Authors :
Presenting Author: Lyndsey Anderson, PhD – Praxis Precision Medicines
Kristopher Kahlig, PhD – Praxis Precision Medicines
Brian Hannigan, BS – Praxis Precision Medicines
Marcio Souza, PharmD, MBA – Praxis Precision Medicines
Steven Petrou, PhD – Praxis Precision Medicines
Rationale:
Central to the development of novel treatments is testing of anticonvulsant activity in preclinical seizure models. While various models exist, the predictive validity of each across the spectrum of epilepsy indications is less clear. The Praxis Analysis of Concordance (PAC) framework was recently developed to assess the translational concordance of common preclinical seizure models for focal onset seizures (FOS) and generalized epilepsies. Here, we sought to establish concordance between commonly used preclinical models and broad developmental and epileptic encephalopathies (DEEs), thus further extending our work to capture human genetic epilepsies.
Methods:
Performance of 32 approved ASMs across established preclinical seizure and genetic epilepsy models was evaluated based on reported TD50 and ED50 values. Protective index values were calculated and a weighted scale representing relative antiseizure efficacy was used to grade preclinical ASM response for each ASM in each seizure and genetic epilepsy model. ASM clinical use and perceived efficacy were similarly evaluated, and a weighted scale used to grade clinical ASM response for each ASM in each seizure indication. Predictive validity of preclinical models was assessed using the Praxis Analysis of Concordance (PAC) scoring matrix. Concordance scores were assigned spanning the spectrum from complete discordance (-1) to complete concordance (1) between preclinical and clinical ASM responses. Scores were then summed and normalized to generate a global translational concordance score.
Results:
Findings from our PAC-DEE framework revealed variable levels of concordance between commonly used preclinical seizure models and the broad spectrum of DEEs. Preliminary analyses suggest that certain preclinical seizure models may exhibit predictive validity for specific DEEs. In general, genetic models demonstrated greater concordance than preclinical seizure models with DEEs.
Conclusions:
Using the newly developed PAC framework, findings from this study extend our insights into the predictive validity of commonly used seizure models across broad DEEs and underscore the importance of appropriate model selection in ASM drug discovery efforts. Together with previous findings in FOS and generalized epilepsy, we anticipate findings from the PAC-DEE extension to have important implications for accelerating research efforts and promoting efficient resourcing for novel ASM drug development across the full spectrum of human epilepsies.
Funding:
Praxis Precision Medicines