VT3989 / Vivace Therap - LARVOL DELTA

sTEADfast: A Phase 3 Trial in Advanced Epithelioid Mesothelioma (clinicaltrials.gov) - P3 | N=350 | Not yet recruiting | Sponsor: Vivace Therapeutics, Inc

New P3 trial • Epithelioid Mesothelioma • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor

First-in-class, first-in-human phase 1 trial of VT3989, an inhibitor of yes-associated protein (YAP)/transcriptional enhancer activator domain (TEAD), in patients (pts) with advanced solid tumors enriched for malignant mesothelioma and other tumors with neurofibromatosis 2 (NF2) mutations (AACR 2023) - "All MM pts had progressed on prior platinum/pemetrexed; all but 2 had prior immune checkpoint inhibitors.VT3989 is safe and well tolerated with no dose limiting toxicities. VT3989 is safe and well tolerated with durable RECIST v1.1 antitumor responses in pts with advanced MM and NF2m cancers, providing the first early clinical proof-of-concept for effectively drugging the Hippo-YAP-TEAD pathway. RP2D optimization including further schedule evaluation and expansion are ongoing in pts with MM and NF2m tumors."

Clinical • IO biomarker • Metastases • P1 data • Brain Cancer • CNS Tumor • Lung Cancer • Meningioma • Mesothelioma • Oncology • Sarcoma • Solid Tumor

Safety and efficacy of first-in-class, YAP/TEAD inhibitor, VT3989 in refractory pleural and non-pleural mesothelioma: A phase I/II study (ESMO 2025) - P1/2 | "Conclusions VT3989 is well tolerated with promising antitumor activity in pts with refractory mesothelioma. Based on these data, a randomized phase 3 study is planned for further evaluation of VT3989 in mesothelioma."

Clinical • IO biomarker • P1/2 data • Brain Cancer • Malignant Pleural Mesothelioma • Meningioma • Mesothelioma • Oncology • Pleural Mesothelioma • Sarcoma • Solid Tumor • Spindle Cell Sarcoma • NF2

YAP-TEAD-driven CPA4 promotes NF2-deficient meningioma growth. (PubMed, bioRxiv) - "CPA4 links NF2 loss to oncogenic YAP-TEAD transcription, sustains meningioma growth, and marks tumor sensitivity to pharmacologic TEAD inhibition. These findings establish CPA4 as a tumor-promoting effector and potential biomarker of an actionable pathway shared across NF2- deficient cancers."

Journal • Brain Cancer • Meningioma • Oncology • Solid Tumor • NF1 • NF2

Tumor pharmacokinetics and pharmacodynamics assessment of TEAD inhibitor VT03989 in patient-derived xenograft models of glioblastoma (AACR 2024) - "VT03989 is well tolerated, achieves pharmacologically relevant unbound concentrations in GBM PDX models, and is associated with significant target modulation. Ongoing studies are evaluating in vivo survival benefits from combining VT03989 inhibition with radiation therapy"

PK/PD data • Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CASP3 • CCN1 • CTGF

The selective Yap/Tead inhibitor TY-1054 re-sensitizes acquired resistance to multiple tyrosine kinase-based targeted therapies (AACR 2025) - P1, P1/2 | "Small molecules that block auto-palmitoylation of TEADs, such as VT3989 (NCT04665206) and BPI-460372 (NCT05789602), have been successfully to enter the clinical trials. TY-1054 had excellent efficacy in the H226 CDX and HNSCC PDX mouse models. TY-9591 is a third-generation EGFR inhibitor developed by TYK Medicines and is currently under pivotal Phase III clinical investigation in China. Our studies showed that TY-9591 had excellent efficacy in the PC9 CDX mouse model, but tumors gradually recurred, as Osimertinib did."

Preclinical • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

Comparing TEAD palmitoylation inhibitors with differential TEAD selectivity in combination efficacy with targeted therapies and in renal safety (AACR 2024) - "One of these compounds, VT3989, is being evaluated in an ongoing phase 1 clinical trial, where partial responses in mesothelioma patients have been demonstrated, showing for the first time that the Hippo pathway is druggable and that the Hippo pathway is now a validated target for cancer therapy...In 14-day/28-day rat studies, TEAD1-selective TEAD inhibitors also exhibited proteinuric nephropathy similar to that observed with pan-/multiple-TEAD inhibitors. Therefore, based on our findings, we can conclude that TEAD1-selective TEAD palmitoylation inhibitors can have similar on-target effect on kidneys as TEAD inhibitors with broader TEAD selectivity while having reduced anti-tumor efficacy and durability of response in combination with targeted therapies."

Clinical • Mesothelioma • Oncology • Solid Tumor • EGFR • KRAS • NF2 • TEAD1 • TEAD2 • TEAD3 • TEAD4

VT3989-001: Study to Evaluate VT3989 in Patients With Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=434 | Recruiting | Sponsor: Vivace Therapeutics, Inc | Trial completion date: Jun 2027 ➔ Mar 2030 | Trial primary completion date: Dec 2026 ➔ Nov 2029

Trial completion date • Trial primary completion date • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Evaluation of TEAD inhibitor, VT03989 treatment on growth of aggressive meningioma preclinical models (AACR 2024) - "VT3989 treatment led to downregulation of TEAD direct targets CTGF and CYR61 and inhibited cell viability of both IOMM-Lee cell and MG309 meningioma lines. RNA-seq analysis identified cell cycle and DDR pathway genes to be downregulated upon TEAD inhibition."

IO biomarker • Preclinical • Brain Cancer • CNS Tumor • Meningioma • Oncology • Solid Tumor • BCL2 • BIRC5 • CCN1 • CTGF • NF2

Identification of small molecule Pan-TEAD inhibitors disrupting YAP-TEAD protein-protein interaction and targeting gastric cancer cells (AACR 2024) - P1, P1/2 | "Despite the progresses, only 3 small molecule TEAD inhibitors are currently being tested in Phase I clinical trials which includes: VT3989b NCT04665206 from Vivacare, IK-930b NCT05228015 from Ikena Oncology and IAG-933, NCT0485737 from the Novartis Oncology. With our exciting key data, we are exploring multiple other oncology targets to use our Pan-TEAD inhibitors either as a monotherapy or combination therapy. We expect to complete our Technology Disclosure on additional targets before the meeting and to add exciting data for the Cancer drug development community."

Late-breaking abstract • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • TAFAZZIN • TEAD1 • YAP1

TEAD1/4 inhibitors exhibit deeper biological impact and broader activity compared to TEAD1-only inhibitors in both monotherapy and combination without additional kidney toxicity (AACR 2024) - "However, the TEAD1-preferential inhibitor IK930 did not yield any objective responses but also showed a more favorable safety profile especially with respect to proteinuria. We show that 1) SPR1 displays broader and deeper cell-based activity and extends the utility of TEAD inhibitors outside of mesothelioma and NF2 mutants 2) SPR1 shows stronger activity than TEAD1-only inhibitors in combination with MAPK and EGFR inhibitors in vitro and in vivo 3) SPR1 does not cause proteinuria in mice; dogs or rats even above therapeutic doses 4) SPR1 does not show the context-specific stimulation of tumor growth in Lung PDX previously observed with VT3989 and other inhibitors that include TEAD2 in their profile. Taken together - the data suggests SPR1 is positioned to become a best-in-class TEAD palmitic acid site inhibitor with broad utility in both monotherapy and combination setting."

Monotherapy • Mesothelioma • Oncology • Solid Tumor • NF2 • TEAD1 • TEAD2 • TEAD3

Pharmacologic Inhibition of YAP/TEAD and Development of New Chorioretinal Atrophy. (PubMed, JAMA Ophthalmol) - "The patient was treated with VT3989, a YAP/TEAD inhibitor, for 5 cycles...Downregulation of the Hippo signaling pathway via YAP/TEAD inhibition in an adult patient may result in a phenotype resembling a mild form of HPCD (Sveinsson chorioretinal atrophy), underscoring the importance of this pathway in maintenance of the adult retina and retinal pigment epithelium. As novel cancer therapeutics continue to emerge, it may be important to ensure ophthalmologic monitoring of patients on drugs targeting the Hippo pathway."

Journal • Mesothelioma • Oncology • Ophthalmology • Solid Tumor • TEAD1

Evaluation of TEAD inhibitor, VT3989, treatment in aggressive meningioma. (SNO 2025) - "Meningioma cells harboring NF2 loss exhibited higher sensitivity and a more robust response to VT3989 compared to NF2 wild-type cells. Evaluation of VT3989 in ex-vivo treated patient tissue samples and PDX mouse models is ongoing."

Brain Cancer • Meningioma • Solid Tumor • ANKRD1 • CCN1 • CTGF • NF2

TEAD inhibitor VT3989, in combination with Brigatinib prevents NF2-deficient meningioma and schwannoma growth. (SNO 2025) - "Further validation of these processes is underway to identify synthetic lethality targets and determine the mechanism behind VT3989 and brigatinib synergy. Together, our data demonstrates the therapeutic efficacy of VT3989 in combination with brigatinib, highlighting its potential clinical benefit for future NF2-SWN patients."

Combination therapy • Brain Cancer • Ependymoma • Meningioma • Solid Tumor • NF2 • POSTN

TEAD inhibitor VT3989, in combination with Brigatinib prevents NF2-deficient meningioma and schwannoma growth. (SNO 2025) - "Further validation of these processes is underway to identify synthetic lethality targets and determine the mechanism behind VT3989 and brigatinib synergy. Together, our data demonstrates the therapeutic efficacy of VT3989 in combination with brigatinib, highlighting its potential clinical benefit for future NF2-SWN patients."

Combination therapy • Brain Cancer • Ependymoma • Meningioma • Solid Tumor • NF2 • POSTN

Variable Schwann cell merlin inactivation is targetable with TEAD1 inhibition in schwannomas. (PubMed, bioRxiv) - "These findings, and tumor cell growth suppression were confirmed in NF2 fl/fl;Peri-Cre mouse model 7 , and in human derived schwannoma cells treated with a pan-TEAD auto palmitoylation inhibitor VT3989. 8 Our computational and experimental results confirm that TEAD1 inhibition could be a potent, targeted strategy for schwannomas."

Journal • Brain Cancer • Genetic Disorders • Neurofibromatosis • Oncology • Otorhinolaryngology • Solid Tumor • NF2 • TEAD1

SAFETY AND EARLY EFFICACY OF VT3989, A TEAD INHIBITOR, IN PATIENTS WITH ADVANCED EPITHELIOID HEMANGIOENDOTHELIOMA (EHE): A PHASE I/II STUDY (CTOS 2025) - No abstract available

Clinical • Metastases • P1/2 data • Oncology • Sarcoma • Solid Tumor

Evaluation of TEAD inhibitor, VT3989, treatment in aggressive meningioma. (WFNOS 2025) - "Meningioma cells harboring NF2 loss exhibited higher sensitivity and a more robust response to VT3989 compared to NF2 wild-type cells. Evaluation of VT3989 in ex-vivo treated patient tissue samples and PDX mouse models is ongoing."

Brain Cancer • Meningioma • Oncology • Solid Tumor • ANKRD1 • CCN1 • CTGF • NF2

TEAD inhibitor VT3989, in combination with Brigatinib prevents NF2-deficient meningioma and schwannoma growth. (WFNOS 2025) - "Further validation of these processes is underway to identify synthetic lethality targets and determine the mechanism behind VT3989 and brigatinib synergy. Together, our data demonstrates the therapeutic efficacy of VT3989 in combination with brigatinib, highlighting its potential clinical benefit for future NF2-SWN patients."

Combination therapy • Brain Cancer • Ependymoma • Meningioma • Solid Tumor • NF2 • POSTN

TEAD inhibitor VT3989, in combination with Brigatinib prevents NF2-deficient meningioma and schwannoma growth. (WFNOS 2025) - "Further validation of these processes is underway to identify synthetic lethality targets and determine the mechanism behind VT3989 and brigatinib synergy. Together, our data demonstrates the therapeutic efficacy of VT3989 in combination with brigatinib, highlighting its potential clinical benefit for future NF2-SWN patients."

Combination therapy • Brain Cancer • Ependymoma • Glioma • Meningioma • Oncology • Solid Tumor • NF2 • POSTN

YAP/TEAD inhibitor VT3989 in solid tumors: a phase 1/2 trial. (PubMed, Nat Med) - P1/2 | "VT3989 was recently awarded orphan drug designation and fast-track designation for the treatment of mesothelioma by the US Food and Drug Administration (FDA). ClinicalTrials.gov Identifier: NCT04665206 ."

Journal • P1/2 data • Fatigue • Mesothelioma • Oncology • Renal Disease • Solid Tumor

VT3989, Vivace Therapeutics' Best-in-Class, Hippo Pathway-Targeting Therapy, Demonstrates Promising Antitumor Activity in Refractory Mesothelioma (PRNewswire) - "Latest data from phase I/II study reported in an oral presentation at the European Society for Medical Oncology (ESMO) Congress 2025....Key findings for VT3989 in this population include: Objective Response Rate (ORR) of 32% (7 of 22 patients achieved a partial response). Disease Control Rate (DCR) of 86% (19 of 22 patients achieved a partial response or stable disease). Median Progression-Free Survival (PFS) of 40 weeks, which is more than double the 15-week benchmark....Vivace to Advance VT3989 into Phase 3 Registrational Trial in Mesothelioma Patients in First Half of 2026."

New P3 trial • P1/2 data • Mesothelioma

First-in-class treatment for refractory mesothelioma (MD Anderson Press Release) - "As the chair of the ESMO Congress 2025 Developmental Therapeutics track, I’m excited about the many significant studies that MD Anderson researchers are presenting at this year’s meeting....I will be presenting results from a Phase I/II trial assessing the first-in-class drug VT3989."

P1/2 data • Mesothelioma

Vivace Therapeutics' VT3989 Granted Fast Track Designation by the U.S. Food and Drug Administration for the Treatment of Mesothelioma (PRNewswire) - "The designation pertains to VT3989's use as a treatment for patients with unresectable malignant nonpleural or pleural mesothelioma whose disease has progressed on prior immune checkpoint inhibitor therapy and platinum-based chemotherapy....The compound has been evaluated in more than 200 patients to date in an ongoing, open-label Phase 1 clinical study and, to the company's knowledge, is the first and only member of the TEAD autopalmitoylation inhibitor class for which compelling clinical efficacy data have been publicly reported."

Fast track • Malignant Pleural Mesothelioma

VT3989-001: Study to Evaluate VT3989 in Patients With Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=336 | Recruiting | Sponsor: Vivace Therapeutics, Inc | Phase classification: P1 ➔ P1/2

Phase classification • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • NF2