NDA Submission of Vepdegestrant (ARV-471) to U.S. FDA: The Beginning of a New Era of PROTAC Degraders

RecommendationsT argeted protein degradation (TPD) technologies includ- ing proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs) are emerging as paradigm-shifting therapeutic strategies for drug discovery.As depicted in Figure 1, the first peptide-based PROTAC was reported by Crews and co-workers in 2001.1,2 The development of PROTAC technology has progressed rapidly over the past two decades.This unique modality is revolutionizing the field of precision medicine, particularly in cancer treatment, completing the process from proof of concept (POC) validation to clinical transformation (Figure 1).[3][4][5][6][7][8][9][10] Very recently, Arvinas and Pfizer have submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for vepdegestrant (ARV-471), an orally bioavailable PROTAC protein degrader targeting the estrogen receptor (ER), for patients with ESR1-mutated, ER+/HER2-advanced or metastatic breast cancers, according to a press release from Arvinas on June 6, 2025.11 This NDA application is based on positive results from the Phase 3 VERITAC-2 trial, indicating that vepdegestrant is anticipated to be the first FDA-approved PROTAC degrader.Such an exciting milestone marks the beginning of a new era of PROTAC degraders, tremendously inspiring PROTAC technology development and its growing impact on drug discovery and clinical trials.As alternatives to traditional small molecule inhibitors, PROTACs are a novel class of molecules that work by selectively degrading disease-causing their function.[12][13][14][15][16][17][18] PROTACs represent a truly transformative approach to drug discovery and belong to the family of small molecule chemical inducers of proximity (CIPs).19,20 These heterobifunctional molecules consist of three components, including a binder for the protein-of-interest (POI), a binder for the E3 ligase, and a connecting linker.PROTACs induce the formation of a ternary complex of POI-PROTAC-E3, resulting in polyubiquitination and proteasomal degradation of the POI by hijacking inherent ubiquitin-proteasome system (UPS) in the human body (Figure 2A).PROTACs offer several attractive advantages compared to small molecule inhibitors.2,7,8,12,16,17 The most unique feature of PROTACs is that they induce POI degradation at a substoichiometric amount, acting as chemical catalysts.PROTACs take an "event-driven" mode instead of the "occupancy-driven" mode by small molecules inhibitors.PROTACs can thus mitigate the off-target effects of small molecular inhibitors with high systematic exposure to make sure sufficient effect.PROTACs take effect by eliminating the POI rather than mere inhibition like inhibitors.Thus, ligands