Considerations for infection risks identified in target safety review

Area of Science:

• Pharmacology
• Toxicology
• Drug Development

Background:

• Target Safety Review (TSR) aims to predict on-target safety risks, but nonclinical toxicity studies have limitations in predicting clinical safety.
• Understanding the predictive accuracy of nonclinical studies for clinical infection risks is essential for safe therapeutic agent development.

Purpose of the Study:

• To investigate the predictive capability of nonclinical toxicity studies for clinical infection risks identified in TSR.
• To analyze the relationship between nonclinical immune-related toxicities and clinical infection risks for various drug targets.

Main Methods:

• Utilized the OFF-X database to identify targets and drugs associated with infection risks.
• Applied filters including "drug alert," "on-target," "causality with severity," "class score," and "evidence levels" to focus on biologics approved by PMDA.
• Extracted immune-related findings from nonclinical studies and clinical infection risks from regulatory documents.

Main Results:

• Nonclinical studies accurately predicted immune-related toxicities for CD20, TNF-alpha, and IL-6R inhibitors (e.g., B cell depletion, thymus atrophy).
• For IL-17, IL-23, and IL-1beta inhibitors, nonclinical studies did not consistently predict observed clinical infection risks.
• The predictive power of nonclinical studies for specific mechanisms of action and infection risks was found to be limited.

Conclusions:

• Nonclinical toxicity studies offer insights into potential on-target infection risks but have limitations in predicting clinical outcomes.
• Early identification and mitigation of risks through TSR and understanding drug mechanisms of action are vital for safe drug development.