Evaluating AZD9668 as a repurposed medication for the treatment of inflammatory bowel disease
Embargo Date
2028-02-26
OA Version
Citation
Abstract
Neutrophil elastase (NE) is a serine protease released by neutrophils, a component of the innate immune system, upon their activation in an inflammatory milieu. Its mechanisms of action are pleiotropic and involve bacterial killing, tissue remodeling, activation of cellular receptors and cytokines, and recruitment of immune cells. While NE is an essential part of the host’s immune defense against pathogens, its aberrant and chronic expression appears to be destructive and has been associated with several pathologic conditions. As such, it represents a compelling target for therapeutics. AZD9668 is a small molecule NE inhibitor developed for the treatment of lung diseases such as chronic obstructive pulmonary disease and bronchiectasis. The drug was tested in humans in the early phases of clinical trials and was found to be safe and well tolerated. However, further clinical development was abandoned due to lack of efficacy. Outside of the lung, neutrophils are implicated in the pathogenesis of Inflammatory Bowel Disease (IBD), a chronic, debilitating condition that affects 3 million patients in the US alone, including children and young adults. While several new therapies have been approved for the treatment of IBD, only a fraction of patients (30- 40%) respond to treatment. As such, the need for better, more efficacious drugs remains unmet. We hypothesized that AZD9668 might represent a potential treatment for IBD for the following reasons: a) increased levels of NE have been reported in the blood, colonic tissue and luminal content of patients with IBD and in proportion to their disease severity; b) studies in mice with experimental colitis, an animal model for IBD, have shown that genetic ablation of NE makes the mice resistant to colitis, a phenotype that could be recapitulated by overexpression of several endogenous inhibitors of NE; c) using a NE pharmacological inhibitor (different from AZD9668) to treat mice with colitis resulted in attenuation of inflammation and acceleration of intestinal healing. To our knowledge, there are no current clinical trials evaluating a NE inhibitor for IBD. To repurpose AZD9668 for the treatment of IBD, we must generate, at the preclinical level, strong evidence supporting our proposed drug therapy in proof-of- concept studies. Traditionally, this is done using mice models but increasing evidence has suggested that animal models lack high translational value for humans, resulting in >90% drug failure. To address this issue, we pursued an innovative methodology using tissue explants from patients (termed Patient-Derived Explants or PDEs) rather than treating patients themselves in a “clinical trial in a dish” laboratory setting. Using this approach, intestinal mucosal explants from 4 different patients with IBD were treated with AZD9668 or vehicle for 22 hrs. Gene expression changes in response to treatment were evaluated by bulk RNA-sequencing analysis. Based on a 15 gene signature that we generated, we identified 3 out of 4 patients (75%) as responders to the treatment. While this sample is too small to draw meaningful conclusions from, we have confirmed the feasibility of this study and established relevant experimental approaches as well as analytical tools for future investigations.
Description
2025