Nonclinical Safety Assessment of Targeted Protein Degraders: An Industry Perspective

Registration is required for this free webinar 

Hosted by the SOT Women in Toxicology Special Interest Group and Drug Discovery Specialty Section 

Part 1 of the WIT-DDTSS Protein Degrader Webinars

The nonclinical toxicology assessment for protein degraders—either molecular glues or heterobifunctional targeted protein degraders (TPDs)—shares the same principles as for classical small molecules with some additional considerations due to the modality. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium) convened a Protein Degrader Working Group to benchmark the current preclinical safety assessment practices for TPDs; a companion group addressed current ADME practices. The aim of the surveys was to aid in more rigorous, effective, and swift nonclinical safety and ADME assessments of TPDs being developed for treatment of human disease. This webinar will discuss the survey findings regarding current practices across the industry for in vitro and in vivo nonclinical safety assessments for heterobifunctional TPDs. Approaches for selecting a toxicologically relevant species for in vivo studies will also be discussed. 

TPDs, specifically bifunctional protein degraders, consist of two linked ligands for a protein of interest and an E3 ligase, resulting in molecules that largely violate accepted physicochemical limits (e.g., Lipinski's Rule of Five) for oral bioavailability. In 2021, the IQ Consortium Degrader DMPK/ADME Working Group undertook a survey of 18 IQ member and nonmember companies working on degraders to understand whether the characterization and optimization of these molecules were different from any other beyond the Rule of Five (bRo5) compounds. Additionally, the working group sought to identify pharmacokinetic (PK)/absorption, distribution, metabolism, and excretion areas in need of further evaluation and where additional tools could aid in more rapid advancement of TPDs to patients. An overview of the survey results will be shared in this webinar. Based on the survey results, the Degrader DMPK/ADME Working Group concluded that TPD evaluation does not fundamentally differ from other bRo5 compounds but requires some modification compared with traditional small molecules and proposes a generic workflow for PK/ADME evaluation of bifunctional TPDs. 

Speakers 

Jessica Sims, PhD, DABT, Genentech 

Laurie Volak, PhD, Rapport Therapeutics