A PHASE 1, NON-RANDOMIZED, OPEN-LABEL, SINGLE-DOSE, PARALLEL GROUP STUDY TO COMPARE THE PHARMACOKINETICS OF VEPDEGESTRANT (PF-07850327) IN ADULT PARTICIPANTS WITH MODERATE AND SEVERE HEPATIC IMPAIRMENT RELATIVE TO HEALTHY PARTICIPANTS WITH NORMAL HEPATIC FUNCTION

The purpose of the study is to look at how the body processes a study medicine called vepdegestrant in participants with loss of liver function relative to people with normal liver function.
This study is seeking participants who are:
* females who cannot have children or males
* between 18 and 70 years of age
* weigh more than 50 Kilograms (110 pounds)
* either healthy with normal liver function or have loss of liver function
All participants in this study will take one dose of vepdegestrant by mouth. This study looks at how the medicine is changed and removed from the body after being taken by the participants. The amount of vepdegestrant in participants with loss of liver function will be compared to the amount of vepdegestrant in participants with normal liver function.
All participants will stay at the study clinic for about 11 days and 10 nights.

Start Date04 Nov 2025

Sponsor / Collaborator

Pfizer Inc.

[+1]

NCT06911788

/ CompletedPhase 1

A PHASE 1, OPEN-LABEL, FIXED SEQUENCE, 2-PERIOD, SINGLE-DOSE, CROSS-OVER STUDY TO ESTIMATE THE ABSOLUTE BIOAVAILABILITY OF VEPDEGESTRANT (ARV-471, PF-07850327) FOLLOWING ORAL AND INTRAVENOUS DOSING OF THE DRUG TO HEALTHY PARTICIPANTS

The purpose of this study is to learn how much of the study medicine called Vepdegestrant will reach the bloodstream when given orally compared to given intravenously.
This study is seeking participants who:
* are healthy males and healthy females who cannot have children.
* are 18 years or older.
* are healthy as decided by medical tests.
* have a body mass index (BMI) of 16 to 32 kilogram per meter squared.
* have a total body weight of more than 45 kilograms (99 pounds).
In Period 1, all participants will receive one dose of Vepdegestrant by IV. In Period 2, all participants will receive one dose of Vepdegestrant by mouth following a high-fat breakfast. The levels of Vepdegestrant in Period 1 will be compared to the levels of Vepdegestrant in Period 2 and the bioavailablility of the oral formulation of Vepdegestrant will be determined.
The study duration is 22 days and includes two periods. Participants will stay in the clinical research unit for 9 days (8 nights) during each period. A follow-up visit for each participant takes place at 28 to 35 days after taking the study medicine for the last time.

Start Date03 Apr 2025

Sponsor / Collaborator

Pfizer Inc.

[+1]

NCT06645938

/ CompletedPhase 1

A PHASE I, RANDOMIZED, OPEN-LABEL, 2-PERIOD, 2-TREATMENT, 2-SEQUENCE, CROSSOVER, SINGLE-DOSE STUDY IN HEALTHY ADULT PARTICIPANTS TO ESTIMATE THE BIOAVAILABILITY OF AN VARIANT (HIGH HARDNESS) TABLET OF VEPDEGESTRANT (ARV-471, PF-07850327) RELATIVE TO THE REGISTRATIONAL TABLET

The purpose of the study is to compare the amount vepdegestrant available from two different tablet formulations under fed conditions in healthy adult participants; 200 mg vepdegestrant alternative tablet formulation compared to 200 mg vepdegestrant standard tablet formulation.
This study is seeking male or female participants of non-childbearing potential age who:
* are 18 years or older
* are healthy as decided by medical tests.
* have a Body mass index (BMI) of 16 to 32 kilogram per meter squared; and a total body weight of more than 45 kilograms (99 pounds).
All participants will be put into groups to receive one of the 2 treatments in each period. This study will consist of 2 treatment sequences:
* Sequence 1: Single 200 mg dose of vepdegestrant registrational tablet in Period 1, followed by a single 200 mg dose of vepdegestrant variant tablet in Period 2.
* Sequence 2: Single 200 mg dose of vepdegestrant variant tablet in Period 1, followed by a single 200 mg dose of vepdegestrant registrational tablet in Period 2.
Participants will be in the study for about 11 weeks.

Start Date16 Oct 2024

Sponsor / Collaborator

Pfizer Inc.

[+1]

100 Clinical Results associated with Vepdegestrant

100 Translational Medicine associated with Vepdegestrant

100 Patents (Medical) associated with Vepdegestrant

Literatures (Medical) associated with Vepdegestrant

01 Feb 2026·CLINICAL THERAPEUTICS

The Effect of Itraconazole on the Pharmacokinetics of Vepdegestrant, a PROteolysis TArgeting Chimera Estrogen Receptor Degrader, in Healthy Adult Participants

Article

Author: Stouffs, Alexandre ; Tran, Lana ; Tan, Weiwei ; Lee, Kimberly C ; Zhang, Yuanyuan ; Matschke, Kyle T ; Winton, Jennifer A

PURPOSE:

Vepdegestrant (ARV-471) is an orally administered PROteolysis TArgeting Chimera estrogen receptor (ER) degrader that directly binds an E3 ligase and ER to trigger ubiquitination and subsequent proteasomal degradation of ER. Based on findings from a first-in-human phase 1/2 trial, vepdegestrant 200 mg once daily was selected as the recommended phase 3 dose and was evaluated in the phase 3 clinical study VERITAC-2 (NCT05654623) for the treatment of patients with ER-positive human epidermal growth factor receptor 2-negative breast cancer. Vepdegestrant is a substrate of cytochrome P450 (CYP)3A4 in vitro; therefore, its plasma exposure may increase when coadministered with CYP3A4 inhibitors, such as the strong index CYP3A4 inhibitor itraconazole. This study evaluated the effect of itraconazole on the pharmacokinetics (PK) and safety of vepdegestrant in healthy adults.

METHODS:

During this phase 1, open-label, 2-period, fixed-sequence study (NCT05538312), participants received 2 doses of vepdegestrant and multiple doses of itraconazole. In period 1, participants received a single dose of vepdegestrant 200 mg under fed conditions followed by a washout period of at least 10 days. In period 2, participants received itraconazole 200 mg once daily under fasted conditions on days 1-11 and a single dose of vepdegestrant 200 mg under fed conditions on day 5 with concomitant itraconazole administration. Plasma samples were collected predose and serially following each vepdegestrant dose. PK parameters calculated for vepdegestrant and its epimer metabolite, ARV-473, included area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC_inf) and maximum plasma concentration (C_max). Safety was monitored throughout the study.

FINDINGS:

A total of 12 healthy adult participants received vepdegestrant with (test) and without (reference) itraconazole. The vepdegestrant test/reference ratios of the adjusted geometric means (90% confidence intervals) for AUC_inf and C_max were 168.9% (157.7-180.9) and 152.2% (136.9-169.2), respectively. Similar increases in exposure were observed for ARV-473. All adverse events were mild or moderate, and no participants discontinued from the study due to adverse events.

IMPLICATIONS:

Coadministration of multiple doses of itraconazole, a strong CYP3A4 inhibitor, increased vepdegestrant exposure by 69%, suggesting the involvement of CYP3A4-mediated metabolism, albeit not predominantly, in vepdegestrant elimination.

01 Feb 2026·DRUG METABOLISM AND DISPOSITION

Preclinical translational physiologically based pharmacokinetic modeling for predicting human pharmacokinetics of proteolysis targeting chimeras: Case studies of vepdegestrant (ARV-471) and bavdegalutamide (ARV-110)

Article

Author: Mao, Jialin ; Ubhayakar, Savita ; Rudolph, Joachim ; Deshmukh, Gauri ; Levy, Elizabeth ; Sharpnack, Danielle ; Liu, Liling ; Cheong, Jonathan ; Villemure, Elisia ; Ma, Bin ; Rachumallu, Ramakrishna

Proteolysis targeting chimeras (PROTACs), a class of targeted protein degraders, are advancing in clinical development, necessitating the accurate prediction of human pharmacokinetics (PK). This study developed a physiologically based pharmacokinetic (PBPK) modeling approach informed by in vitro to in vivo extrapolation to predict the human PK of 2 PROTACs: vepdegestrant (ARV-471) and bavdegalutamide (ARV-110). Bottom-up PBPK models were built in mouse (ARV-471), and in mouse, rat, and dog (ARV-110) using physicochemical and in vitro absorption, distribution, metabolism, and excretion data, including solubility, permeability from a modified Genentech Madin-Darby canine kidney cells assay with 4% bovine serum albumin, and liver microsomal intrinsic clearance (CL). In vitro to in vivo extrapolation gaps were identified and addressed using empirical scalars, including additional systemic CL and tissue partition coefficient scalars, to capture observed intravenous PK. Oral absorption and exposure in preclinical species were predicted using a mechanistic absorption model, assuming passive diffusion driven by total drug concentration. Based on the preclinical PBPK strategy, predicted human apparent CL after oral administration and apparent volume of distribution after oral dosing values for ARV-110 at 35 mg aligned within 2-fold of clinical observations. For ARV-471 at 30 mg oral dose, apparent volume of distribution after oral dosing predictions were within range, but apparent CL after oral administration was overpredicted. To improve alignment with the observed clinical PK, model refinement was limited to adjusting the additional systemic CL scalar, whereas absorption and distribution parameters remained unchanged. The refined PBPK models successfully simulated human oral PK within 2-fold of observed values across multiple doses (60-360 mg for ARV-471 and 70-140 mg for ARV-110). This PBPK modeling framework may support human PK prediction of PROTACs during late-stage drug discovery and development. SIGNIFICANCE STATEMENT: This study highlights that a physiologically based pharmacokinetic (PK)-in vitro to in vivo extrapolation strategy can reliably predict the human PK of proteolysis targeting chimeras, an emerging therapeutic class with complex absorption, distribution, metabolism, and excretion properties. Incorporating mechanistic absorption modeling and permeability data from modified in vitro assays (Genentech Madin-Darby canine kidney cells with 4% bovine serum albumin) improved oral absorption predictions, whereas the integration of multispecies preclinical PK data enhanced the translational accuracy of human PK predictions. Together, these findings establish a translational physiologically based PK framework for estimating oral exposure in first-in-human studies and supporting model-informed development of proteolysis targeting chimeras drug candidates.

01 Jan 2026·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Highly potent and selective degrader targeting ERα to improve the treatment outcomes of breast cancer

Article

Author: Bao, Xueting ; Zheng, Zhe ; Li, Jie ; Yin, Xunkai ; Wang, Jianing ; Zhu, Haohao ; Li, Nianguang ; Zhu, ZhenZhen ; Xu, Songyun ; Mei, Shulan ; Xu, Jinjing ; Dai, Rupeng ; Cai, Yihui ; Xu, Wenzhuo ; Lu, Wenyu ; Liu, Jian

Estrogen receptor alpha (ERα) is overexpressed in approximately 70 % of breast cancer cases; therefore, it is considered a primary therapeutic target for breast cancer. Several therapeutic agents, including selective estrogen receptor modulators, aromatase inhibitors, selective estrogen receptor degraders, and proteolysis-targeting chimeras (PROTACs), have been developed to antagonize and degrade ERα. The representative ERα-targeting PROTAC (ERα-PROTAC) agent ARV-471 has been used to treat locally advanced or metastatic breast cancer in clinical trials. Herein, we designed, synthesized, and evaluated several novel ERα-PROTAC agents. After systematic structural optimization, compound A16 was found to have excellent antiproliferative and ERα-inhibitory activities in the breast cancer cell line MCF-7. A16 selectively degraded ERα (DC₅₀ = 3.78 nM) through the ubiquitin-proteasome pathway in a time- and concentration-dependent manner. It effectively attenuated drug resistance (MCF-7 Y537S cells; IC₅₀ = 1.3 nM), inhibited proliferation, and induced apoptosis in MCF-7 cells. In addition, it exhibited excellent antitumor effects (10 mg/kg/d intraperitoneal injection; total growth inhibition = 80.11 %) and a good safety profile in an MCF-7 xenograft model, highlighting its potential as a novel drug candidate for breast cancer.

132

News (Medical) associated with Vepdegestrant

18 Mar 2026

·www.biospace.com

Arvinas Announces Positive Phase 1 Data for ARV-102 Showing Greater Than 50% LRRK2 Degradation in the CSF of Patients with Parkinson’s Disease Treated for 28 Days

– ARV-102 reduced endolysosomal and neuroinflammatory biomarkers implicated in Parkinson’s disease and progressive supranuclear palsy – – ARV-102 was well tolerated across all dose levels following 28 days of once-daily dosing – – Data support further development of ARV-102 in additional neurodegenerative diseases characterized by lysosomal dysfunction, including progressive supranuclear palsy, a rapidly progressing and devastating tauopathy – – Data presented during an oral session at the Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders Conference – NEW HAVEN, Conn., March 18, 2026 (GLOBE NEWSWIRE) -- Arvinas, Inc. (Nasdaq: ARVN), a clinical-stage biotechnology company working to create a new class of drugs based on targeted protein degradation, today presented data from a Phase 1 clinical trial of ARV-102, an investigational PROteolysis TArgeting Chimera (PROTAC) degrader designed to specifically target and degrade leucine-rich repeat kinase 2 (LRRK2). In the trial, ARV-102 demonstrated approximately 50% or greater reduction of LRRK2 in cerebrospinal fluid (CSF) at all doses by day 14 and maintained the reduction through day 28 in patients with Parkinson’s disease (PD). The Company targeted a 50% reduction based on data showing that patients with PD have a two-fold elevation of LRRK2. Results from the single-center, randomized, double-blind, placebo-controlled, multiple dose (MD) cohort of the Phase 1 clinical trial were shared in an oral presentation at the 2026 International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders (AD/PD™ 2026) in Copenhagen, Denmark. The MD cohort of the Phase 1 clinical trial conducted in patients with PD evaluated ARV-102 oral doses ranging from 20 mg to 80 mg daily for 28 days. Key findings from the trial showed: ARV-102 exposure in CSF increased in a dose-dependent manner after multiple doses, indicating brain penetration. ARV-102 achieved approximately 50% or greater LRRK2 reduction in CSF at all doses by day 14 and maintained the reduction through day 28, indicating substantial central LRRK2 protein degradation. Treatment resulted in reduction of LRRK2 variant and expression-dependent endolysosomal and neuroinflammatory biomarkers (e.g., CD68, GPNMB) previously shown to be elevated in neurodegenerative diseases like PD and progressive supranuclear palsy (PSP). ARV-102 was generally safe and well tolerated with no serious adverse events (SAEs) reported after multiple doses. ARV-102 is an investigational, orally bioavailable PROTAC designed to cross the blood-brain barrier and specifically target and degrade LRRK2. While LRRK2 is primarily known for its role in PD, emerging evidence suggests that it also plays a role in tauopathies, including PSP, and that LRRK2 dysfunction may contribute to the development and progression of both diseases. “These data represent exciting progress in the Parkinson’s disease treatment landscape,” said Andrew Siderowf, M.D., Chair of the Parkinson Study Group. “Importantly, ARV-102’s reduction of LRRK2 protein levels and other key biomarkers in patients with Parkinson’s disease suggests that PROTACs may offer a path for future treatment approaches. I look forward to following the continued advancement of ARV-102 and what it could bring for patients." “We are pleased to see compelling and consistent data that reinforce the continued development of ARV-102 as a potential treatment for neurodegenerative diseases like Parkinson’s disease and progressive supranuclear palsy that profoundly impact millions of patients and their families worldwide,” said Noah Berkowitz, M.D., Ph.D., Chief Medical Officer of Arvinas. “To our knowledge, this level of biomarker modulation has not previously been demonstrated by LRRK2 inhibitors, and we believe these data serve as the first of its kind. There is strong evidence that lysosomal dysfunction driven by increased LRRK2 in patients with PSP leads to significant declines in function over one year. Building on these results, and pending regulatory feedback, we intend to initiate a Phase 1b clinical trial in PSP in the second quarter of 2026, with the potential to initiate a registrational trial in late 2026, while we continue evaluating development options for ARV-102 in Parkinson’s disease.” Data presented at AD/PD™ 2026 The ARV-102 Phase 1 clinical trial is designed to assess the safety, pharmacokinetics, and pharmacodynamics of orally administered ARV-102 in patients with PD. Data presented are from the MD cohort of the single-center, randomized, double-blind, placebo-controlled trial. In the MD cohort, patients were randomized to either placebo or multiple oral doses of ARV-102 (20 mg, 40 mg, or 80 mg) for 28 days with follow-up at day 42. Safety Profile Multiple oral doses of ARV-102 (20 mg, 40 mg, or 80 mg once daily for 28 days) were well tolerated in participants with PD. All treatment-emergent adverse events and treatment-related adverse events were mild in severity, with no SAEs, discontinuations, or deaths reported. No significant changes in lung functions or respiratory symptoms were observed during the 28 days of treatment or during follow-up. Pharmacokinetic and Pharmacodynamic Evaluation ARV-102 levels in CSF increased in a dose-dependent manner after multiple doses, indicating brain penetration. The area under the concentration-time curve (AUC 0-24 ) and the maximum plasma concentration (C max ) after daily dosing increased with dose with a mean terminal plasma half-life (t 1/2 ) of 68 hours. ARV-102 achieved peripheral LRRK2 degradation and dose-dependent degradation of LRRK2 in CSF, with approximately 50% or greater degradation observed at all doses by day 14 and maintained through day 28. Endolysosomal and neuroinflammatory pathway proteins that are elevated in LRRK2-related PD (e.g., CD68, GPNMB) were reduced with ARV-102. Pharmacology and changes in peripheral biomarkers in patients with PD were consistent with observations in healthy volunteers dosed with ARV-102. Based on the positive outcomes of the Phase 1 clinical trial, Arvinas plans to continue investigation of ARV-102 in neurodegenerative diseases associated with LRRK2 and endolysosomal dysfunction. Additional detail on the ARV-102 data presentation at AD/PD™ 2026 follows below: Presentation Title: Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of ARV-102, a PROTAC LRRK2 Degrader, in Participants with Parkinson’s Disease Session Title: Modulating Neuroinflammation, Α-Synuclein, LRRK2, and Dopaminergic Repair: Early Human Data Session Type: Symposium Session Location: Hall 180-181 Date: March 18, 2026 Lecture Time: 3:30-3:45 PM CET About ARV-102 ARV-102 is an investigational, orally bioavailable PROTAC designed to cross the blood-brain barrier and specifically target and degrade leucine-rich repeat kinase 2 (LRRK2), a large, multidomain scaffolding kinase with GTPase activity. Increased activity and overexpression of LRRK2 have been implicated in the pathogenesis of neurological diseases, including Parkinson’s disease and progressive supranuclear palsy (PSP). ARV-102 is currently being evaluated in a Phase 1 clinical trial in patients with Parkinson’s disease and Arvinas plans to initiate a Phase 1b clinical trial with ARV-102 in patients with PSP, pending regulatory feedback, in the second quarter of 2026. About Parkinson’s Disease Parkinson’s disease is a progressive brain disease that damages dopamine-producing neurons, leading to progression of symptoms including motor-related symptoms like tremors and limb stiffness, as well as non-motor symptoms including depression, sleep disorders, cognitive decline, and more. LRRK2 activity is abnormally increased in Parkinson’s—and experimental studies strongly suggest that blocking LRRK2 may be neuroprotective. About Progressive Supranuclear Palsy Progressive supranuclear palsy (PSP) is a rare, rapidly progressing neurodegenerative disease that affects brain cells that control balance and coordination, eye movement, speech, swallowing, and thinking. Symptoms may start as early as a patient’s 40s. PSP is characterized by widespread tau pathology. LRRK2 influences tau pathology by directly modifying it and indirectly by disrupting cellular processes (actin, mitochondria, endocytosis) crucial for tau’s normal function and clearance, promoting its toxic accumulation and spread. About Arvinas Arvinas (Nasdaq: ARVN) is a clinical-stage biotechnology company dedicated to improving the lives of patients suffering from debilitating and life-threatening diseases. Through its PROteolysis TArgeting Chimera (PROTAC) protein degrader platform, Arvinas is pioneering the development of protein degradation therapies designed to harness the body’s natural protein disposal system to selectively and efficiently degrade and remove disease-causing proteins. Arvinas is currently progressing multiple investigational drugs through clinical development programs, including ARV-102, targeting LRRK2 for neurodegenerative diseases; ARV-806, targeting KRAS G12D for mutated cancers, including pancreatic, colorectal, and non-small cell lung cancers; ARV-393, targeting BCL6 for relapsed/refractory non-Hodgkin Lymphoma; ARV-027, targeting the polyglutamine-expanded androgen receptor, or polyQ-AR, in skeletal muscle; and vepdegestrant, targeting the estrogen receptor for patients with locally advanced or metastatic ER+/HER2- breast cancer. Arvinas is headquartered in New Haven, Connecticut. For more information about Arvinas, visit and connect on LinkedIn and X . Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties, including statements regarding: the potential of ARV-102, including its degradation of leucine-rich repeat kinase 2 (“LRRK2”), and potential future benefit to patients; the potential of PROteolysis TArgeting Chimeras; Arvinas’ belief that the data presented related to the level of biomarker modulation has not previously been demonstrated by LRRK2 inhibitors and serves as the first of its kind; Arvinas’ plans with respect to ARV-102, including its development and, pending regulatory feedback, the initiation of a Phase 1b clinical trial of ARV-102 in patients with progressive supranuclear palsy, and the initiation of a registrational trial, and the timings thereof; Arvinas’ potential development plans with respect to ARV-102 in Parkinson’s disease; and whether LRRK2 dysfunction contributes to the development and progression Parkinson’s disease and progressive supranuclear palsy. All statements, other than statements of historical fact, contained in this press release, including statements regarding Arvinas’ strategy, development plans, future operations, prospects, plans and objectives of management and the statements identified in the prior paragraph, are forward-looking statements. The words “ability,” “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “target,” “goal,” “potential,” “whether,” “will,” “would,” “could,” “reliance,” “should,” “look forward,” “seek,” “continue,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Arvinas may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements, and you should not place undue reliance on such forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements Arvinas makes as a result of various risks and uncertainties, including but not limited to: whether Arvinas will be able to successfully conduct and complete development for its product candidates, including ARV-102, on its current timelines or at all; risks related to clinical trial results and the interpretation thereof, including with respect to ARV-102; Arvinas’ ability to protect its intellectual property portfolio; Arvinas’ reliance on third parties; whether Arvinas will be able to raise capital when needed; whether Arvinas’ cash and cash equivalents will be sufficient to fund its foreseeable and unforeseeable operating expenses and capital expenditure requirements; and other important factors discussed in the “Risk Factors” section of Arvinas’ Annual Report on Form 10-K for the year ended December 31, 2025 and subsequent other reports filed with the U.S. Securities and Exchange Commission. The forward-looking statements contained in this press release reflect Arvinas’ current views with respect to future events, and Arvinas assumes no obligation to update any forward-looking statements, except as required by applicable law. These forward-looking statements should not be relied upon as representing Arvinas’ views as of any date subsequent to the date of this release. Contacts: Investors: Jeff Boyle +1 (347) 247-5089 Jeff.Boyle@arvinas.com Media: Kirsten Owens +1 (203) 584-0307 Kirsten.Owens@arvinas.com

Phase 1Clinical ResultPROTACs

09 Mar 2026

·www.biospace.com

PROTAC drug discovery for new cancer therapies

Bild: pexels.com/Pavel Danilyuk From inhibition to degradation: How proteolysis-targeting chimeras (PROTACs) are breaking down the barriers of “undruggability” and paving the way for next-generation cancer therapies. In modern oncology, classic small-molecule inhibitors (SMIs) regularly reach their limits. While conventional inhibitors block the function of a protein by occupying its active site (occupation-based paradigm), research with proteolysis-targeting chimeras (PROTACs) is pursuing a radically new approach: targeted proteosomal degradation. For physicians and researchers, this means access to target proteins that were previously considered “undruggable.” The mechanism: The ubiquitin-proteasome system as an ally PROTACs are heterobifunctional molecules that act as a molecular bridge. They consist of three components: ● a ligand that binds specifically to the target protein (protein of interest, POI) ● a ligand that recruits an E3 ubiquitin ligase ● a chemical linker that connects both functional units The spatial proximity causes the target protein to be ubiquitinated and subsequently degraded by the cellular 26S proteasome. This catalytic mechanism of action enables a single PROTAC molecule to tag numerous target proteins in succession, resulting in high efficiency at lower doses. Strategic relevance for clinical research A key advantage over traditional inhibitors is the ability to overcome resistance. Tumor cells often develop mutations in the active site that prevent inhibitors from binding. However, since PROTACs do not necessarily have to bind to the catalytic site but can use any accessible pocket on the protein surface, they open up new therapeutic windows. Analytical techniques used in PROTAC research include AlphaScreen®, TR-FRET (fluorescence resonance energy transfer), and NanoBRET TM as a luminescence method. Real-time monitoring of the ubiquitin conjugation and deconjugation phases is possible using the UbiReal test principle as a high-throughput screening method. International research projects and global collaborations The momentum in PROTAC development is being driven by well-funded international consortia. Academic-industrial partnerships: In the US and Asia, heavyweights such as Arvinas, Pfizer, and Roche are collaborating intensively with university hospitals to optimize the pharmacokinetics of the often quite large-molecular chimeras. A particular focus is on overcoming the blood-brain barrier for the treatment of CNS metastases. EU initiatives: Projects such as the European Research Council (ERC)-funded project on the “Design and biological evaluation of PROTACs as anti-cancer agents” (H2020) focus on the development of novel E3 ligase ligands beyond Cereblon (CRBN) and VHL. The breakthrough: Clinical milestones in Phase III For a long time, PROTAC technology was considered experimental. This has changed fundamentally. We are currently observing the entry of the first candidates into the regulatory trial phases: Vepdegestrant (ARV-471): The company Arvina is well advanced in its research into protein degradation therapies. The orally available estrogen receptor (ER) degrader vepdegestrant is currently being investigated in a large-scale Phase III study (VERITAC-2) in patients with ER-positive/HER2-negative locally advanced or metastatic breast cancer. Phase I/II data have already shown a significant reduction in ER levels in tumor tissue and a clinical benefit rate that potentially eclipses conventional fulvestrant therapies. Bavdegalamide (ARV-110): The target here is the androgen receptor (AR). Following promising results in patients with metastatic castration-resistant prostate cancer (mCRPC) who had already received multiple prior therapies, the developers are paving the way for broader clinical applications in advanced stages. Outlook for clinical practice PROTAC technology is transforming oncology from functional blockade to physical elimination of pathogenic proteins. For the medical profession, this means new treatment options for patients who no longer respond to standard therapies. While we await the final data from the Phase III studies, one thing is already clear: targeted protein degradation will become a cornerstone of personalized cancer therapy.

Phase 3PROTACs

09 Mar 2026

·allsci.com

Roche reports Phase III miss for giredestrant in first-line breast cancer setting

Roche’s giredestrant misses primary endpoint in persevERA trial for ER-positive advanced breast cancer Roche announced that the Phase III persevERA Breast Cancer study evaluating giredestrant in combination with palbociclib did not meet its primary endpoint of a statistically significant improvement in progression-free survival in ER-positive, HER2-negative locally advanced or metastatic breast cancer. The result complicates the trajectory of Roche’s oral selective estrogen receptor degrader (SERD) in the first-line advanced setting, even as the company points to positive Phase III readouts from two other giredestrant trials to sustain its broader development program. The persevERA Breast Cancer study is a Phase III, randomized, double-blind, placebo-controlled, multicenter trial that enrolled 992 patients globally. Participants with ER-positive, HER2-negative locally advanced or metastatic breast cancer were randomized to receive either giredestrant plus palbociclib or letrozole plus palbociclib as first-line treatment. The primary endpoint was investigator-assessed progression-free survival. Key secondary endpoints included overall survival, objective response rate, duration of response, and safety. While the study did not achieve statistical significance on its primary endpoint, Roche reported that a numerical improvement in PFS was observed, though no hazard ratio or p-value were disclosed. Adverse events in the giredestrant arm were described as manageable and consistent with the known safety profiles of each treatment. Full results are expected at an upcoming medical meeting. Despite the miss, Roche signaled continued commitment to giredestrant across multiple settings. The US FDA recently accepted a New Drug Application based on the Phase III evERA study, which showed positive results for giredestrant plus everolimus in previously treated advanced disease. Roche also plans to submit Phase III lidERA data in early-stage adjuvant breast cancer to the US FDA in the coming weeks. A second first-line advanced study, pionERA, evaluating giredestrant with physician’s choice of CDK4/6 inhibitor in endocrine-resistant disease, is expected to read out in 2027. Levi Garraway, Roche’s Chief Medical Officer, stated: “We believe there is a path forward for combining giredestrant with a CDK4/6 inhibitor in the adjuvant setting and we are conducting further studies”. Giredestrant has not received regulatory approval for any indication to date. Giredestrant is an oral SERD and full antagonist designed to block estrogen from binding to ERα and trigger receptor degradation. Unlike fulvestrant, the only approved SERD, giredestrant is orally administered and active against ESR1-mutant forms of the receptor that commonly arise during endocrine resistance. ER-positive breast cancer accounts for approximately 70% of all breast cancer cases, and despite advances with CDK4/6 inhibitors and aromatase inhibitors, up to a third of early-stage patients eventually experience recurrence, while resistance in the advanced setting remains a persistent clinical challenge. The oral SERD class has attracted substantial investment, though clinical setbacks have been common. Key competitors include: Menarini/Stemline’s elacestrant (Orserdu), the first oral SERD approved by the US FDA in 2023 for ESR1-mutated ER-positive metastatic breast cancer. Eli Lilly’s imlunestrant (EMBER-3), an oral SERD that received US FDA approval in early 2026 for ESR1-mutated advanced breast cancer. AstraZeneca’s camizestrant (SERENA program), a next-generation oral SERD in Phase III development for both early and advanced ER-positive breast cancer settings. Earlier stage programs include Accutar Biotechnology’s AC699, palazestrant (Olema Oncology) and vepdegestrant (Arvinas/Pfizer). The persevERA miss narrows the differentiation case for giredestrant in the first-line combination setting, where letrozole plus a CDK4/6 inhibitor remains standard of care. Roche’s strategy now depends on the pending NDA review for evERA, the lidERA adjuvant submission, and the pionERA readout to establish giredestrant’s clinical position across the ER-positive breast cancer treatment continuum. Your email address will not be published. Required fields are marked * Comment * Name * Email * Website

Phase 3Clinical ResultDrug Approval

100 Deals associated with Vepdegestrant

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
ER-positive/HER2-negative/ ESR1-mutated breast cancer	NDA/BLA	United States	Arvinas, Inc.	06 Jun 2025
Advanced breast cancer	Phase 3	United States	Arvinas Estrogen Receptor, Inc.	09 Aug 2023
Advanced breast cancer	Phase 3	United States	Pfizer Inc.	09 Aug 2023
Advanced breast cancer	Phase 3	China	Pfizer Inc.	09 Aug 2023
Advanced breast cancer	Phase 3	China	Arvinas Estrogen Receptor, Inc.	09 Aug 2023
Advanced breast cancer	Phase 3	Japan	Arvinas Estrogen Receptor, Inc.	09 Aug 2023
Advanced breast cancer	Phase 3	Japan	Pfizer Inc.	09 Aug 2023
Advanced breast cancer	Phase 3	Australia	Arvinas Estrogen Receptor, Inc.	09 Aug 2023
Advanced breast cancer	Phase 3	Australia	Pfizer Inc.	09 Aug 2023
Advanced breast cancer	Phase 3	Brazil	Arvinas Estrogen Receptor, Inc.	09 Aug 2023

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


AACR2026	Phase 2/3	Hormone receptor positive HER2 negative breast cancer HR Positive \| HER2 Negative	16	Imlunestrant alone	wxwjlecerg(wayxrdskkv) = usrasiclai opulkooavz (lyxgbvbcer ) View more	Positive	21 Apr 2026
				Camizestrant 75mg	wxwjlecerg(snanwkwlvc) = rfzdpryuqz ddqgjulidw (gpchpcvwjb ) View more
NCT05654623 (VERITAC-2, CTgov)	Phase 3	ER-positive/HER2-negative Breast Cancer	624	fulvestrant	vlqyostfkl(pbtvttntce) = addojenauq qvraepsanx (hdanlhzpfe, lptsvjlbxi - nhepixykqr) View more	-	03 Feb 2026
NCT04072952 (SABCS2025)	Phase 1/2	ER-positive/HER2-negative Breast Cancer ESR1 mutation	138	Vepdegestrant (ER-positive/HER2-negative advanced breast cancer)	kzljohjttb(fbnedzowxn) = bcqczknthb tgwlonxkhj (vwmlxjuzls ) View more	Positive	10 Dec 2025
NCT05549505 (TACTIVE-N, CTgov)	Phase 2	ER-positive/HER2-negative Breast Cancer	152	Surgical resection of breast tumor+ARV-471 (Arm A: ARV-471 (Experimental))	vqehlhdavt = sscnlnffjs jdzqgtlvtz (sqzdhrlbvg, ylbxlwaweb - jfxmhkkaxo) View more	-	29 Aug 2025
				Surgical resection of breast tumor+anastrozole (Arm B: Anastrozole)	vqehlhdavt = jajgzzfdnm jdzqgtlvtz (sqzdhrlbvg, ujqmrlfjob - qodybhagof) View more
NCT05654623 (VERITAC-2, Pubmed \| N Engl J Med)	Phase 3	Advanced breast cancer	624	Vepdegestrant 200 mg	gnwnysiqre(ulrdrnyurs) = in 2.9% and 0.7% of the patients, respectively qewltpjgdh (dylwirflsu ) View more	Positive	07 Aug 2025
				Fulvestrant 500 mg
NCT05654623 (VERITAC-2, ASCO2025 \| Company_Website) Manual	Phase 3	ER-positive/HER2-negative Breast Cancer ER Positive \| HER2 Negative	624	Vepdegestrant	vuhnqxwgvo(kxyifocytr) = hfdoslfoth bmbuswzqpz (wqvatmffhx, 3.6–5.3) View more	Positive	30 May 2025
				fulvestrant	vuhnqxwgvo(kxyifocytr) = thxwcvlhzi bmbuswzqpz (wqvatmffhx, 2.2–3.8) View more
NCT05654623 (VERITAC-2, Company_Website) Manual	Phase 3	ER-positive/HER2-negative Breast Cancer ESR1 Mutation	-	Vepdegestrant (ESR1 mutant)	hclmohsklx(gusnitacwy) = The results exceeded the pre-specified target hazard ratio of 0.60 in the ESR1m population. The trial did not reach statistical significance in improvement in PFS in the intent-to-treat (ITT) population. kkrrugqrva (zjuqowerqu )	Negative	11 Mar 2025
				fulvestrant (ESR1 mutant)
NCT05548127 (TACTIVE-U, GlobeNewswire) Manual	Phase 1	ER-positive/HER2-negative Breast Cancer Third line	16	Vepdegestrant + Abemaciclib	qbokzfelqr(tjmntmklvk) = None tqosoqxvdz (jlhduhhcks ) View more	Positive	10 Dec 2024
				Vepdegestrant + Abemaciclib (mutant ESR1)
NCT05463952 (Pubmed \| Int J Clin Oncol)	Phase 1	Locally Advanced Unresectable Breast Carcinoma \| Breast Cancer \| Estrogen receptor positive breast cancer ... estrogen receptor (ER) View more	6	Vepdegestrant 200 mg QD	gjpnjnkyfd(wlcihdlgcy) = Four (66.7%) patients experienced adverse events; none led to dose reduction or discontinuation jhqwkkkhbr (lzkuynuqaf ) View more	-	20 Nov 2024
NCT05463952 (CTgov)	Phase 1	Locally Advanced Unresectable Breast Carcinoma \| Breast Cancer \| Estrogen receptor positive breast cancer ... View more	6	ARV-471	mwqmtjpcrg = kuhprypfip mlgrtwbxjn (bllqvstlmy, yuxidkdlku - aqurzjqnwu) View more	-	23 Sep 2024

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