Recently, Pfizer and Arvinas announced a partnership to develop and commercialize ARV-471, an oral PROTAC estrogen receptor protein degrader under development. Estrogen receptor (ER) is a well-known disease driver in most breast cancers. Currently, ARV-471 is under a phase 2 dose expansion clinical trial for the treatment of locally advanced or metastatic breast cancer patients with estrogen receptor positive/human epidermal growth factor receptor 2 negative (ER+/HER2-).
Under the terms of the agreement, Pfizer will pay Arvinas an advance of $650 million and potentially up to $1.4 billion in milestone payments ($400m in regulatory approval milestone payments + $1 billion in commercial milestone payments). In addition, Pfizer will make a $350 million equity investment in Arvinas. The total amount of cooperation reached 2.4 billion US dollars. The two companies will share global development costs, commercialization costs, and profits equally.
Dr. Jeff Settleman, Pfizer’s chief scientific officer of oncology research and development, said, “Based on Pfizer’s established leadership in breast cancer and CDK4/6 inhibition, we are pleased to work with Arvinas to maximize the use of ARV-471, which is the first PROTAC for breast cancer, with encouraging early clinical data, and has the potential to become a new backbone hormone therapy for HR+ breast cancer. From adjuvant therapy to the treatment of metastatic diseases. This partnership complements Pfizer’s research activities in breast cancer, including a variety of new-generation CDK inhibitors that are currently in the early stages of clinical development. “
PROTAC: degradation of pathogenic proteins induced by natural protein processing system—ubiquitin-proteasome system (UPS)
A key component of the human 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 mark them with ubiquitin protein molecules. The ubiquitin tag transduces the target proteins into the proteasome, a large intracellular complex that then degrades the labeled proteins into small peptides. PROTAC protein degraders work by tightly binding a selected E3 ligase to a specific disease-causing protein so that it can be labeled by ubiquitin and degraded by proteasomes. After the protein is degraded, PROTAC is released to continue its degradation duty.
PROTAC-mediated protein degradation has several benefits over other methods:
- Be able to target “undruggable” targets—traditional small molecular inhibitors need to strongly bind to the target protein, usually with its active site. As PROTAC protein degraders can specifically label it only by weakly binding to the target protein, it can resolve about 80% of the undruggable proteome at present.
- Multiple administration approaches—PROTAC protein degraders that can be administered by oral administration, injection, and infusion are developed according to diseases and needs.
- Crossing the blood/brain barrier—in preclinical studies, Arvinas’ PROTAC protein degrader has successfully crossed the blood-brain barrier, which is a key step in the development of drugs for the treatment of neurodegenerative diseases.
- Tissue specific targeting potential—unlike other small molecules, PROTAC degraders can target specific tissues by recruiting E3 ligases expressed only in one cell line.
- Benefits of small molecules— PROTAC protein degraders are widely distributed in the body and can be manufactured using conventional processes.
Estrogen receptor (ER) is the main driver of hormone receptor (HR) positive breast cancer, the most common subtype of breast cancer. Endocrine therapy is a pillar therapy for ER+ breast cancer and is used as a monotherapy or combination therapy as a standard care regimen in a variety of treatment environments. Arvinas and Pfizer are exploring to develop ARV-471 as a potential endocrine therapy.
Mid-term data from the phase 1 dose increasing clinical trial of ARV-471 in patients with locally advanced or metastatic ER+/HER2- breast cancer released in December 2020 showed the potential of ARV-471 as a new oral ER targeted therapy. The study included patients who had been heavily pretreated, all of whom had been treated with cyclin-dependent kinase (CDK) 4 and 6 inhibitors. Although these patients have advanced diseases and have previously received a large number of regimens, mid-term data as of December 2020 show that ARV-471 can promote significant degradation of ER, showing encouraging clinical efficacy and tolerance.
At present, ARV-471 is under evaluation of the treatment of metastatic breast cancer in phase 1 dose increment study, phase 1b combination study (in combination with CDK4/6 inhibitor Ibrance), and phase 2 single drug dose expansion study (VERITAC). Arvinas and Pfizer are expected to launch two additional ARV-471 trials in 2021, including a second phase 1b joint study (in conjunction with Ivimus) and a neoadjuvant therapy trial. In 2022, Arvinas and Pfizer are expected to launch phase 3 studies for the treatment of metastatic breast cancer, including combination therapy with Ibrance, followed by key studies for early breast cancer.