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Ponatinib, a multi-targeted TKI and potent pan-ABL inhibitor, approved for the treatment of Ph + ALL and CML, was temporarily withdrawn from the U.S. market due to severe vascular adverse events. Cardiac-specific toxicities including myocardial infarction, severe congestive heart failure, and cardiac arrhythmias have also been shown with ponatinib. Targeted oncology agents such as ponatinib have transformed cancer treatment but often induce toxicity due to inhibition of survival pathways shared by both cancer and cardiac cells. These toxicities are often missed by the standard preclinical toxicity assessment methods, which include human Ether-à-go-go-related gene (hERG) and animal toxicity testing. In this study, we show that a multiparameter in vitro toxicity screening approach using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) accurately predicted the cardiac toxicity potential of ponatinib. This in vitro model evaluated ponatinib's effect on the overall cell health, mitochondrial stress, and function of hiPSC-CM and also provided mechanistic insight into the signaling pathways and cellular structures altered with treatment. We show here that ponatinib rapidly inhibits prosurvival signaling pathways, induces structural cardiac toxicity (as shown by actin cytoskeleton damage, mitochondrial stress, cell death, and troponin secretion), and disrupts cardiac cell beating. Most of these effects occurred at doses between 10× and 50× ponatinib's Cmax, a dose range shown to be relevant for accurate prediction of in vivo toxicity. Together these studies show that a comprehensive in vitro screening tool in a more relevant human cardiac cell model can improve the detection of cardiac toxicity with targeted oncology agents such as ponatinib.

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Rats develop translatable pulmonary arterial hypertension (PAH) after exposure to the VEGF antagonist semaxanib (SU5416) concurrent with hypoxia. Sildenafil is used clinically for PAH and as a positive control in this preclinical model. A longitudinal analysis was constructed by pooling data from discrete rat PAH studies conducted over an 8-year period to evaluate the stability and reproducibility of the SU5416/Hypoxia rodent model as well as the response to sildenafil. Sprague-Dawley rats were administered SU5416 on Day 1 and subsequently maintained in a low oxygen environment for 28 days. Sildenafil was given as a positive control in either prevention or treatment mode. Pulmonary hemodynamics were obtained on the final day as appropriate by design; hearts were also assessed for right ventricular hypertrophy. Prevention studies (≥17) were terminated following 28 days of hypoxia while most treatment studies (≥17) had a protocol-defined period of normoxia following hypoxia. In prevention studies, the mean of both systolic pulmonary arterial pressure (sPAP) and the right ventricular hypertrophy Fulton’s Index (FI) remained consistent across studies over the 7-year period: sPAP: PAH vehicle control (PAH-VC) 70 ± 19 mmHg (n = 190), sildenafil 51 ± 15 mmHg (n = 165), p<.05; FI: PAH-VC 0.5573 ± 0.1048 (n = 210), sildenafil 0.4984 ± 0.1007 (n = 172), p<.05. Sildenafil elicited mean reductions in sPAP of 28% and FI of 11% over the 7-year period. Mean survival rate was comparable for PAH-VC (96%) and sildenafil groups (99%).In treatment studies, the mean of both sPAP and FI remained consistent across studies over the 8-year period: sPAP: PAH-VC 89 ± 24 mmHg (n = 148) vs. sildenafil 67 ± 22 mmHg (n = 168), p<.05 vs PAH-VC; FI: PAH-VC 0.5938 ± 0.0944 (n = 168) vs. sildenafil 0.5336 ± 0.1077 (n = 173), p<.05 vs PAH-VC. Sildenafil elicited mean reductions in sPAP of 25% and FI of 10% over the 8-year period. Mean survival rate was comparable for PAH-VC (91%) and sildenafil groups (95%).The effects of sildenafil on reduction of PAH were stable and of similar magnitude in both prevention and treatment studies over an 8-year period. Thus, this longitudinal analysis indicates a reproducible and consistent effect of both the SU5416/Hypoxia PAH model and the use of sildenafil as a positive control.