Gastroenterology
Ulcerative Colitis
Novel Therapeutic Targets in Ulcerative Colitis
With the recent US Food and Drug Administration (FDA) approval of several novel agents for ulcerative colitis targeting IL-23, attention is shifting to the next therapeutic targets on the horizon. The most promising targets with agents in clinical development are TL1A inhibition, microRNA-124 upregulation, and NLRX1 agonism. Combination therapies evaluating multiple therapeutic targets are also being considered.
A novel class of agents that many of us are excited about and that has reasonable preliminary data are TL1A inhibitors. TL1A gene expression seems to correspond to ulcerative colitis disease severity. In earlier-phase studies, it demonstrated effectiveness in patients with ulcerative colitis. The thought is that inhibiting TL1A may have not only direct anti-inflammatory aspects but also antifibrotic aspects. In patients with inflammatory bowel disease, there is clearly an inflammatory component, and there is also a fibrosis-generating component in the wall of the bowel, so this could be an interesting target.
Thus far, there appears to be some effectiveness with anti-TL1A compared with placebo, and phase 2b and 3 studies are moving forward. There may be a companion diagnostic that helps to tell us if someone may be more likely to respond to this class of agents. A couple of the anti-TL1A agents in development are looking at companion diagnostics.
Other novel therapeutic targets with agents in development include microRNA-124 upregulators and NLRX1 agonists. Although these agents are not yet ready for clinical practice, the future is bright, particularly as we have more and more drugs with a variety of mechanisms and with excellent safety profiles.
I am interested to see if these will move forward. Certainly, there is an unmet need in ulcerative colitis management because we see that some patients with ulcerative colitis do not respond to traditional therapeutic mechanisms, and some patients may respond to a therapy for a while but then lose response. In fact, the rate of colectomy in ulcerative colitis is still approximately 15% to 20%.
In the future, the idea of combining some of our currently available agents to improve efficacy and to better control inflammation is of great importance, particularly if we do not see a negative safety impact. The VEGA trial looked at combining guselkumab, an anti–IL-23 agent, with golimumab, an FDA-approved anti-TNF medication, vs either agent alone as induction therapy. The preliminary data looked excellent, and there seemed to be a benefit to the combination. Ultimately, we would still need to understand how long dual therapy may be needed and if it would also need to continue for maintenance. Other studies moving forward are looking at combining other agents with the hope of improving efficacy while not sacrificing safety.
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