Target safety assessmentの実施及び開発戦略事例の共有

抄録

Target safety assessment (TSA) is performed at an early stage in drug discovery to estimate what kind of on-target toxicity might occur in normal tissues, and to determine what kind of non-clinical safety assessments would be needed going forward.

The main purpose of a TSA is to identify potential toxicities early so as to avoid the risk of dropout in later stages. Three important points must be considered when performing TSA: 1) information retrieval, 2) species selection, and 3) non-clinical safety assessment strategy suggestion. Information retrieval is the most important step in assessing potential risk. Target information can be obtained from literature, public databases, and in-house databases, and licensed software is useful for quickly sorting through vast amounts of such data when timelines are limited. Since public databases do not have enough information about target expression in various organs/tissues, a TSA relies on the in-house data. In some cases, knockout mice are used to obtain proof of concept. In particular for small molecule, not only metabolite profile/exposure level, but also pharmacological relevancy (expression, potency, pharmacodynamics) is important for non-clinical species selection. When selecting a species for a toxicity study, pharmacological relevancy should be experimentally confirmed by experiments for each project. Moreover, although information retrieval can be outsourced, the non-clinical safety assessment strategy must always be prepared internally by those familiar with the company’s drug discovery strategy. Altogether, TSA is accomplished through a review of public domain information and by leveraging internal company expertise.

In this presentation, we share our TSA strategies and give examples of how we apply TSA to non-clinical safety assessment.