The “Cardiovascular Effects Are Still Causing Late Attrition of Novel Therapeutics: Developing Solutions to Detect and Avoid Cardiovascular Toxicity in the Clinic” Scientific Session during the 2018 Annual Meeting and ToxExpo provided a comprehensive overview of the various tools available to assess the potential of drug candidates to induce adverse cardiovascular events. For instance, human induced pluripotent stem cell-derived cardiomyocytes (hIPSC-CM) hold promise in predicting adverse cardiovascular event liability early in the drug development process since these cells develop features that closely resemble the adult cardiomyocyte phenotype (structurally and functionally) with increasing time in culture.
An important point that I took away from this session was the importance of incorporating and evaluating cardiovascular safety endpoints (e.g., blood pressure, heart rate, left ventricular pressure, body temperature, etc.) as early on as possible, particularly in the early efficacy and safety studies. This might provide early insight into the likelihood that a compound will show signs of cardiovascular toxicity at later stages of development.
One of the presentations discussed the use of clinically-relevant large animal models of heart failure to evaluate efficacy of drug candidates in development. This talk was interesting because it made me realize that animals and humans with a disease might exhibit differential susceptibility to cardiotoxicity from a drug in comparison to normal, healthy subjects. The presenter highlighted that these models could be useful for safety pharmacology testing since heart failure subjects are often more susceptible to cardiovascular-related issues.
Regarding translating knowledge gained from nonclinical studies to potential clinical outcomes, another presentation emphasized the importance of bringing together and integrating data from in vitro, in vivo, and in silico models to optimize our ability to accurately predict which drugs are most likely to lead to adverse cardiovascular events in patients. Related to this, a member of the audience brought up an important concern regarding specificity of the variety of assays available to detect cardiovascular toxicity liability, mentioning that sensitivity is typically not the issue. The challenge is in accurately extrapolating these findings in nonclinical models to humans.
A recurring theme throughout many of the talks in this session was that “all models are wrong, but some are useful.” We need to work toward identifying the models and tools that are not very predictive and phase them out to improve specificity without compromising sensitivity. A task that is, of course, much easier said than done, but nonetheless something to continue to work toward.
This blog was prepared by an SOT Reporter. SOT Reporters are SOT members who volunteer to write about sessions and events they attend during the SOT Annual Meeting and ToxExpo. If you are interested in participating in the SOT Reporter program in the future, please email SOT Communications Director Michelle Werts.