September 23, 2023

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Pfizer new oral PROTAC protein degradation agent ARV-471

Pfizer new oral PROTAC protein degradation agent ARV-471: The degradation rate of ER reaches 90%, and the clinical benefit rate is 41%!


Pfizer new oral PROTAC protein degradation agent ARV-471: The degradation rate of ER reaches 90%, and the clinical benefit rate is 41%!

Pfizer and Arvinas recently announced that they will announce updated safety and efficacy data from a Phase 1 dose escalation study of ARV-471 at the San Antonio Breast Cancer Symposium (SABCS) in 2021 .

ARV-471 is a new oral estrogen receptor (ER) targeted proteolytic targeted chimera (PROTAC) protein degradation agent , jointly developed by Pfizer and Arvinas, for the treatment of estrogen receptor positive/human epidermal growth Factor receptor 2 negative (ER+/HER2-) breast cancer patients.

ARV-471 is an oral bioavailable PROTAC® protein degrading agent that specifically targets and degrades the estrogen receptor (ER). ER is a well-known disease driver in most breast cancers .

In preclinical studies, ARV-471 showed nearly complete ER degradation in tumor cells . As a monotherapy, it effectively induces tumor size reduction in multiple ER-driven xenograft models.

It is also used as a monotherapy and with CDK4/ 6 When the inhibitor is used in combination, it shows superior anti- tumor activity compared with the standard treatment drug fulvestrant .

In July 2021, Pfizer and Arvinas reached a global cooperation totaling US$2.4 billion to jointly develop and commercialize ARV-471.

Both parties will equally share global development costs, commercialization costs and profits.

The abstract titled at the SABCS meeting is: Research on the human safety and activity of the new PROTAC® estrogen receptor degrading agent ARV-471 in ER+/HER2-locally advanced or metastatic breast cancer
This is a multi-center, first human, open-label study that is evaluating the safety and preliminary anti- tumor activity of ARV-471 in the treatment of ER+/HER2- advanced or metastatic breast cancer .

The phase 1 single-agent dose escalation adopted a 3+3 design to evaluate ARV-471 in the treatment of premenopausal/postmenopausal female patients.

Premenopausal women must receive ovarian suppression therapy.

The patients in this study have previously received at least one CDK4/6 inhibitor, at least two endocrine treatments, and a maximum of three chemotherapy sessions.

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

Analysis of 12 pairs of biopsies performed on patients taking 30-360 mg per day showed that in tumors expressing wild-type or mutant ER, the degradation rate of ER was as high as 90%.

34 patients were evaluated for clinical benefit (confirmed complete remission, partial remission, stable disease ≥24 weeks) , and the clinical benefit rate (CBR) was 41% .

As of the data cutoff date, 6 of the 34 patients continued to receive study drug treatment, including 2 patients who received treatment for more than 16 months of palliative treatment.

Two confirmed partial remissions were observed in 28 patients with baseline measurable disease and at least one tumor evaluation during the treatment period .

Conclusion: ARV-471 is well tolerated at a total daily dose of up to 700 mg, without dose limiting toxicity (DLT).

ARV-471 showed strong ER degradation in paired biopsy samples, and encouraging clinical activity was observed in patients who had previously received CDK4/6 inhibitors (CBR=41%) .

Currently, ARV-471 is being evaluated in the VERITAC Phase 2 monotherapy expansion, once a day, at doses of 200 mg and 500 mg.

Pfizer new oral PROTAC protein degradation agent ARV-471PROTAC protein degradation agent (picture source:


In July 2021, Pfizer and Arvinas reached a global cooperation to develop and commercialize ARV-471.

Under the terms of the agreement, Pfizer will pay Arvinas an upfront payment of US$650 million and a potential total of up to US$1.4 billion in milestone payments (US$400 million in regulatory approval milestone payments + US$1 billion in commercial milestone payments).

In addition, Pfizer will make a US$350 million equity investment in Arvinas.

The total amount of cooperation reached 2.4 billion US dollars. The two companies will share the global development costs, commercialization costs and profits equally.

Arvinas is a clinical-stage biopharmaceutical company dedicated to improving the lives of patients by discovering, developing and commercializing treatments that degrade disease-causing proteins.

Arvinas uses its proprietary PROTAC® Discovery Engine platform (PROTAC® Discovery Engine platform) to design Proteolysis-Targeting Chimeras (PROTAC), or PROTAC® targeted protein degradation agents .

This type of therapy aims Using the body’s own natural protein processing system to selectively and efficiently degrade and remove disease-causing proteins.

In addition to developing a powerful preclinical pipeline of PROTAC® protein degradants for validated targets and “non-drug-resistant” targets, Arvinas also has two clinical phase projects: ARV-110 for the treatment of metastatic castration resistant prostate Cancer, ARV-471 treats locally advanced or metastatic ER+/HER2- breast cancer.

Dr. Jeff Settleman, Chief Scientific Officer of Pfizer’s Oncology R&D, previously stated: “Based on Pfizer’s established leadership in breast cancer science and CDK4/6 inhibition, we are delighted to work with Arvinas to maximize the use of ARV-471.

PROTAC, the first treatment for breast cancer, has encouraging early clinical data and has the potential to become a new hormone therapy backbone therapy for HR+ breast cancer, ranging from adjuvant therapy to metastatic disease treatment .

This partnership complements Pfizer Strong research activities in breast cancer include a variety of new-generation CDK inhibitors that we are currently in early clinical development.”

Pfizer new oral PROTAC protein degradation agent ARV-471PROTAC: Utilize the natural protein processing system-ubiquitin-proteasome system (UPS) to induce the degradation of disease-causing proteins


A key component of the human body’s natural protein processing system is a large class of proteins called E3 ligases, which recognize mutations and misfolded proteins, or proteins that are no longer needed, and label them with ubiquitin protein molecules.

This ubiquitin tag introduces the target protein into the proteasome, which is a large intracellular complex that then degrades the labeled protein into small peptides.

The working principle of PROTAC protein degradation agent is to tightly bind a selected E3 ligase to a specific disease-causing protein so that it can be labeled with ubiquitin and degraded by the proteasome.

After the protein is degraded, PROTAC is released to continue its degradation task.

PROTAC-mediated protein degradation has many benefits compared with other methods:

(1) It can target “non-drugable” targets—traditional small molecule inhibitors need to bind strongly to the target protein, usually at its active site. Since the PROTAC protein degradation agent only needs to weakly bind to the target protein to specifically “label” it, the PROTAC degradation agent can solve about 80% of the current “undruggable” proteome .

(2) Multiple routes of administration-According to diseases and needs, PROTAC protein degradation agents that can be administered by oral, injection, and infusion have been developed.

(3) Crossing the blood/brain barrier-In pre-clinical studies, the PROTAC protein degradation agent of Arvinas has successfully crossed the blood-brain barrier, which is a key step in the development of drugs for the treatment of neurodegenerative diseases.

(4) Tissue-specific targeting potential-unlike other small molecules, the activity of PROTAC degradation agents can target specific tissues by recruiting E3 ligase expressed only in a certain cell line.

(5) The benefits of small molecules-Compared with other new methods, PROTAC protein degradation agents are widely distributed in the body and can be manufactured using well-known processes.

Pfizer new oral PROTAC protein degradation agent ARV-471ARV-471 degrades estrogen receptor (ER): an average reduction of 62%, up to 90% (click on the picture to see a larger image)


Estrogen receptor (ER) is the main driver of hormone receptor (HR)-positive breast cancer, which is the most common breast cancer subtype.

Endocrine therapy is one of the mainstays of ER+ breast cancer treatment, and is used as monotherapy or combination therapy as the standard care regimen in multiple treatment settings.

Arvinas and Pfizer are seeking to develop ARV-471 as a potential endocrine therapy.

In December 2020, the interim data from the Phase 1 dose-escalation clinical trial of ARV-471 for the treatment of locally advanced or metastatic ER+/HER2- breast cancer patients showed the potential of ARV-471 as a new type of oral ER targeted therapy.

This study enrolled patients who had previously received multiple regimens (heavily pretreated), and all patients had been treated with cyclin-dependent kinase (CDK) 4/6 inhibitors.

Although these patients have advanced disease and have received a large number of regimens before, as of December 2020, interim data show that ARV-471 can promote a large amount of ER degradation and shows encouraging clinical efficacy and tolerability .






(source:internet, reference only)

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