November 17, 2024
ACT 2024 -- Antibody-drug conjugates (ADCs) have been in development for the treatment of advanced stage cancer for over 25 years. Currently, there are 13 approved ADCs that have been approved by FDA and EU. While there are no specific regulatory guidance documents that provide detailed guidance on the nonclinical development of ADCs, several regulatory guidance documents provide a recommended framework for the nonclinical development of ADCs including: ICH S6(R1) Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals, and ICH S9 Nonclinical Evaluation for Anticancer Pharmaceuticals and the associated Questions and Answers Guidance Document. In May 2023, a new guidance, Generally Accepted Scientific Knowledge (GASK) in Applications for Drug and Biological Products: Nonclinical Information, was published by the FDA. We reviewed all 13 of the publicly available pharmacology and toxicology reviews for approved ADCs. Of these 13 ADCs, 7 were products that utilized microtubulin inhibitor payloads and all of these nonclinical safety programs included either stand-alone, payload-only studies or additional dose groups that were administered the payload alone in rats, dogs and/or nonhuman primates (NHPs). Given the robust assessment of microtubulin inhibitors and similarity in toxicological findings of the microtubulin inhibitors in approved ADC drugs and the literature, we propose that developers of novel ADCs could leverage the GASK guidance to develop a rationale for health authorities to replace the need to conduct characterization of previously characterized microtubulin inhibitors. If accepted by regulators, this could accelerate the nonclinical development of ADCs, reduce animal use and bring life-saving medicines to patients faster.
