AbbVie announced that Rinvoq (upadacitinib), a JAK inhibitor, has been approved by the European Commission (EC) for the treatment of moderate to severe active Crohn's disease in adult patients. This makes Rinvoq the only JAK inhibitor approved in the European Union for this condition. Merck also acquired Prometheus Biosciences, whose product PRA023 has shown promise in two phase 2 clinical trials for treating ulcerative colitis and Crohn's disease. PRA023 has the potential to be the first or best-in-class drug of its kind. This advancement undoubtedly provides new hope for symptom relief to patients suffering from inflammatory bowel disease (IBD).

Background

IBD is a chronic, idiopathic, inflammatory disease of the digestive tract, including two phenotypes: ulcerative colitis (UC) and Crohn's disease (CD). While UC affects only the colon, CD can affect any part of the digestive system, from the mouth to the anus^[1]. IBD is characterized by its incurable nature, recurrent course, difficulty in treatment, and predilection for young adults^[2]. Patients with IBD commonly present with symptoms such as abdominal pain, diarrhea, low-grade fever, and malnutrition. UC patients may experience symptoms such as bloody diarrhea, inflammation, and ulceration limited to the mucosal layer of the colon^[3], while CD patients may exhibit chronic inflammatory responses throughout the digestive tract, leading to stenosis, fistulae, and intestinal obstruction.

Treatment

Currently, there is no cure for IBD, and treatment aims to reduce inflammation, alleviate symptoms, prevent complications, and improve quality of life. Treatment options include drug therapy such as anti-inflammatory drugs, immunosuppressants, and biologics, as well as surgical resection of damaged or diseased portions of the digestive tract^[4]. Even in moderate to severe cases, conventional medicines at higher dosages may still be ineffective in controlling symptoms. This is especially true for individuals who have not responded well to early treatment with medications, including aminosalicylates, corticosteroids, and immunosuppressants. The approval of TNF-α monoclonal antibodies for the treatment of moderate to severe IBD has laid the groundwork for treating these cases, effectively improving patient outcomes and decreasing the necessity for surgical intervention.

In recent years, researchers have explored new treatment mechanisms by targeting key steps in known immune pathways, resulting in the development of numerous new biological therapies. Among them, natalizumab (an α4 integrin antagonist) became the first approved drug for IBD that utilized a new mechanism in 2008 by inhibiting T-cell homing. AbbVie's risankizumab, approved by the FDA in June 2022 for the treatment of CD, became the first drug to target IL-23 for the treatment of IBD, while several other drugs with the same target entered clinical trials. Despite these developments, there are still unresolved issues in IBD treatment, such as the reliance on immunosuppressive therapies, which can increase the risk of adverse events such as infections and tumors. Although biological agents have significantly improved IBD treatment, their efficacy is still not ideal. Additionally, due to individual differences in how IBD patients respond to medications, the concept of precision medicine needs to be introduced, which further stimulates the development of more innovative drugs.

GemPharmatech’s IBD models

Choosing the appropriate animal model for studying a new drug is a crucial first step. GemPharmatech has developed several animal models of inflammatory bowel disease (IBD), including induced models and genetically modified models of spontaneous colitis, which will aid in preclinical medication evaluation and mechanism studies.

DSS-induced UC model

Cyclosporine A ameliorated DSS-induced colitis model

References:

1. https://www.nhs.uk/conditions/inflammatory-bowel-disease/

2. Kaplan, G.G. and S.C. Ng, Understanding and Preventing the Global Increase of Inflammatory Bowel Disease. Gastroenterology, 2017. 152(2): p. 313-321.e2.

3. Ungaro, R., et al., Ulcerative colitis. Lancet, 2017. 389: p. 1756-1770.

4. https://www.mayoclinic.org/diseases-conditions/inflammatory-bowel-disease/diagnosis-treatment/drc-20353320