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Functional GI Disorders: from Animal Models to Drug Development Recent advances in basic science Functional GI disorders: from Gut: first published as 10.1136/gut.2006.101675 on 26 October 2007. Downloaded from animal models to drug development E A Mayer,1 S Bradesi,2 L Chang,2 B M R Spiegel,3 J A Bueller,2 B D Naliboff4 1 UCLA Center for Neurovisceral ABSTRACT There have been advances in the field including Sciences & Women’s Health, Despite considerable efforts by academic researchers and development of agreed upon definitions of the Departments of Medicine, by the pharmaceutical industry, the development of novel Physiology and Psychiatry, David major syndromes (as well as a myriad of other 4 Geffen School of Medicine at pharmacological treatments for irritable bowel syndrome FGIDs), animal models with some face and UCLA, Los Angeles, CA, USA; (IBS) and other functional gastrointestinal (GI) disorders construct validity for the human syndrome5 and 2 UCLA Center for Neurovisceral has been slow and disappointing. The traditional approach identification of a continuously increasing number Sciences & Women’s Health, to identifying and evaluating novel drugs for these Departments of Medicine, David of molecular targets on epithelial and immune cells 6 Geffen School of Medicine at symptom-based syndromes has relied on a fairly standard and visceral afferent neurons, and in the central UCLA, Los Angeles, CA, USA; algorithm using animal models, experimental medicine nervous system (CNS).3 Furthermore, several 3 UCLA Center for Neurovisceral models and clinical trials. In the current article, the potential ‘‘biomarkers’’ have been postulated in Sciences & Women’s Health, empirical basis for this process is reviewed, focusing on IBS patients (ranging from abnormal bacterial Departments of Medicine, the utility of the assessment of visceral hypersensitivity 7 Center for Outcomes Research flora to mucosal immune activation (reviewed in and Education, David Geffen and GI transit, in both animals and humans, as well as the Spiller et al8) and abnormal perceptual and brain School of Medicine at UCLA, Los predictive validity of preclinical and clinical models of IBS responses (reviewed in Mayer et al9). Despite the Angeles, CA and VA Greater Los for identifying successful treatments for IBS symptoms lack of an agreed upon pathophysiology, a standard Angeles Healthcare System, Los and IBS-related quality of life impairment. A review of Angeles, CA, USA; 4 UCLA strategy for drug discovery, including preclinical Center for Neurovisceral published evidence suggests that abdominal pain, and clinical studies on GI motility and colorectal Sciences & Women’s Health, defecation-related symptoms (urgency, straining) and sensitivity, as well as large phase II and III efficacy Departments of Medicine and psychological factors all contribute to overall symptom trials, have been followed by most of the pharma- Psychiatry, David Geffen School severity and to health-related quality of life. Correlations ceutical companies involved in this field. of Medicine at UCLA, Los between readouts obtained in preclinical and clinical Angeles, CA and VA Greater Los Why have these accomplishments not translated models and respective symptoms are small, and the Angeles Healthcare System, Los into more effective treatments? Is there a funda- ability to predict drug effectiveness for specific as well as Angeles, CA, USA mental flaw in the drug discovery and develop- for global IBS symptoms is limited. One possible drug ment strategies that have been followed during the http://gut.bmj.com/ Correspondence to: development algorithm is proposed which focuses on Professor E A Mayer, UCLA past decade? Is it premature to embark on costly pharmacological imaging approaches in both preclinical Center for Neurovisceral drug development strategies for complex symp- and clinical models, with decreased emphasis on Sciences & Women’s Health, tom-based disorders like IBS or other FGIDs as long VAGLAHS, Bldg. 115, Room evaluating compounds in symptom-related animal models, as a full understanding of the pathophysiology of 223, 11301 Wilshire Blvd, Los and more rapid screening of promising candidate Angeles, CA 90073, USA; these syndromes is not available and the treatment compounds in man. [email protected] targets remain ‘‘moving targets’’? The situation is further complicated by rapid advances in the scope on September 28, 2021 by guest. Protected copyright. Revised 27 August 2007 Accepted 8 September 2007 Despite the tremendous efforts by academia and and speed of drug discovery efforts in the Published Online First industry alike during the past 15 years, the success pharmaceutical industry over the past decade so 19 October 2007 rate for effective drug development for irritable that the field is now faced with a rapidly growing bowel syndrome (IBS) and other functional gastro- number of candidate compounds emerging from intestinal (GI) disorders (FGIDs) remains unim- preclinical development without a cost-effective pressive. Only two new IBS treatments—that is, strategy to screen these compounds efficiently for alosetron and tegaserod—have gained initial Food their usefulness in human patients. and Drug Administration (FDA) approval as a new In the following review, we will focus on the IBS treatment so far. However, both of these ‘‘process’’ of drug development in IBS, by critically medications are only available in the USA as part reviewing three areas in the current assumptions of a restricted access programme, due to side and strategies of drug development efforts in IBS: effects.1 Of the many failed compounds that never (1) What is the current approach to drug develop- saw the light of the peer-reviewed literature, only a ment in IBS, and what is the strength of the small number were officially announced as a evidence supporting this approach? (2) What is the failure, including the peripheral visceral k-opioid predictive validity of commonly employed experi- agonist fedotozine, the selective m3 muscarinic mental medicine models for IBS symptoms. (3) receptor antagonist darifenacin and the selective What is the predictive validity of existing animal NK3 receptor antagonist talnetant. Despite this models and the molecular targets identified in discouraging news, and despite the fact that several these models for the human disorder? Based on this major companies have decided to leave the IBS field review, we are proposing possible modifications in altogether, several new and promising compounds the existing strategies which could avoid the are in various stages of early clinical develop- pitfalls of the past and present, and hopefully ment.23 translate into more cost-effective development 384 Gut 2008;57:384–404. doi:10.1136/gut.2006.101675 Recent advances in basic science strategies for this important area of gastroenterol- specific IBS symptoms serve as a basis for the ogy. development of animal models (nociceptive reflex Gut: first published as 10.1136/gut.2006.101675 on 26 October 2007. Downloaded from responses to colorectal distension, faecal pellet output or transit studies) which in turn aim to THE CURRENT APPROACH TO DRUG mimic the human biomarkers or intermediate DEVELOPMENT phenotypes (fig 1C).10 Molecular targets are identi- The current approach to drug development for IBS fied in these animal models which are thought to and other FGIDs is illustrated in fig 1. Syndromes mediate the characteristic features exhibited by the are defined by their primary symptoms, in the case animal model (eg, ion channels and receptors on of IBS in terms of chronically recurring abdominal visceral afferent neurons, enterochromaffin cells, pain or discomfort associated with alterations in enteric neurons, central stress circuits). Highly bowel habits4 (fig 1A). Human biological markers selective, candidate compounds aimed at these including perceptual hypersensitivity to experi- molecular targets are developed and optimised mental rectal or sigmoid distension (referred to (fig 1E), which in turn are tested in the respective throughout as ‘‘visceral hypersensitivity’’), and animal models and, if shown to be effective and altered intestinal transit (whole gut or regional safe, are tested in human experimental medicine colonic transit) which are thought to underlie models (phase I and IIa) for their ability to affect http://gut.bmj.com/ on September 28, 2021 by guest. Protected copyright. 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. Gut 2008;57:384–404. doi:10.1136/gut.2006.101675 385 Recent advances in basic science GI transit or visceral sensitivity. Either sequentially However, before accepting the most commonly or in parallel, candidate compounds are being used surrogate markers for abdominal pain and for Gut: first published as 10.1136/gut.2006.101675 on 26 October 2007. Downloaded from evaluated in small proof of concept (POC) studies altered bowel habits as meeting the requirements (phase IIa) and large phase II/III multicentre of predicting the effectiveness of a candidate drug studies, using global (as opposed to specific on IBS, several points have to be considered. The symptom-related)
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