Utilization of phase I studies for target validation of first-in-class drugs

• Published in: Drug discovery today 2024-11, Vol.29 (11), p.104200, Article 104200
• Main Authors: Kawabe, Yoshiki, Himori, Motomu, Watanabe, Yoshinori, Davis, Jacob, Hamada, Hiromasa
• Format: Article
• Language: English
• Subjects: Animals; Clinical Trials, Phase I as Topic - methods; drug development; Drug Development - methods; Drug Discovery - methods; first-in-class drugs; functional changes necessary for therapeutic effect; Humans; phase I; proof of concept; target validation
• ISSN: 1359-6446; 1878-5832; 1878-5832
• DOI: 10.1016/j.drudis.2024.104200

•Two target validation approaches are emerging as useful in phase I (P1): P1-PIV and P1-FCTE.•P1-PIV uses primary endpoints in pivotal clinical studies (PIV).•P1-FCTE uses functional changes necessary for therapeutic effects (FCTE).•Their benefits and challenges are compared with those of the conventional P1 approach. This review discusses the growing importance of target validation within phase I (P1) trials as a new trend in drug development, especially in establishing proof of concept (POC) for first-in-class drugs. The paper describes two approaches: the P1-PIV approach, which directly evaluates the primary endpoint for a pivotal clinical study to confirm therapeutic effects during P1, and the newly introduced P1-FCTE, which assesses functional changes necessary for therapeutic effect as a novel target validation milestone in P1. By providing practical examples of first-in-class drugs, we compare the benefits, costs, hurdles and applicable therapeutic areas of these approaches. Finally, we discuss the potential of these novel approaches to facilitate POC success, shorten development timelines and ultimately increase drug discovery success rates.