From preclinical to clinical development: the example of a novel treatment for obesity.

ABSTRACT

Clinical development of drugs for CNS disorders can be a challenging and risky endeavor. In this article we look at the steps required to move a preclinical candidate compound into clinical development. We use the case study of ALB-127158(a), an MCH1 antagonist for the treatment of obesity via a central mechanism to highlight the steps needed to move into early clinical development. Preclinical studies demonstrated that the compound produced significant weight loss in rodents. Based on the observation that the weight loss was caused by a reduction in food intake it was possible to build measures of ingestive behavior into the early clinical development plan. Single and multiple ascending dose studies were conducted in normal and overweight volunteers. The compound was safe and well tolerated with good PK characteristics. ALB-127158(a) was shown to have some effects on measures of 'hunger' and 'desire to eat', unfortunately these effects only occurred at doses higher than those predicted from the preclinical studies. A subsequent study looking at compound levels in the cerebrospinal fluid (CSF) suggested lower brain exposure than seen in the preclinical models. Based on this data and the limited efficacy observed it was possible to terminate further progression of this compound for obesity before costly long-term weight loss studies were initiated. However, recent reports have demonstrated that MCH acting via MCH1 receptors located on intestinal epithelial cells may be a critical mediator of inflammatory responses within the gastrointestinal (GI) tract. MCH1 receptor antagonists may therefore have a beneficial effect in disorders such as inflammatory bowel disease (IBD). Based on this evidence a peripherally selective MCH1 receptor antagonist such as ALB-127158(a) may be a potential treatment for IBD. This example demonstrates how using data from the preclinical studies is possible to build decision points into an early clinical development plan that will allow early assessment of potential efficacy and allow timely go/no go decisions.