The IBDs are a heterogeneous group of conditions divided into two predominant groups, CD and UC. These conditions are characterized by chronic inflammation, a relapsing and remitting clinical course, requirement for lifelong medication, and often significant morbidity. While multiple effective therapeutic options exist for the treatment of IBD, a proportion of patients will either not respond to or lose response to therapy. This emphasizes the significance of exploring and identifying therapies with novel therapeutic targets for patients with IBD [4].
GLP-2 is an intestinally derived hormone that enhances intestinal growth, digestion, absorption, barrier function, and blood flow in healthy animals, as well as preventing damage and improving repair in preclinical models of enteritis and colitis, and following substantial small bowel resection. These beneficial effects of GLP-2 on the intestinal tract are largely recapitulated in humans with intestinal failure [14].
Glepaglutide is a long-acting GLP-2R agonist in clinical development for short bowel syndrome. Here, we have shown that glepaglutide activates the hGLP-2R in vitro with a potency similar to that of native GLP-2, and that glepaglutide significantly increases small intestinal mass in naive Wistar rats. Based on the vast amount of published literature on the mechanism of action of GLP-2, we speculate that this growth effect of glepaglutide is mediated via stimulation of crypt cell proliferation and inhibition of villus cell apoptosis leading to increased mucosal growth [15, 16]. The intestinotrophic effects of glepaglutide were apparent 7 days after dosing started and were further increased (80 nmol/kg dose group) or maintained (400 nmol/kg dose group) after an additional week of dosing, suggesting that maximal small intestinal growth had been attained.
In addition, we have shown that glepaglutide administered at the time of the onset of inflammation or during the active inflammation phase was therapeutically active in a rat model of INDO-induced small intestinal inflammation. This model is well established as a model of CD, because the small intestine inflammation induced by INDO shares a number of pathological similarities with CD [29]. Both co- and post-treatment with glepaglutide (400 nmol/kg) had beneficial but slightly different effects on the studied parameters. Co-treatment with glepaglutide decreased acute body weight loss, reversed small intestinal shortening, and decreased ileal α-1-AGP and MPO concentrations. Post-treatment with glepaglutide had no effect on acute body weight loss, but reversed small intestinal shortening and decreased both jejunal and ileal α-1-AGP and jejunal MPO concentrations. The difference in the effect on body weight could be due to the difference in dosing regimens (3 days vs 2 days) during the active inflammation phase and the state of inflammation at the onset of treatment. Interestingly, post-treatment with glepaglutide had a more pronounced effect than co-treatment on jejunal and ileal α-1-AGP and jejunal MPO concentrations, indicating that the intestine was responsive to treatment with glepaglutide despite the progressive inflammation-induced damage.
Our study further demonstrates that glepaglutide effectively decreases inflammation without the need for a pre-treatment period. This could be of great potential clinical interest in the IBD patient populations.
Inflammation within the small intestine increases epithelial cell proliferation as a means of repairing damage [31]. During the inflammation phase, small intestinal mass was significantly increased in INDO controls but decreased gradually as the animals recovered. Despite the similarity in small intestinal mass between glepaglutide-treated and INDO control animals during the active inflammation phase, the significantly lower levels of a-1-AGP and MPO in the glepaglutide-treated animals suggest that the rise in small intestinal mass was due, at least in part, to other factors/mechanisms taking place in the inflamed intestine of the glepaglutide-treated animals. In both co- and post-treated animals, jejunal and ileal mass were markedly increased compared with INDO controls in the body weight recovery phase. We hypothesize that the significantly increased small intestinal mass in glepaglutide-treated animals was due to one or more of the following factors: increased cell proliferation, inhibition of apoptosis, increased blood flow to the small intestine, and/or increased protein synthesis [15, 16].
The anti-inflammatory and intestinal growth effects mediated by glepaglutide, coupled with the exclusive localization of the GLP-2R in the gastrointestinal tract, make this peptide an interesting therapeutic candidate for treatment of IBD. There is currently much focus on the importance of mucosal healing as a means of changing the natural course of disease in patients with IBD [6, 7]. Mucosal healing is expected to lead to symptom improvement, to decrease relapse and/or recurrence rates, to reduce complications such as the need for surgical interventions, and to abate the incidence of cancer and associated risk of death in IBD [6, 7]. Conventional therapies have little or no effects on mucosal healing. Immunosuppressants and biologics are reported to heal the mucosa but have slow onsets of action, requiring several months of dosing before healing is achieved, whereas steroids do not heal the mucosa [7]. These insufficiencies of conventional therapies are thought to play a role in the inadequacies in IBD treatment [3, 7].
Use of GLP-2 agonists for the treatment of IBD is not a novel concept. In a double-blind, placebo-controlled, phase 2a proof-of-concept study, the ability of teduglutide to induce remission or to reduce the Crohn’s disease activity index (CDAI) score by at least 100 points after 8 weeks of treatment was examined in patients with moderate to severe CD [32]. It was shown that teduglutide had a positive, dose-dependent effect on the CDAI score but that this failed to reach statistical significance. We speculate that the study was underpowered and that the assessment of mucosal healing, rather than the CDAI, would have been a better endpoint to assess the effect of treatment, because GLP-2 is known to act directly on the small intestinal mucosa. However, measurement of mucosal healing, which is still largely observational and requires repeated invasive endoscopic examinations, sometimes with mucosal biopsies, has only recently become more established [6].