Quantitative Systems Pharmacologist Pfizer, United States
Disclosure(s):
Lyndsey Meyer: No relevant disclosure to display
Background: Incretin therapies (e.g., GLP-1 receptor agonists) are the leading class of weight loss drugs worldwide. Despite the proven potential of targeting incretin signaling, translating in vitro and pre-clinical measurements of potency and efficacy to predictions of clinical weight loss remains a significant challenge. Translatability of potency is confounded in in vitro assays by different cell lines, assay conditions, and instrumentation which can lead to uncertainty in potency measurements especially when comparing across experiments. The interpretation of weight loss in DIO mouse models is complicated by metabolic differences in mice and humans. Mice have a much higher metabolic rate by comparison, and do not experience emesis which presents challenges for translation.
Objective: : To develop a translational framework to predict clinical weight loss for novel incretin therapies or combinations of incretin therapies from in vitro or in vivo measures of potency.
Methods: We conducted a retrospective analysis of pharmacokinetics, in vitro potency, in vivo potency, and in vivo weight loss to identify potential predictors of clinical efficacy. Using a previously published model of body composition for C57BL6 mice [1-3], we estimated the effects of incretin therapies alone or in combination to identify possible additive or synergistic effects on food intake or weight loss in DIO mice. Applying the same approach to phase 1 clinical data, we tested the hypothesis that early measures of in vivo potency translated to weight loss efficacy in humans.
Results: In the retrospective analysis, we found a poor correlation between reported in vitro potency measures and clinical weight loss, however, we found a strong correlation (rho = 0.94) between the response to an acute glucose tolerance test (GTT) and preclinical weight loss. We identified the GTT AUC ratio (AUC treatment/AUC control) as a potential predictor of efficacy and early measure to compare potency across 5 of different compounds and combinations of incretin therapies.
Conclusions: Using a modeling and simulation framework we demonstrated the GTT AUC ratio accurately projected weight loss efficacy across different incretin therapies in mice. While predicting weight loss from an early measure of potency is an efficient way to evaluate novel therapies pre-clinically, additional clinical studies are needed to validate efficacy in humans.
Citations: 1. Guo, J. and K.D. Hall. PLOS Computational Biology, 2009. 5(9): p. e1000511. 2. Guo, J. and K.D. Hall. PLoS One, 2011. 6(1): p. e15961. 3. Gennemark, P., et al. J Pharmacokinet Pharmacodyn, 2013. 40(6): p. 651-67.
