Characterization of a guinea pig model to evaluate cardiovascular toxicity risk for targeted protein degraders - Insights and lessons learned

Targeted protein degradation is an active area of pharmaceutical research and development with the promise to increase the potential number of druggable targets across numerous therapeutic areas. One challenge in their current development has been unexpected cardiovascular findings that have been reported during clinical trials with some degraders, primarily delayed ventricular repolarization manifested as longer corrected QT (QTc) intervals and potential for increased arrhythmic risk. The objective of this study was to investigate whether guinea pigs might be a suitable small animal model to characterize potential cardiovascular effects earlier in degrader development in alignment with 3R principles. The pharmacokinetics and cardiovascular effects were measured in naïve guinea pigs using 4 distinct degraders previously tested in non-human primates. We found exposures were broadly lower in guinea pigs than non-human primates, and dose-limiting toxicity was observed with some degraders after increasing the dose (mg/kg) in guinea pigs to account for the lower exposures. No consistent CV changes were observed across all 4 degraders, which was not translatable to the QTc interval prolongation observed in non-human primates administered the same degraders. Lastly, an anesthetized guinea pig model was investigated to evaluate acute cardiovascular changes at elevated in vivo exposures beyond those achieved in the conscious preparations. However, no consistent changes were observed in QTc intervals. In this context of this preliminary investigation of 4 degraders, the guinea pig model was not a suitable option for evaluating cardiovascular liabilities.