Discussion
gout, human disease
GOUT
These data demonstrate the utility of advanced These data are timely given that the febuxostat FDA warning was recently challenged by the FAST clinical trial (EudraCT 2011-001883-23) [This study also extends earlier work examining vascular xanthine oxidase [Our study has several limitations. Many mechanisms likely contribute to cardiovascular risk, and the role of chemical motifs or causal pathways for the 33 test articles carrying FDA-labeled cardiovascular risk remain unknown. Thus, we took an unbiased approach to determine if cardiovascular signaling pathways regulated by febuxostat may overlap with pathways modulated by drugs with known cardiovascular risk. Regardless, it is critical that future work interrogate pathways we identified to evaluate their correlation to cardiovascular risk. Additionally, compounds were only evaluated in the context of an atheroprone environment, which is more similar to the CARES rather than the FAST trial; however, these data suggest this platform should be used towards that end in future work. Despite these limitations, we suggest these data both support CARES while providing an excellent platform to better understand both FAST trial outcomes and novel medications under development in future work.In summary, comparing the transcriptomic response of novel drug entities within advanced human disease model systems could provide insight into potential liabilities that may not otherwise be uncovered until large and late-stage clinical trials are conducted. This potential utility is demonstrated here using the FAST-CARES trial inspired controversy over FDA cardiovascular risk labelling of the gout medication febuxostat. Due to febuxostat-mediated signaling within human SMCs in a pattern similar to other drugs FDA-labeled for heightened cardiovascular risk, this model supports the FDA warning and further suggests that this liability may be related to chemical structure rather than on-target activity. Results of this study also support the promise of developing and utilizing new drug discovery tools to uncover potential risk earlier in the drug development process and could help enable best-in-class and first-in-class future therapeutics.