Bridging the Gap Between Preclinical and Clinical Evaluation of Therapeutic Candidates

Session 5

Innovative Approaches to Integrate Decision Making Across Disease and Drug Platforms – Metabolic Syndrome and the PPAR Platform

Eiry W. Roberts, M.D.
Eli Lilly and Company

Currently, metabolic syndrome and associated atherosclerosis represent a major health issue for patients around the world. Despite significant investment in the discovery and development of new therapeutic agents for the treatment of these conditions, very few innovative therapies have been able to deliver meaningful improved clinical outcomes for patients. Much of the challenge in this arena relates to the complex pharmacology inherent in many of the classes of therapeutic agents under study. This complexity provides a huge challenge in the estimation and evaluation of benefit/risk for patients.

One class of therapeutic agents that exemplify these challenges and have been widely studied in recent years, are the Peroxisome Proliferated Activated Receptor (PPAR) agonists. This class of drugs, which includes the PPAR gamma agonists, PPAR alpha agonists, PPAR delta agonists and dual mixed agonists, have been widely evaluated by multiple pharmaceutical companies with the filing of approximately 50 different investigational drug applications in recent years. Unfortunately, the probability of technical success for these investigational therapies has been sufficiently low that very little translation of the science into meaningful clinical therapy has occurred.

For the pharmaceutical industry, evaluation of these types of investigational therapies with low individual technical probability driven by complex pharmacology and the need to have objective meaningful evaluation of benefit/risk, provides a significant challenge with respect to portfolio investment and decision making.

This presentation will provide an overview of one company’s (Eli Lilly) approach to the discovery and early clinical development activities for its extensive platform of PPAR candidate molecules. The presentation will highlight the use of a wide variety of established and novel biomarkers to assess benefit and risk in preclinical and clinical development and will demonstrate how these data were effectively integrated through the application of modeling and simulation techniques, to enable decision making in the preclinical and clinical arena. Furthermore this robust assessment of “clinical utility index” coupled with disease based modeling was used to streamline the individual trail design and clinical trial program as a whole. At a portfolio level, integration of data across molecules was performed in order to streamline translation and decision making at that level.

Two key additional areas are key to the success of such an effort. Firstly the disease and exposure response modeling rely heavily on the use of public domain data and reinforce the need to transparency in early publication of data from clinical trials, both positive and negative in outcome. Secondly, the future of biomarker discovery and development, both of which were critical to the effective delivery of this portfolio to an appropriate set of go/no go decisions is dependent on consortia, which must continue to be supported and developed in the public/private domain.

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