Pfizer and Arvinas Announce $2.4 Billion Global Collaboration to Develop Oral PROTAC Protein Degrader ARV-471 for ER+ Breast Cancer

PROTAC protein degrader (Image source: arvinas.com)

July 22, 2021 /BioonBIOON/ --Pfizer(Pfizer) and Arvinas recently announced a global collaboration to develop and commercializeARV-471. This is an investigationalOral PROTAC Estrogen Receptor Protein Degrader。Estrogen receptor (ER) is the majority ofBreast cancerWell-Known Disease Drivers. Currently, ARV-471 is undergoing a Phase 2 dose expansion`Clinical Trial`, indicated for the treatment of patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) locally advanced or metastatic breast cancer.

Under the terms of the agreement, Pfizer will pay Arvinas a $650 million upfront payment, along with potential milestone payments totaling up to $1.4 billion ($400 million in regulatory approval milestone payments + $1 billion in commercial milestone payments). Additionally, Pfizer will make a $350 million equity investment in Arvinas.The total collaboration value reached $2.4 billion.. The two companies will equally share global development costs, commercialization expenses, and profits.

PfizerTumorDr. Jeff Settleman, Chief Scientific Officer of Research & Development, stated: “Building on Pfizer’s established leadership in breast cancer science and CDK4/6 inhibition, we are pleased to partner with Arvinas to maximize the potential of ARV-471, the first PROTAC for breast cancer, which has demonstrated encouraging early clinical data and holds the potential to become a new backbone endocrine therapy for HR+ breast cancer, from the adjuvant setting to metastatic disease. This collaboration complements Pfizer’s robust research activities in breast cancer, including our multiple next-generation CDK inhibitors currently in early clinical development.”

Arvinas is a clinical-stage biopharmaceutical company dedicated to improving patients' lives through the discovery, development, and commercialization of therapies that degrade disease-causing proteins. Arvinas uses its proprietary PROTAC® Discovery Engine platform to design proteolysis-targeting chimeras (Proteolysis-Targeting Chimeras, PROTAC), also known asPROTAC® Targeted Protein Degrader, these therapies aim toHarnessing the body's endogenous protein degradation machinery to selectively and efficiently degrade and eliminate disease-causing proteins.. In addition to a robust preclinical pipeline of PROTAC® protein degraders targeting both validated and "undruggable" targets, Arvinas also 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.

PROTAC Protein Degraders: Utilizing the Ubiquitin-Proteasome System to Induce Degradation of Disease-Causing Proteins (Click Image to Enlarge)

A key component of the human body's endogenous protein processing system is a large class of proteins known asE3 ligase, it recognizes mutated and misfolded proteins, or proteins that are no longer needed, and uses`Ubiquitin Protein Molecular Marker`Them. This ubiquitin tag directs the target protein intoProteasome, the proteasome is a large intracellular complex that subsequently degrades tagged proteins into small peptides.PROTAC protein degraders function by tightly binding a selected E3 ligase to a specific disease-causing protein, thereby enabling it to be ubiquitinated and subsequently degraded by the proteasome.。After the protein is degraded, the PROTAC is released to continue its degradation task.

PROTAC-mediated protein degradation offers several advantages over other approaches: (1)Capable of targeting "undruggable" targets——Traditional small-molecule inhibitors require strong binding to target proteins, typically at their active sites. Since PROTAC protein degraders only require weak binding to target proteins to specifically "tag" them, PROTAC degraders can address approximately 80% of currently "undruggable" targets.`Proteome`。（2）Multiple Routes of Administration——Based on disease indications and clinical requirements, develop PROTAC protein degraders that can be administered via oral, injection, or infusion routes. (3)Crossing the Blood-Brain Barrier——In preclinical studies, Arvinas’s PROTAC protein degrader has successfully crossed the blood-brain barrier, marking a critical step in the development of therapeutics for neurodegenerative diseases. (4)Tissue-Specific Targeting Potential——Unlike other small molecules, the activity of PROTAC degraders can be targeted to specific tissues by recruiting E3 ligases expressed exclusively in a specific cell line. (5)Benefits of Small Molecules- Compared with other novel modalities, PROTAC protein degraders exhibit broad in vivo distribution 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 subtype of breast cancer. Endocrine therapy is a cornerstone of treatment for ER+ breast cancer and is used as monotherapy or in combination 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, Data from the Phase 1 Dose Escalation of ARV-471 in Patients with Locally Advanced or Metastatic ER+/HER2- Breast CancerClinical Trialinterim data demonstrated the potential of ARV-471 as a novel oral ER-targeted therapy. The study enrolled heavily pretreated patients, all of whom had previously received cyclin-dependent kinase (CDK) 4/6 inhibitor therapy. Despite the patients having advanced disease and extensive prior treatment, interim data as of December 2020 indicated that,ARV-471 induces substantial degradation of ER and demonstrates encouraging clinical efficacy and tolerability.

Currently, ARV-471 is being evaluated for the treatment of metastatic breast cancer in a Phase 1 dose-escalation study, a Phase 1b combination study (with the CDK4/6 inhibitor Ibrance), and a Phase 2 monotherapy dose-expansion study (VERITAC). Arvinas and Pfizer expect to initiate two additional ARV-471 trials in 2021, including a second Phase 1b combination study (with everolimus) and a neoadjuvant therapy trial. In 2022, Arvinas and Pfizer anticipate launching a Phase 3 study for the treatment of metastatic breast cancer, including combination therapy with Ibrance, followed by a pivotal study in early breast cancer. Previously, in 2018, Arvinas and Pfizer announced a separate research collaboration and license agreement to discover and develop drug candidates utilizing Arvinas' PROTAC technology. (Bioon.com)