AZD9668 is an oral inhibitor of human neutrophil elastase (NE) developed for the treatment of lung diseases such as chronic obstructive pulmonary disease, cystic fibrosis and bronchiectasis. However, neutrophil infiltration is the histologic hallmark of additional chronic inflammatory conditions, including Crohn's disease and ulcerative colitis, collectively known as inflammatory bowel disease (IBD). Indeed, systemic and fecal levels of NE are increased in patients with IBD and in proportion to disease activity. We hypothesized that treatment with AZD9668, alone or in combination with other medications, might benefit patients with IBD, particularly during the acute phase of the disease. The candidate drug for repurposing was identified via an independent crowdsourcing effort publicly available (Open Innovation Platform sponsored by Astra Zeneca). Previous studies in animals have shown that NE pharmacological antagonism or overexpression of NE natural inhibitors attenuated experimental colitis. Advantages of repurposing AZD9668 for the treatment of IBD include a favorable safety profile based on its testing in more than 1000 patients so far and for up to 12 weeks of treatment, which is suitable for IBD. We propose a comprehensive preclinical evaluation of AZD9668 using three different mouse models of experimental colitis that will provide complementary mechanistic insights (AIM 1) and mucosal explants from patients with IBD that can predict clinical efficacy (AIM 2). The latter will inform a precision medicine approach for patient selection in subsequent phase 2a clinical trials. Moreover, through a proteomics analysis of biopsy culture supernatants we will be able to shed light to the biological pathways affected by NE inhibition and in parallel develop biomarkers for patient follow-up. From a drug development perspective, it takes about 15 years and $1 billion to develop a successful drug with >95% failure rates. Owing to drug repurposing, we envision that the drug under investigation upon its successful preclinical and clinical evaluation can move forward in IBD therapeutics in the foreseeable future and at a fraction of the cost. It will thus fulfill an unmet need for about 1.4 million patients with IBD in US alone, about of half of whom do not respond in the long-term to current treatments even after the introduction of biological therapies like anti-TNF.

Public Health Relevance

It is estimated that 1.4 million Americans suffer from Inflammatory Bowel Disease (IBD), a chronic debilitating condition affecting primarily young adults. Newest therapies with biologics like anti-TNF have been associated with rare but serious side effects, are expensive and can benefit only about half of the patients in the long-term. In this proposal we will evaluate as a potential treatment for IBD the neutrophil elastase inhibitor AZD9668, a drug offered for repurposing through crowdsourcing. We will test the drug in mouse models of experimental colitis and in biopsies from patients with IBD. The drug candidate has been previously evaluated in clinical trials for another disease indication and was safe and well tolerated. Owing to drug repurposing, we envision our target to reach the market in the foreseeable future, fulfilling thus an unmet medical need in IBD therapeutics.

National Institute of Health (NIH)
National Center for Advancing Translational Sciences (NCATS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZTR1-DPI-2 (01))
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Austin, Bobbie Ann
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Beth Israel Deaconess Medical Center
United States
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