Pfizer and Arvinas Highlight ARV-471, a Novel Oral PROTAC Estrogen Receptor Degrader, Demonstrating Up to 90% ER Degradation and 41% Clinical Benefit Rate in ER+ Breast Cancer

November 21, 2021 /BioValleyBIOON/ --Pfizer(Pfizer) and Arvinas, Inc. recently announced that they will present at the 2021 San AntonioBreast CancerUpdated Safety and Efficacy Data from a Phase 1 Dose-Escalation Study of ARV-471 Presented at the SABCS.ARV-471 is a novel oral estrogen receptor (ER)-targeted PROTAC protein degrader., jointly developed by Pfizer and Arvinas, for the treatment ofEstrogen Receptor Positive/Human Epidermal Growth Factor Receptor 2 Negative (ER+/HER2-) Breast CancerPatient.

ARV-471 is an orally bioavailable PROTAC® protein degrader that specifically targets and degrades estrogen receptor (ER). ER is a well-known disease driver in the majority of breast cancers.. In preclinical studies,ARV-471 Demonstrates Near-Complete ER Degradation in Tumor Cells, as a single-agent therapy, effectively induced tumor volume reduction in various ER-driven xenograft models. Additionally, both as a single agent and in combination with CDK4/6 inhibitors, it demonstrated superior anti-tumor activity compared to the standard treatment drug fulvestrant.TumorActivity. In July 2021, Pfizer and Arvinas reached a global collaboration worth up to $2.4 billion to jointly develop and commercialize ARV-471. The two parties will equally share global development costs, commercialization expenses, and profits.

This is a multi-center, first-in-human, open-label study evaluating the safety and preliminary efficacy of ARV-471 in treating ER+/HER2- advanced or metastatic breast cancer.TumorActivity. The Phase 1 monotherapy dose escalation adopted a 3+3 design to evaluate ARV-471 in treating premenopausal/postmenopausal female patients. Premenopausal women must receive ovarian suppression therapy. Patients in this study had previously received at least one CDK4/6 inhibitor, at least two endocrine therapies, and were allowed up to three chemotherapies.

As of June 6, 2021, 50 patients received ARV-471 monotherapy dose escalation treatment: daily doses were 30mg (n=3), 60mg (n=3), 120mg (n=7), 180/200mg (n=11), 360mg (n=15), 500mg (n=8), and the maximum dose of 700mg (n=3).The maximum tolerated dose has not been reached, and no dose-limiting toxicity (DLT) has been observed.

A biopsy analysis of 12 pairs of patients receiving daily doses of 30-360mg showed that ER degradation rates reached up to 90% in tumors expressing either wild-type or mutant ER. Analysis was conducted on 34 patients.Clinical Benefit Assessment (Confirmed Complete Response, Partial Response, Stable Disease ≥24 Weeks)，Clinical Benefit Rate (CBR) was 41%As of the data cutoff date, 6 of the 34 patients continued to receive the study drug treatment, including 2 patients who had been receiving treatment for more than 16 months. These patients had measurable disease at baseline and had undergone at least one treatment period.TumorTwo confirmed partial responses were observed among the 28 patients evaluated.

Conclusion: ARV-471 was well tolerated at total daily doses up to 700mg, with no dose-limiting toxicity (DLT).ARV-471 demonstrated potent ER degradation in paired biopsy samples, with encouraging clinical activity observed in patients previously treated with a CDK4/6 inhibitor (CBR=41%).Currently, ARV-471 is being evaluated in the VERITAC Phase 2 monotherapy expansion at doses of 200mg and 500mg once daily.

PROTAC Protein Degraders (Image Source: arvinas.com)

In July 2021, Pfizer and Arvinas reached a global collaboration to develop and commercialize ARV-471. According to the terms of the agreement, Pfizer will pay Arvinas an upfront payment of $650 million, as well as potential milestone payments totaling up to $1.4 billion ($400 million in regulatory approval milestones + $1 billion in commercial milestones). Additionally, Pfizer will make a $350 million equity investment in Arvinas. The total value of the collaboration reaches $2.4 billion. The two companies will equally share global development costs, commercialization expenses, and profits.

Arvinas is a clinical-stage biopharmaceutical company dedicated to improving patients' lives by discovering, developing, and commercializing therapies that degrade disease-causing proteins. Arvinas uses its proprietary PROTAC® Discovery Engine platform to designProteolysis-Targeting Chimeras (PROTAC), or PROTAC® Targeted Protein DegradersThese therapies aim to utilize the body's own natural protein processing system to selectively and efficiently degrade and remove pathogenic proteins. In addition to a robust preclinical pipeline of PROTAC® protein degraders targeting validated and "undruggable" targets, Arvinas has two clinical-stage programs: ARV-110 for the treatment of metastatic castration-resistant prostate cancer, and ARV-471 for locally advanced or metastatic ER+/HER2- breast cancer.

PfizerTumorJeff Settleman, Ph.D., Chief Scientific Officer of R&D, previously stated: "Based on Pfizer's established leadership in breast cancer science and CDK4/6 inhibition, we are excited to collaborate with Arvinas to maximize the potential of...ARV-471, the first PROTAC for breast cancer treatment, shows encouraging early clinical data and has the potential to become a new hormonal backbone therapy for HR+ breast cancer, ranging from adjuvant to metastatic disease treatment."This collaboration complements Pfizer's robust research activities in breast cancer, including several next-generation CDK inhibitors currently in early clinical development."

PROTAC: Utilizing the Natural Protein Processing System - Ubiquitin-Proteasome System (UPS) to Induce Degradation of Pathogenic Proteins

A key component of the human body's natural protein processing system is a large class of proteins called E3 ligases, which recognize mutated and misfolded proteins, or proteins that are no longer needed, and tag them with ubiquitin protein molecules. This ubiquitin tag directs the target proteins to the proteasome, a large intracellular complex that subsequently degrades the tagged proteins into small peptide fragments.The working principle of PROTAC protein degraders is to tightly bind a selected E3 ligase with a specific pathogenic protein, so that it can be ubiquitinated and degraded by the proteasome. After the protein is degraded, PROTAC is released to continue its degradation task.

PROTAC-mediated protein degradation offers several advantages over other methods: (1) the ability to target "undruggable" targets — traditional small-molecule inhibitors need to strongly bind to the target protein, usually at its active site. Since PROTAC protein degraders only need to weakly bind to the target protein to specifically "tag" it, PROTAC degraders can address approximately 80% of currently "undruggable" targets.Proteome.(2) Multiple routes of administration - PROTAC protein degraders that can be administered orally, by injection, or by infusion have been developed according to diseases and needs. (3) Crossing the blood-brain barrier - In preclinical studies, Arvinas, Inc.'s PROTAC protein degraders have successfully crossed the blood-brain barrier, a crucial step in developing treatments for neurodegenerative diseases. (4) Potential for tissue-specific targeting - Unlike other small molecules, the activity of PROTAC degraders can target specific tissues by recruiting E3 ligases expressed only in certain cell lines. (5) Advantages of small molecules - Compared to some other novel modalities, PROTAC protein degraders exhibit broad distribution in vivo and can be manufactured using well-established processes.

ARV-471 Degrades Estrogen Receptor (ER): Average Reduction of 62%, Up to 90% (Click Image to Enlarge)

The estrogen receptor (ER) is the primary driver of hormone receptor (HR)-positive breast cancer, the most common breast cancer subtype. Endocrine therapy is a cornerstone in the treatment of ER+ breast cancer and is used as a monotherapy or combination therapy as the standard of care across various treatment settings. Arvinas and Pfizer are seeking to develop ARV-471 as a potential endocrine therapy.

In December 2020, Phase 1 dose escalation of ARV-471 in patients with locally advanced or metastatic ER+/HER2- breast cancerClinical TrialThe interim data demonstrated the potential of ARV-471 as a novel oral ER-targeted therapy. This study enrolled heavily pretreated patients, all of whom had previously received cyclin-dependent kinase (CDK) 4/6 inhibitor treatment. Despite the advanced stage of their disease and prior extensive treatments, the interim data as of December 2020 indicated that ARV-471 achieved substantial ER degradation and showed encouraging clinical efficacy and tolerability. (Bioon.com)

Source of the original text:ARVINAS AND PFIZER ANNOUNCE UPDATED PHASE 1 DOSE ESCALATION DATA FOR ARV-471 TO BE PRESENTED IN SPOTLIGHT POSTER SESSION AT 2021 SAN ANTONIO BREAST CANCER SYMPOSIUM