Implementation of Target Safety Review into Drug Discovery

抄録

The value of exploratory non-clinical safety evaluation is to decrease safety-related attrition through a focus on candidate quality to provide safe therapeutics for people. As a part of this value, Takeda Discovery Toxicology team is providing a comprehensive assessment of the potential safety liabilities associated by target modulation through the Target Safety Review (TSR) to all projects at Project Start. The TSR includes biological information (e.g., biology, homology, and expression levels in human/animals), on-target safety liabilities (e.g., disease association, transgenic/knockout animal phenotype, and clinical competitors), off-target safety liabilities (e.g., modality-based information), and risk assessment strategy (e.g., potential safety biomarkers and decision flow). The potential adverse outcomes of exaggerated pharmacology associated with a specific target modulation are ranked, and safety risk assessment strategy will be generated to include experimental safety investigations at early project stage. Some examples are described here. Lipase X was a project for NASH indication. A number of potential systemic liabilities had been reported in literatures. On the other hand, since the TSR did not identify any specific risks for liver, PJ team modified their strategy from general small molecule lipase X inhibitor to identifying liver-selective lipase X inhibition by new modality. Kinase Y was also identified for NASH indication. There were strong links to potential hepatotoxicity (including extremely rapid hepatic tumor development in KO animals) identified in TSR. Although TSR itself doesn’t make Go/No-go decision generally, Takeda Discovery Toxicology team recommended not to move forward with this target in this case because there were limited/no good approaches to definitively derisk the liver tumor potential.