Vepdegestrant

{{Short description|Chemical compound}} {{Use dmy dates|date=May 2026}} {{cs1 config|display-authors=6}} {{Infobox drug | image = Vepdegestrant.svg | image_class = skin-invert-image | alt = | caption =

| pronounce = {{IPAc-en|ˌ|v|ɛ|p|d|ə|ˈ|dʒ|ɛ|s|t|r|ə|n|t}}<br />{{respell|VEP|də|JES|trənt}} | tradename = Veppanu | Drugs.com = {{drugs.com|Parent|veppanu}} | MedlinePlus = | DailyMedID = Vepdegestrant | pregnancy_AU =  | pregnancy_AU_comment = | pregnancy_category = | routes_of_administration = By mouth | class = Estrogen receptor antagonist | ATC_prefix = None | ATC_suffix = | ATC_supplemental =

| legal_AU =  | legal_AU_comment = | legal_BR =  | legal_BR_comment = | legal_CA =  | legal_CA_comment = | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK =  | legal_UK_comment = | legal_US = Rx-only | legal_US_comment = <ref name="Veppanu FDA label">{{Cite web |url=https://www.arvinas.com/wp-content/uploads/2026/05/NDA-219835_Approval-Rx-ONLY.pdf |title=Veppanu (vepdegestrant) tablets, for oral use |website=arvinas.com |access-date=2026-05-06}}</ref> | legal_EU = | legal_EU_comment = | legal_UN =  | legal_UN_comment = | legal_status =

| IUPAC_name = (3''S'')-3-[6-[4-<nowiki>[[</nowiki>1-[4-[(1''R'',2''S'')-6-Hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl]phenyl]piperidin-4-yl]methyl]piperazin-1-yl]-3-oxo-1''H''-isoindol-2-yl]piperidine-2,6-dione | C = 45 | H = 49 | N = 5 | O = 4 | SMILES = C1CC2=C(C=CC(=C2)O)[C@H]([C@H]1C3=CC=CC=C3)C4=CC=C(C=C4)N5CCC(CC5)CN6CCN(CC6)C7=CC8=C(C=C7)C(=O)N(C8)[C@H]9CCC(=O)NC9=O | StdInChI = 1S/C45H49N5O4/c51-37-12-15-39-33(27-37)8-13-38(31-4-2-1-3-5-31)43(39)32-6-9-35(10-7-32)48-20-18-30(19-21-48)28-47-22-24-49(25-23-47)36-11-14-40-34(26-36)29-50(45(40)54)41-16-17-42(52)46-44(41)53/h1-7,9-12,14-15,26-27,30,38,41,43,51H,8,13,16-25,28-29H2,(H,46,52,53)/t38-,41+,43+/m1/s1 | StdInChI_comment = | StdInChIKey = TZZDVPMABRWKIZ-XMOGEVODSA-N | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

'''Vepdegestrant''', sold under the brand name '''Veppanu''', is an anti-cancer medication used for the treatment of breast cancer.<ref name="Veppanu FDA label" /><ref name="FDA 20210501" /> It is a heterobifunctional protein degrader.<ref name="Veppanu FDA label" /><ref name="FDA 20210501" /> It was developed by Arvinas and Pfizer.<ref>{{Cite web |title=Arvinas, Pfizer reworking partnership on 'Protac' cancer drug |url=https://www.biopharmadive.com/news/arvinas-pfizer-vepdegestrant-partnership-rework-breast-cancer/757043/ |access-date=17 September 2025 |website=BioPharma Dive }}</ref> It is taken by mouth.<ref name="Veppanu FDA label" /><ref name="FDA 20210501" />

Vepdegestrant was approved for medical use in the United States in May 2026.<ref name="FDA 20210501">{{cite web | title=FDA approves vepdegestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer | website=U.S. Food and Drug Administration (FDA) | date=1 May 2026 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-vepdegestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast | access-date=5 May 2026}} {{PD-notice}}</ref>

== Medical uses == Veppanu is indicated for the treatment of adults with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, estrogen receptor-1 (ESR1)-mutated advanced or metastatic breast cancer, as detected by an FDA-authorized test, with disease progression following at least one line of endocrine therapy.<ref name="Veppanu FDA label" /><ref name="FDA 20210501" /><ref name="Novel Drug Approvals for 2026">{{cite web | title=Novel Drug Approvals for 2026 | website=U.S. Food and Drug Administration (FDA) | date=1 May 2026 | url=https://www.fda.gov/drugs/novel-drug-approvals-fda/novel-drug-approvals-2026 | access-date=5 May 2026}} {{PD-notice}}</ref>

== Adverse effects == The US prescribing information includes warnings and precautions for QTc interval prolongation and embryo-fetal toxicity.<ref name="Veppanu FDA label" /><ref name="FDA 20210501" />

== Mechanism of action == Vepdegestrant is designed as a PROTAC that recruits the ubiquitin-proteasome system to target the estrogen receptor for degradation.<ref name="arvinas_er">{{cite web |title=Estrogen Receptor |website=Arvinas |url=https://www.arvinas.com/research-and-development/estrogen-receptor/ |access-date=17 September 2025}}</ref> The compound contains both an E3 ubiquitin ligase-binding moiety and an estrogen receptor-binding domain, intended to bring these proteins into proximity to trigger ubiquitination and subsequent proteasomal degradation of the ER protein.<ref name="protac_nature">{{cite journal |last1=Sakamoto |first1=Kathryn M. |last2=Kim |first2=Kwon B. |last3=Kumagai |first3=Ayumu |last4=Mercurio |first4=Frank |last5=Crews |first5=Craig M. |last6=Deshaies |first6=Raymond J. |title=PROTAC targeted protein degraders: the past is prologue |journal=Nature Reviews Drug Discovery |date=18 January 2022 |volume=21 |issue=3 |pages=181–200 |doi=10.1038/s41573-021-00371-6 |pmid=35046570|pmc=8765495 }}</ref> In laboratory studies, vepdegestrant demonstrated ER degradation in ER-positive breast cancer cell lines with reported DC50 values of approximately 1-2 nM.<ref name="medchemexpress">{{cite web |title=Vepdegestrant (ARV-471) PROTAC ER Degrader |website=MedChemExpress |url=https://www.medchemexpress.com/vepdegestrant.html |access-date=17 September 2025}}</ref>

== History == Efficacy was evaluated in VERITAC-2 (NCT05654623), a randomized, open-label, active-controlled, multi-center trial in 624 adults with ER-positive, HER2-negative, advanced or metastatic breast cancer, of whom 270 had tumors carrying ESR1 mutations.<ref name="FDA 20210501" /> Participants were required to have disease progression on one to two lines of endocrine therapy, including one line with a CDK4/6 inhibitor.<ref name="FDA 20210501" /> Participants were randomized (1:1) to receive vepdegestrant orally once daily, or fulvestrant intramuscularly on days 1 and 15 of cycle 1 and then once monthly thereafter.<ref name="FDA 20210501" /> Randomization was stratified by ESR1 mutation status and visceral metastasis.<ref name="FDA 20210501" /> ESR1 mutational status was determined by blood circulating tumor deoxyribonucleic acid (ctDNA) using central or local testing.<ref name="FDA 20210501" />

=== Phase I/II trials === Vepdegestrant has been evaluated in early-phase clinical trials as both monotherapy and in combination with other agents in patients with ER+/HER2- breast cancer. In a first-in-human Phase I/II study, vepdegestrant monotherapy was well tolerated and showed clinical activity in pretreated patients.<ref name="veritac2_study">{{Cite journal |last1=Hamilton |first1=Erika P. |last2=Ma |first2=Cynthia |last3=De Laurentiis |first3=Michelino |last4=Iwata |first4=Hiroji |last5=Hurvitz |first5=Sara A. |last6=Wander |first6=Seth A. |last7=Danso |first7=Michael |last8=Lu |first8=Dongrui R. |last9=Perkins Smith |first9=Julia |last10=Liu |first10=Yuan |last11=Tran |first11=Lana |last12=Anderson |first12=Sibyl |last13=Campone |first13=Mario |date=2024 |title=VERITAC-2: a Phase III study of vepdegestrant, a PROTAC ER degrader, versus fulvestrant in ER+/HER2- advanced breast cancer |journal=Future Oncology (London, England) |volume=20 |issue=32 |pages=2447–2455 |doi=10.1080/14796694.2024.2377530 |issn=1744-8301 |pmc=11524203 |pmid=39072356}}</ref>

=== Phase III VERITAC-2 trial === The Phase III VERITAC-2 trial (NCT05654623) is a randomized, open-label study comparing vepdegestrant to fulvestrant in patients with ER+/HER2- advanced breast cancer.<ref name="clinical_trials">{{cite journal |title=A Study to Compare the Efficacy and Safety of Vepdegestrant (ARV-471) Versus Fulvestrant in Participants With Estrogen Receptor-positive, HER2-negative Advanced Breast Cancer (VERITAC-2) |website=ClinicalTrials.gov |date=30 June 2025 |url=https://clinicaltrials.gov/study/NCT05654623 |access-date=17 September 2025}}</ref> The trial enrolled 624 patients at sites in 26 countries who had previously received treatment with a CDK4/6 inhibitor plus endocrine therapy.<ref name="veritac_details">{{cite web |title=Arvinas and Pfizer Announce Positive Topline Results from Phase 3 VERITAC-2 Clinical Trial |website=Arvinas |url=https://ir.arvinas.com/news-releases/news-release-details/arvinas-and-pfizer-announce-positive-topline-results-phase-3/ |access-date=17 September 2025}}</ref>

In March 2025, results were announced from the VERITAC-2 trial. According to company statements, the study met its primary endpoint in the ESR1-mutant patient population, showing improvement in progression-free survival compared to fulvestrant.<ref name="veritac_details" /> However, the trial did not achieve statistical significance in the overall intent-to-treat population.<ref name="asco_veritac">{{cite web |title=VERITAC-2 Trial Shows Vepdegestrant Significantly Improves Survival in ESR1-Mutant Breast Cancer |website=Applied Clinical Trials Online |date=24 March 2025 |url=https://www.appliedclinicaltrialsonline.com/view/veritac-trial-vepdegestrant-survival-esr1-mutant-breast-cancer |access-date=17 September 2025}}</ref> Detailed results were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.<ref name="asco_presentation">{{cite web |title=Arvinas Announces Results from the VERITAC-2 Trial Selected as Late-Breaking Oral Presentation at the 2025 ASCO Annual Meeting |website=Arvinas |date=23 April 2025 |url=https://ir.arvinas.com/news-releases/news-release-details/arvinas-announces-results-veritac-2-trial-selected-late-breaking |access-date=17 September 2025}}</ref>

=== Preclinical studies === In preclinical studies, vepdegestrant achieved greater ER degradation ''in vivo'' compared with fulvestrant, which correlated with improved tumor growth inhibition (TGI).<ref name="preclinical_ccr">{{cite journal |last1=Gough |first1=Sheryl M. |last2=Flanagan |first2=John J. |last3=Teh |first3=Jimmy |title=Oral Estrogen Receptor PROTAC Vepdegestrant (ARV-471) Is Highly Efficacious as Monotherapy and in Combination with CDK4/6 or PI3K/mTOR Pathway Inhibitors in Preclinical ER+ Breast Cancer Models |journal=Clinical Cancer Research |volume=30 |issue=16 |pages=3549–3562 |date=15 August 2024 |pmid=38819400 |doi=10.1158/1078-0432.CCR-23-3465 |pmc=11325148 }}</ref> The compound showed high efficacy as monotherapy and demonstrated synergistic effects when combined with CDK4/6 inhibitors or PI3K/mTOR pathway inhibitors in preclinical ER+ breast cancer models.<ref name="preclinical_ccr" />

== Society and culture == === Legal status === The US Food and Drug Administration (FDA) granted fast track designation to vepdegestrant in February 2024, as a monotherapy for the treatment of adults with ER+/HER2- metastatic breast cancer.<ref name="pfizer_fast_track">{{cite news |title=FDA Grants Fast Track Status to Vepdegestrant for ER+/HER2– Metastatic Breast Cancer |website=Oncology Live|date=6 February 2024 |url=https://www.onclive.com/view/fda-grants-fast-track-status-to-vepdegestrant-for-er-her2-metastatic-breast-cancer |access-date=17 September 2025}}</ref><ref name="fda_fast_track">{{cite news |title=Vepdegestrant Gains FDA Fast Track Designation in ER+/HER2- Breast Cancer |website=Targeted Oncology |date=6 February 2024 |url=https://www.targetedonc.com/view/vepdegestrant-gains-fda-fast-track-designation-in-er-her2--breast-cancer |access-date=17 September 2025}}</ref>

Vepdegestrant was approved for medical use in the United States in May 2026.<ref name="FDA 20210501" /><ref>{{cite press release | title=Arvinas Announces FDA Approval of Veppanu (vepdegestrant) for the Treatment of ESR1m, ER+/HER2- Advanced Breast Cancer | website=Arvinas | url=https://ir.arvinas.com/news-releases/news-release-details/arvinas-announces-fda-approval-veppanu-vepdegestrant-treatment | access-date=5 May 2026}}</ref>

=== Names === Vepdegestrant is the international nonproprietary name.<ref>{{cite journal | vauthors = ((World Health Organization)) | year = 2023 | title = International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 89 | journal = WHO Drug Information | volume = 37 | issue = 1 | hdl = 10665/366661 | hdl-access = free | author-link = World Health Organization }}</ref>

Vepdegestrant is sold under the brand name Veppanu.<ref name="FDA 20210501" />

==References== {{reflist}}

== Further reading == * {{cite journal |last1=Iwata |first1=H. |last2=Hamilton |first2=E.P. |last3=Ma |first3=C.X. |last4=De Laurentiis |first4=M. |last5=Hurvitz |first5=S.A. |last6=Wander |first6=S.A. |last7=Danso |first7=M.A. |last8=Lu |first8=D.R. |last9=Perkins |first9=J. |last10=Liu |first10=Y. |last11=Tran |first11=L. |last12=Anderson |first12=S. |last13=Chappey |first13=C. |last14=Yang |first14=D.Z. |last15=Campone |first15=M. |title=73TiP Global phase III studies evaluating vepdegestrant in estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer: VERITAC-2 and VERITAC-3 |journal=Annals of Oncology |date=November 2023 |volume=34 |pages=S1493 |doi=10.1016/j.annonc.2023.10.207|s2cid=265654990 |doi-access=free }} * {{cite journal |last1=Iwata |first1=H. |last2=Naito |first2=Y. |last3=Hattori |first3=M. |last4=Yoshimura |first4=A. |last5=Yonemori |first5=K. |last6=Aizawa |first6=M. |last7=Mori |first7=Y. |last8=Yoshimitsu |first8=J. |last9=Umeyama |first9=Y. |last10=Mukohara |first10=T. |title=58P Safety and pharmacokinetics (PK) of vepdegestrant in Japanese patients with estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer: Results from a Japanese phase I study |journal=Annals of Oncology |date=November 2023 |volume=34 |pages=S1488–S1489 |doi=10.1016/j.annonc.2023.10.193|s2cid=265657144 |doi-access= }}

== External links == * {{ClinicalTrialsGov|NCT05654623|A Study to Learn About a New Medicine Called Vepdegestrant (ARV-471, PF-07850327) in People Who Have Advanced Metastatic Breast Cancer (VERITAC-2)}}

Category:Proteolysis targeting chimeras Category:Selective estrogen receptor degraders Category:Piperidines Category:Piperazines Category:Glutarimides Category:Hydroxyarenes