Secondary Pharmacology Profiling Panels as a Tool to Predict Clinical Safety Risks

Attrition during clinical development remains a major obstacle for efficient drug discovery. Despite strong preclinical data packages, a substantial proportion of investigational compounds are discontinued in clinical trials due to adverse events. These outcomes are frequently linked to off-target pharmacology – interactions with receptors, ion channels, transporters, or enzymes outside the intended mechanism of action.

In our recent study, published in ACS Pharmacology & Translational Science, we systematically evaluated clinically discontinued compounds using a standardized in vitro secondary pharmacology panel. Our findings suggest that if secondary pharmacology profiling were routinely applied during lead optimization, it could help anticipate safety liabilities at an earlier stage, thereby reducing the likelihood of compounds progressing into clinical trials only to fail later due to adverse events.

Rationale

Traditional toxicology studies remain indispensable in drug development, yet they may not always capture the mechanistic origins of adverse events. Some safety issues arise from subtle interactions at receptors, ion channels, transporters, or enzymes that are not directly assessed in standard toxicology studies. Moreover, toxicology evaluations are typically conducted relatively late in the discovery process, whereas in vitro secondary pharmacology assays can be performed much earlier – even during structure–activity relationship (SAR) exploration – offering an opportunity to identify potential liabilities at a stage when chemical design is still highly flexible.

Our aim was therefore to examine whether secondary pharmacology data, if available earlier, might have provided additional context around the safety challenges that ultimately led to clinical discontinuation.

Methodology

• Compound Set: The dataset comprised 52 compounds discontinued in clinical trials between July 2001 and July 2021 due to safety concerns.
• Secondary Pharmacology Panel: Each compound was screened using the SAFETYscan47 panel, which contains a wide array of molecular targets with established roles in safety pharmacology, including GPCRs, ion channels, nuclear receptors, transporters, and enzymes.
• Analysis: Observed off-target effects were compared with reported adverse events to gain mechanistic insights.

Findings

1. Comprehensive Target Profiling
   The broad scope of the panel allowed for the detection of diverse off-target effects across multiple biological systems, highlighting its utility in generating a more comprehensive pharmacological profile of each compound.
2. Translational Insight
   The panel data offered a framework to better connect molecular pharmacology with observed clinical outcomes, helping to bridge the gap between preclinical findings and clinical observations.
3. Alignment with Clinical Adverse Events
   Several compounds demonstrated activity at targets mechanistically linked to their reported safety issues (e.g., hERG channel interactions correlating with cardiac liabilities).

Implications for Drug Discovery

• Early Risk Assessment
  Integration of secondary pharmacology panels during lead optimization could enable earlier deselection of compounds with safety liabilities.
• Mechanistic Decision Support
  Off-target functional data provide a framework for mechanistic hypotheses linking molecular pharmacology to adverse outcomes, strengthening internal decision-making.
• Regulatory Alignment
  Both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) increasingly emphasize secondary pharmacology data in Investigational New Drug (IND) submissions. Proactive profiling aligns with these expectations and facilitates regulatory dialogue.
• Alignment with New Approach Methodologies (NAMs)
  Secondary pharmacology panels qualify as a New Approach Methodology (NAM), in line with current regulatory guidance and the field’s movement toward reducing reliance on animal studies. By leveraging in vitro and computational approaches, it provides mechanistic insights early in drug discovery while supporting more ethical and sustainable development practices.
• Enabling Predictive Models
  Retrospective datasets, such as the one presented in our work, can inform computational models aimed at predicting off-target risk in silico, extending the utility of the approach beyond laboratory screening.

Conclusion

Our study demonstrates that in vitro secondary pharmacology panels represent a valuable tool for anticipating clinical safety risks. By capturing mechanistically relevant off-target interactions, these assays can reduce the likelihood of late-stage safety failures, improve patient protection, and optimize R&D resource allocation.

Given the findings, the integration of such approaches into early development should be a serious consideration for any drug discovery process to build a more predictive and efficient pipeline.

Read the full publication: DOI: 10.1021/acsptsci.5c00452

Explore SAFETYscan47 target list: SAFETYscan47 LeadHunter Panel (87-1003DR)