Janssen reports positive topline results for Tremfya in Crohn’s at week 48

The IL-23 Pathway and Its Pivotal Role in Inflammatory Bowel Disease Research

The incidence of inflammatory bowel disease (IBD), which includes both Crohn’s disease (CD) and ulcerative colitis (UC), has increased over the last two decades. While anti-tumor necrosis factor (TNF) therapies have been a mainstay of treatment in IBD, additional options are needed for those patients still experiencing active disease. These patients are the motivating force that inspires the research community to uncover novel treatment approaches and work collaboratively to address unmet needs in gastroenterology.

This has driven an increase in the development of protein-based therapeutic agents, including biologics targeting interleukins which can induce inflammation in the gastrointestinal tract.^1,2 More recently, scientific insights have driven attention to the role of IL-23 in the pathogenesis of inflammatory diseases, and it is one of eight pathways that may offer the greatest opportunity to differentially address current and future unmet needs among patients with immune-mediated diseases.^2,3

The significance of the IL-23 pathway in immune-mediated inflammatory diseases

For years, IL-12 was believed to be a key cytokine in IBD pathogenesis. However, recent studies have also revealed the role of IL-23 in the progression of IBD.^2,3

IL-23 is a naturally occurring protein and research has shown that it is the dominant cytokine for many immunological functions in autoimmune inflammatory diseases.^3,4 It is found to be an important driver of the pathogenesis of inflammatory diseases such as moderate to severe plaque psoriasis (PsO) and active psoriatic arthritis (PsA).⁵ There is also growing evidence of its role in the development of IBD, and the scientific community continues to investigate to build understanding of IL-23 inhibition to inform future IBD treatment strategies.

Selectively targeting IL-23 and its subunits in IBD

^IL-23 is a member of the cytokine family composed of a novel p19 subunit and a p40 subunit.⁴ Laboratory studies have shown that the expressed p19 protein may be playing an independent role in modulating inflammation and has correlated with inflamed mucosa and the severity of endoscopic lesions in IBD.^4,6 Increased expression of p19 has a role in the pathogenesis of ulcerative colitis, and has been associated with disease severity.⁷

The industry is learning more about the role that IL-23 and its subunits play in IBD, and research into more selective IL-23 inhibition is helping to inform which patients may best benefit from these investigational agents. Ongoing clinical trials will provide even greater insight.

Looking ahead: raising the bar in IBD treatment

With a life-long progressive condition like IBD, it’s critical to investigate potential new treatment options and mechanisms of action with the understanding that remission, and helping more patients feel well, is the ultimate goal.

The research into the IL-23 pathway and insights gained so far are helping researchers to zero in on assets and explore new areas of innovation that may have impact on patients. For example, combination therapy involving complementary pathways, like IL-23, that have synergistic effect may play an important strategy in unlocking refractory disease in patients with UC or CD.

Insights from existing IL-23 pathway science and therapeutic development are also being applied to research oral IL-23 agents for eligible people in need. Novel oral therapies could be an option for these patients.

Pathway science has helped researchers to better understand the complex pathogeneses of the diseases and be more dynamic with research and development approaches and could redefine what it means to live with IBD.

Jan Wehkamp, M.D. Ph.D., is Vice President, Gastroenterology Disease Area Leader at The Janssen Pharmaceutical Companies of Johnson & Johnson.

References:

1. Rawla. P., Sunkara, T., Raj, J.P. J Inflamm Res. 2018;11:215-226. Published 2018 May 16. https://doi.org/10.2147/JIR.S165330
2. Regner, E., & Mahadevan, U. (2020). Practical Gastroenterology, 44(7), 34-37. https://practicalgastro.com/2020/08/13/targeting-the-il-12-23-pathway-for-inflammatory-bowel-disease-current-concepts-and-future-directions/
3. Kashani, A., Schwartz, D.A. Gastroenterol Hepatol (N Y). 2019 May;15(5):255-265.  https://pubmed.ncbi.nlm.nih.gov/31360139/
4. Tang, C., Chen, S., Qian, H., Huang, W. Immunology. 2012;135(2):112-124. https://doi.org/10.1111/j.1365-2567.2011.03522.x
5. Benson, J. M., et al. MAbs, 2011:3(6), 535–545. https://doi.org/10.4161/mabs.3.6.17815
6. Liu, Z., Yadav, P.K., Xu, X., Su, J., Chen, C., Tang, M., Lin, H., Yu, J., Qian, J., Yang, P.C., Wang, X. J Leukoc Biol. 2011 Apr;89(4):597-606. https://doi.org/10.1189/jlb.0810456
7. El-Bassat, H., AboAli, L., El Yamany, S., Al Shenawy, H., Al Din, R.A., Taha, A. Adv Dig Med. 2016;3: 88–94. https://doi.org/10.1016/j.aidm.2015.04.002  

Jan Wehkamp

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Jan Wehkamp, M.D. Ph.D., is Vice President, Gastroenterology Disease Area Leader at The Janssen Pharmaceutical Companies of Johnson & Johnson.

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