cells9102162
4. Maasfeh, L., Härtlova, A., Isaksson, S., Sundin, J., Mavroudis, G., Savolainen, O., Strid, H., Öhman, L., & Magnusson, M. K. (2021). Impaired Luminal Control of Intestinal Macrophage Maturation in Patients With Ulcerative Colitis During Remission. Cellular and molecular gastroenterology and hepatology, 12(4), 1415–1432. https://doi.org/10.1016/j.jcmgh.2021.06.004
5. Lee, K. M. C., Achuthan, A. A., & Hamilton, J. A. (2020). GM-CSF: A Promising Target in Inflammation and Autoimmunity. ImmunoTargets and therapy, 9, 225–240. https://doi.org/10.2147/ITT.S262566
6. Reber JD, Barlow JM, Lightner AL, et al. J Pouch: Imaging Findings, Surgical Variations, Natural History, and Common Complications. Radiogr Rev Publ Radiol Soc N Am Inc. 2018;38(4):1073-1088. doi:10.1148/rg.2018170113
7. Kayal, M., Kohler, D., Plietz, M., Khaitov, S., Sylla, P., Greenstein, A., & Dubinsky, M. C. (2022). Early Pouchitis Is Associated With Crohn’s Disease-like Pouch Inflammation in Patients With Ulcerative Colitis. Inflammatory bowel diseases, 28(12), 1821–1825. https://doi.org/10.1093/ibd/izac012
8. Barnes, E. L., Herfarth, H. H., Kappelman, M. D., Zhang, X., Lightner, A., Long, M. D., & Sandler, R. S. (2021). Incidence, Risk Factors, and Outcomes of Pouchitis and Pouch-Related Complications in Patients With Ulcerative Colitis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 19(8), 1583–1591.e4. https://doi.org/10.1016/j.cgh.2020.06.035
K Burisch J et al (J Crohns Colitis 2013;7:322-337), Anand B S et al (Medscape Apr 2022), GlobalData 2020; GDHCER251-20), Reber J D et al (RadioGraphics 2018: 38(4): 1073-1088), Dalal et al (Inflamm Bowel Dis 2018; 23:989–996)
Hurst RD, Molinari M, Chung TP, Rubin M, Michelassi Prospective Study of the Incidence, Timing, and Treatment of Pouchitis in 104 Consecutive Patients After Restorative Proctocolectomy. Arch Surg. 1996;131(5):497-502. doi:10.1001/archsurg.1996.01430170043007
Bobby Lo, Mirabella Zhao & Johan Burisch, Identifying patients with inflammatory bowel disease in the Danish National Patient Register, Ugeskriftet, 2023, https://ugeskriftet.dk/dmj/identifying-patients-inflammatory-bowel-disease-danish-national-patient-register
