Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is a complex, multifactorial disease involving inflammation of the gastrointestinal tract.  The exact cause is unknown, but it is thought to be due to a combination of genetic and environmental factors, leading to defects in intestinal epithelial barrier function and subsequent immune cell activation.

Since the approval of tumour necrosis factor (TNF) inhibitors in the early 2000s, multiple new treatments and mechanisms have been approved in IBD. These therapies have transformed how patients are treated, and increased the number that are able to enter long-term remission. In some instances, these therapies can even alter the course of disease and reduce the number of patients that go on to have further complications or require surgery^[1].

Despite this, achieving remission remains elusive for a large proportion of patients, with most treatments exhibiting remission rates of <40% after 1 year of treatment in clinical trials. In addition, as patients try more therapies, response and remission rates tend to decrease^[2].

We believe that part of the reason for this is that current treatment options tend to be limited to single cytokine targets (e.g., TNF or IL-23) or specific cell types (e.g., S1P or α4β7 integrin inhibiting lymphocyte trafficking). In addition, despite there being multiple products approved for IBD treatment, there is little diversity in the mechanisms that are used. JAK inhibitors, which can affect multiple cytokines, have also been approved and shown to be effective, but are reserved for later line therapies due to safety concerns. As such, unmet need remains for new, safe mechanisms of actions, that can continue to improve outcomes for IBD patients.

In our search for new therapeutic targets, we wanted to go after first-in-class mechanisms with strong validation in IBD. This meant being guided towards targets of interest highlighted in large genetic association studies of the disease^[3][4].

IBD has been linked to environmental factors, but genetics have also been shown to play a role, with over 150 regions of the human genome shown to be linked to increased risk of IBD. In our search, we found the genetic data linking GPR65 and IBD to be particularly compelling, with several IBD-associated variants shown to be significantly associated with GPR65. The most well studied variant is I231L, which has been shown to lead to decreased GPR65 signalling.

GPR65 is a pH sensing GPCR that is predominantly expressed on immune cells. Inflammatory loci tend to be more acidic than non-inflamed tissues due to hypoxia and increased levels of acidic metabolites. Acidic pH can alter the function of inflammatory cells and in an acidic microenvironment, the expression of GPR65 regulates the inflammatory response, mainly through the Gs / cAMP signalling pathway.

After the initial genetic findings, multiple studies have gone on to try and decipher exactly how GPR65 exerts its effect in disease. These have included GPR65 knockouts or I231L knock-ins in multiple preclinical models of colitis, including acute dextran sulfate sodium (DSS), chronic DSS, c. rodentium, Rag1 knockout, TNBS and IL-10 knockout^{[5],[6],[7],[8],[9]}.

Across these studies, GPR65 has been shown to be a homeostatic regulator of inflammation, reducing pro-inflammatory cytokines (e.g., TNF and IL-23) and increasing pro-resolution cytokines (e.g., IL-10). Interestingly, GPR65 has also been shown to play a role maintaining barrier function, with studies looking at GPR65 knockouts in intestinal epithelial cells only, also leading to colitis exacerbation.

At OMass, we are excited about the progress we have been making with our pre-clinical GPR65 agonists . We believe that GPR65 agonists have a differentiated mechanism of action that targets key nodes of the IBD disease pathology, including reducing pro-inflammatory cytokines, increasing pro-resolution cytokines and impacting epithelial barrier repair, which can ultimately improve outcomes in IBD patients.

Continue to watch this space for more news!

References: 

[1] Dulai, Parambir S., et al. “Early intervention with vedolizumab and longer-term surgery rates in Crohn’s disease: post hoc analysis of the GEMINI phase 3 and long-term safety programmes.” Journal of Crohn’s and Colitis 15.2 (2021): 195-202.

[2] Dotan, Iris, et al. “Efficacy of filgotinib in patients with ulcerative colitis by line of therapy in the phase 2b/3 SELECTION trial.” Journal of Crohn’s and Colitis 17.8 (2023): 1207-1216.

[3] Jostins, Luke, et al. “Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease.” Nature 491.7422 (2012): 119-124.

[4] Franke, Andre, et al. “Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci.” Nature genetics 42.12 (2010): 1118-1125.

[5] Li, Gengfeng, et al. “Intestinal epithelial pH-sensing receptor GPR65 maintains mucosal homeostasis via regulating antimicrobial defense and restrains gut inflammation in inflammatory bowel disease.” Gut microbes 15.2 (2023): 2257269.

[6] Marie, Mona A., et al. “GPR65 (TDAG8) inhibits intestinal inflammation and colitis-associated colorectal cancer development in experimental mouse models.” Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 1868.1 (2022): 166288.

[7] Lassen, Kara G., et al. “Genetic coding variant in GPR65 alters lysosomal pH and links lysosomal dysfunction with colitis risk.” Immunity 44.6 (2016): 1392-1405.

[8] Chen, Xiangjun, et al. “pH sensing controls tissue inflammation by modulating cellular metabolism and endo-lysosomal function of immune cells.” Nature immunology 23.7 (2022): 1063-1075.

[9] Perren, Leonie, et al. “OGR1 (GPR68) and TDAG8 (GPR65) Have antagonistic effects in models of colonic inflammation.” International Journal of Molecular Sciences 24.19 (2023): 14855.