BackVepdegestrant (ARV-471)*
Vepdegestrant is an investigational compound. Its safety and efficacy have not been established. * Vepdegestrant is being co-developed with Arvinas.
Overview + Rationale
- Worldwide, female breast cancer has now surpassed lung cancer as the most commonly diagnosed cancer
- ~297,790 women are expected to be diagnosed with invasive breast cancer in the US in 2023
- Metastatic breast cancer accounts for ~6% of newly diagnosed cases
- Estrogen receptor (ER)-positive breast cancers make up ~80% of all breast cancers
- There is an unmet need for patients with ER-positive breast cancers who progress on endocrine therapy and CDK 4/6 inhibitors
- There is a need for novel agents to treat ER+ breast cancer R
In preclinical studies, vepdegestrant:
- Induced ER degradation in multiple ER+ breast cancer cell lines, including MCF-7 cells and ESR1-mutant linesA
- DC50 = 1.8 nM in MCF7 cellsB
Showed promising activity against tumor growth compared to fulvestrantC
- An oral daily dose of vepdegestrant decreased tumor growth by 99% at 10 mpk and 106% at 30 mpk in an ESR1 mutant patient-derived xenograft (PDX) model (shown at right)
In corresponding quantitative western blots, ER was reduced by 79% and 88% in the 10 mpk and 30 mpk arms, respectively, vs. 63% for fulvestrant
A Also tested: MB-134-VI, T47D, D538G, Y537S, ZR-75-1, BT474, CAMA-1; BDC50 = Half-maximal degradation concentration; C Fulvestrant schedule: 2x weekly x2 / q7dx2 nM = nanomolar; mpk = milligrams per kilogram
Mechanism of Action
- PROteolysis TArgeting Chimera (PROTAC) protein degraders are heterobifunctional molecules that consist of a ligand for a target protein (the ER for vepdegestrant) and another ligand, which serves as a substrate for an E3 ubiquitin ligase complex
- Upon binding to ER, the PROTAC vepdegestrant recruits an E3 ubiquitin ligase complex, which marks ER with ubiquitin tags for proteasomal degradation
Stage of Development
ER+/HER2- Metastatic Breast Cancer
Phase 1B Combination
Phase 1B/2 Combination
Phase 1/2 Monotherapy
Phase 2 Monotherapy
Phase 3 Combination
Phase 1B/2 Combination
Phase 1/2 Monotherapy
Phase 2 Monotherapy
Phase 3 Combination
ER+/HER2- Early Breast Cancer
Phase 2 Monotherapy