The purpose of this study was to evaluate the value of model-based, quantitative decision making during the development of
gemcabene, a novel
lipid-altering agent. The decisions were driven by a model of the likely clinical profile of
gemcabene in comparison with its competitors, such as 3-hydroxymethylglutaryl
coenzyme A reductase inhibitors (
statins), the
cholesterol absorption inhibitor
ezetimibe, and their combination. Dose-response models were developed for the
lipid effects (
low-density lipoprotein cholesterol [
LDL-C] and
high-density lipoprotein cholesterol); adverse effects, such as persistent
alanine aminotransferase elevation and
myalgia; tolerability issues, such as
headache; and risk reduction for
coronary artery disease-related events for 5
statins,
ezetimibe,
gemcabene, and their combinations. The integrated model was based on the joint analysis of publicly available summary-level data and proprietary patient-level data and included information from almost 10,000 patients. The model was made available and accessible to the development team by using the Pharsight
Drug Model Explorer model visualization technology. The modeling greatly enhanced the understanding of the clinical profile of
gemcabene when given alone or in combination with a
statin. The interaction between
statins and
gemcabene for the
LDL-C lowering effect was found to be significantly different from the interaction between
statins and
ezetimibe.
Ezetimibe was found to have a pharmacological-independent interaction resulting in additional
LDL-C lowering over the entire
statin dose range. The
gemcabene interaction was found to be less than independent, resulting in almost no additional
LDL-C lowering at high-
statin doses, although the
drug has a significant
LDL-C effect when administered alone or in combination with a low dose of a
statin. The quick availability of the model after completion of the first phase II trial in the target patient population and the ability of the team to explore the potential clinical efficacy and safety of
gemcabene in comparison with alternative treatment options facilitated a quick decision to stop development.