Associate Director for Pharmacology and Toxicology US Food and Drug Administration, Center for Drug Evaluation and Research Silver Spring, Maryland, United States
Targeted protein degradation (TPD) therapies, such as Proteolysis-Targeting Chimeras (PROTACs) or molecular glues, represent a relatively new category of small molecule therapeutics with a unique risk/benefit profile. This presentation will focus on the regulatory perspectives of targeted TPD therapies for oncology and non-oncology indications and will discuss additional safety considerations from traditional small molecule product development. The risk assessment challenges for these products include the potential for 1) adverse effects of species-specific/ cell type-specific off-target protein degradation, 2) adverse effects of co-opting the normal function of the targeted E3 ligase, and 3) on-target adverse effects to be prolonged, due to the need to resynthesize the degraded target. Consideration of the assays and methodologies to assess the pharmacological and toxicologic profile of the targeted protein degrader are important to establish a meaningful nonclinical assessment to ensure clinical safety. These may be additional assessments (e.g., in vivo animal studies, in vitro assays, in silico analyses) needed to identify and mitigate human risk. While TPD therapies have great potential, many regulatory challenges remain to ultimately balance safety and risk identification with the potential for clinical benefit.
