ARV-471: TARGETING THE ESTROGEN RECEPTOR
Developing an Oral PROTACTM Protein Degrader for ER+ Metastatic Breast Cancer
Arvinas is developing a novel ER (estrogen receptor) PROTACTM (proteolysis-targeting chimera) protein degrader for the targeted degradation of ER alpha with the goal of reducing its levels in cancer cells and providing greater clinical benefits to patients. Approximately 80% of all newly diagnosed cases of breast cancer are ER alpha-positive (ER+). While approved treatments have produced some success in this patient population, many ER+ breast cancers become resistant to therapy.
Today, fulvestrant (Faslodex®)—a selective estrogen receptor degrader (SERD)—is the standard of care for ER+ metastatic breast cancer post-anti-estrogen therapy. While fulvestrant has validated the importance of ER degradation as a therapeutic intervention, up to 50% of ER can remain when compared to baseline levels after six months of treatment with fulvestrant. Unlike fulvestrant, which is administered via intramuscular injection, Arvinas’ lead ER PROTAC protein degrader, ARV-471, is being developed for the treatment of women with ER+ metastatic breast cancer as an oral therapy.
This program is wholly owned by Arvinas.
In preclinical studies ARV-471 has shown promising activity as a degrader of ER, demonstrating superior tumor growth inhibition compared to fulvestrant, and potency as both a single agent and as a combination therapy with CDK4/6 inhibitors.
Select In Vitro Data
Select In Vivo Data
In a patient-derived xenograft (PDX) model from an ESR1 mutant patient, an oral dose of ARV-471 inhibited tumor growth by 99% at 10 milligrams per kilogram (mpk) and 106% at 30 mpk (below). This suggests ARV-471’s potential as a superior inhibitor of tumor growth compared to fulvestrant.
CDK4/6 inhibitors, such as palbociclib (Ibrance®), are often used in combination with fulvestrant. In the study below, comparing ARV-471 in combination with palbociclib versus fulvestrant in combination with palbociclib, ARV-471/palbociclib demonstrated superior tumor shrinkage (131% TGI) in comparison to fulvestrant/palbociclib (108% TGI).
Arvinas expects to initiate a Phase 1 study with ARV-471 in Q3 of 2019 for women with locally advanced or metastatic ER+ positive / HER2- negative breast cancer.