Functional GI disorders: from animal models to drug development

Abstract

Despite considerable efforts by academic researchers and by the pharmaceutical industry, the development of novel pharmacological treatments for irritable bowel syndrome (IBS) and other functional gastrointestinal (GI) disorders has been slow and disappointing. The traditional approach to identifying and evaluating novel drugs for these symptom-based syndromes has relied on a fairly standard algorithm using animal models, experimental medicine models and clinical trials. In the current article, the empirical basis for this process is reviewed, focusing on the utility of the assessment of visceral hypersensitivity and GI transit, in both animals and humans, as well as the predictive validity of preclinical and clinical models of IBS for identifying successful treatments for IBS symptoms and IBS-related quality of life impairment. A review of published evidence suggests that abdominal pain, defecation-related symptoms (urgency, straining) and psychological factors all contribute to overall symptom severity and to health-related quality of life. Correlations between readouts obtained in preclinical and clinical models and respective symptoms are small, and the ability to predict drug effectiveness for specific as well as for global IBS symptoms is limited. One possible drug development algorithm is proposed which focuses on pharmacological imaging approaches in both preclinical and clinical models, with decreased emphasis on evaluating compounds in symptom-related animal models, and more rapid screening of promising candidate compounds in man.

Figure 1

General strategy in irritable bowel syndrome (IBS) drug discovery and development. The schematic illustrates the vertical progression from the symptom complex of IBS to target identification in animal cells. For each step the current approach is shown in the left portion of the boxes. In the right portion of each box, suggested modifications to the current approach are shown. The current approach is lengthy, expensive and based on poor correlations between the individual steps. GI, gastrointestinal.

Figure 2

Progression from animal models to human biomarkers to human symptoms and health-related quality of life (QoL) impairment. (A) Current concept. Shown are commonly used assays and measures at these three levels of investigation. Arrows denote correlations/predictive validity from the lower to higher level. Signs next to arrows denote strength of connections: + good, (+) weak, ? not known. (B) Proposed concept. Shown is a proposed modified version of (A), with greater emphasis on brain imaging approaches at both the preclinical and clinical level. The correlations between preclinical and clinical brain imaging approaches, symptom severity and health-related QoL are currently not known (for details, see also fig 3). IBS, irritable bowel syndrome; GI, gastrointestinal.

Figure 3

Functional brain imaging in drug discovery. Known agents and procedures are used to develop disease-relevant biomarkers by cross-validation of data between normal animal and human brain function and between animal disease models and human disease. This process also provides new understanding of brain system functions and aids pharmacological target identification for drug discovery. The effect of a new compound on the previously established biomarker can then be assessed, effective doses evaluated and regulatory evidence collected in efficient POC studies. These POC studies in small cohorts of patients and healthy volunteers can validate our understanding of a mechanism of action and give initial data on efficacy. Reproduced with permission from Wise and Tracey.