Human Cell-Based in vitro Phenotypic Profiling for Drug Safety-Related Attrition

Area of Science:

• Pharmacology
• Toxicology
• Biotechnology

Background:

• Drug safety is paramount, yet 20-30% of clinical trials fail due to unexpected toxicities.
• Current safety assessments heavily rely on animal testing, which has limitations in predicting human responses.
• There is a critical need for improved, human-relevant methods to assess drug safety early in development.

Purpose of the Study:

• To highlight the value of large-scale human cell-based phenotypic profiling for drug safety.
• To discuss the integration of new approach methodologies (NAMs) into drug discovery pipelines.
• To explore the use of Adverse Outcome Pathway (AOP) frameworks for improved safety decisions.

Main Methods:

• Utilizing human primary and induced pluripotent stem cell-derived cells in various in vitro formats.
• Developing in vitro toxicity signatures through phenotypic profiling and analysis of reference datasets.
• Applying Adverse Outcome Pathway (AOP) frameworks to integrate data from diverse platforms.

Main Results:

• Human cell-based phenotypic profiling offers a more clinically relevant approach to de-risking drug candidates.
• Advanced cellular systems like organoids and organs-on-a-chip show promise but face slow adoption.
• Learnings from cell-based assays and reference data aid in creating robust in vitro toxicity signatures.

Conclusions:

• Large-scale human cell-based phenotypic profiling is valuable for incorporating human-specific biology into drug safety assessments.
• Adverse Outcome Pathway (AOP) frameworks can enhance safety-related decision-making in early drug discovery.
• Adoption of these human-based in vitro platforms is crucial for reducing safety-related attrition in drug development.