Vepdegestrant is a potential “first-in-class” oral PROTAC degrader., leveraging the body's natural protein degradation system to specifically target and degrade estrogen receptors.It has received Breakthrough Therapy Designation from the U.S. FDA for the treatment of pretreated ER-positive, HER2-negative breast cancer. The submission of the vepdegestrant marketing application is primarily based on the positive results of the VERITAC-2 Phase 3 clinical trial. Trial analysis shows,In carryingESR1MutatedHormone Receptor (HR)In the population of patients with positive, HER2-negative breast cancer, vepdegestrantCompared with the active control, it brings a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for patients.These patients experienced disease progression after previously receiving CDK4/6 inhibitors and endocrine therapy.In carryingESR1In the patient population with mutations, the risk of disease progression or death was reduced by 43% (HR=0.57；95% CI：0.42–0.77，P<0.001），vThe PFS of patients in the epdegestrant group reached 5.0 months, while that of patients in the control group was only 2.1 months.In carryingESR1Among all patient subgroups with mutations,vThe benefit profile of epdegestrant is consistent.The data for the secondary endpoint, overall survival (OS), is not yet mature and still requires further evaluation in the study.

Arvinas Chairman, CEO and President John Houston, Ph.D., said, "We look forward to the review results of the new drug application, and we also anticipate that this potential first PROTAC ER degrader approved by the FDA could bring a new treatment option to patients in need."

Speaking of the history of PROTAC molecules, it dates back to Arvinas, Inc.UnitedFounder, Professor Craig Crews of Yale University and his collaborators，A landmark paper published in 2001.Researchers have designed an artificial bifunctional molecule, one end of which can bind to the target protein, while the other end is a peptide capable of binding to E3 ligase. Studies have found that this molecule can pull the target protein close to the E3 ligase, allowing the E3 ligase to tag the target protein with ubiquitin, marking it for degradation within the cell's proteasome system.

“In the future, this method is expected to be used for conditional inactivation of proteins and degradation of disease-causing proteins."The abstract of the paper states. This molecule was also named Protein-Targeting Chimeric Molecule-1, abbreviated as Protac-1."

In 2008, scientists from Professor Crews' team took it a step further by developing a bifunctional small-molecule drug.One end of this small molecule can selectively bind to the androgen receptor, while the other end binds to an E3 ligase called MDM2. This type of bifunctional molecule, capable of targeting proteins for degradation, is also named PROTAC (PROteolysis TArgeting Chimera).The term "PROTAC," which we often use today to refer to targeted protein degradation therapy, originates from this.

In 2013, Professor Crews co-founded Arvinas, Inc. to accelerate the scientific translation of this technology. To test the drug feasibility of such molecules,The company prioritized two relatively mature targets: the androgen receptor and the estrogen receptor. The PROTAC molecule targeting the estrogen receptor is vepdegestrant (formerly known as ARV-471), which is the subject of this submission for marketing approval.Due to its excellent ability to selectively degrade wild-type and mutant estrogen receptors in early clinical trials, Pfizer reached a deal worth over $2 billion with Arvinas in 2021.R&D Collaboration, jointly developing this PROTAC molecule into a cornerstone endocrine therapy for treating ER-positive breast cancer patients.

In addition to vepdegestrant, other PROTAC degraders from Arvinas, Inc. have also made significant progress. Last year,Arvinas and Novartis have reached a deal worth over $1 billion for ARV-766, Arvinas' second-generation PROTAC degrader targeting the androgen receptor.R&D CollaborationAgreement.In addition, Arvinas' protein degrader ARV-102 targeting LRRK2 has entered Phase 1 clinical trials, aiming to treat Parkinson's disease. Preliminary analysis shows,A single oral dose ≥60 mg, or a repeated daily oral dose ≥20 mg,The degradation rate of LRRK2 in the patient's cerebrospinal fluid exceeded 50%, and the degradation rate of LRRK2 in peripheral mononuclear cells exceeded 90%, indicating that ARV-102 can significantly degrade LRRK2 protein in both the central nervous system and the periphery.

▲WuXi AppTec's Rapid Construction of a Platform for Bifunctional Degraders

As one of the key enabling platforms for the development of targeted protein degradation drugs in the industry, WuXi AppTec quickly established a comprehensive enabling platform at the very beginning of the rise of such drugs. The platform's capabilities cover major molecular types including PROTAC, molecular glues, AUTAC, LYTAC, DUBTAC, RIBOTAC, PHICS, and DAC. According to information disclosed on last year’s Investor Open Day, since 2021, this platform has provided enabling collaborations to 66% of the active companies in the targeted protein degradation field.

Looking ahead, targeted protein degraders have even deeper significance. As Eric Fischer, a leading authority in this field from the Dana–Farber Cancer Institute, pointed out,Using oral small molecules to degrade proteins can free scientists from the constraints of "drugability," allowing them to truly consider which targets can most significantly alter the course of a disease.We also look forward to seeing moreProtein degradation drugs make positive clinical progress, benefiting a large number of patients.