VT3989 / Vivace Therap - LARVOL DELTA

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

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 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

Vivace Therapeutics Announces Receipt of Orphan Drug Designation for VT3989 for Treatment of Mesothelioma (PRNewswire) - "Vivace Therapeutics...announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to VT3989 for the treatment of mesothelioma in the United States...'We are committed to continuing clinical development of VT3989 and discussing a move into a registrational Phase 3 study in mesothelioma with FDA by the end of 2025.'...In addition to the promising data to date, VT3989 has demonstrated a positive safety profile in the Phase 1 trial, which supports its best-in-class potential....These results will be presented at a major medical conference in the second half of 2025."

New P3 trial • Orphan drug • P1 data • Mesothelioma

Hippo/YAP signaling pathway in colorectal cancer: regulatory mechanisms and potential drug exploration. (PubMed, Front Oncol) - "Preclinical and clinical investigations highlight the efficacy of diverse Hippo/YAP-targeted interventions, with recent clinical trials (e.g., VT3989, IK-930, IAG933, ION537) underscoring the translational promise of this pathway. Integrating cutting-edge insights into its regulatory networks and clinical targeting offers novel perspectives for precision oncology. By bridging fundamental discoveries with translational applications, this review establishes Hippo/YAP as a compelling therapeutic target and provides a theoretical foundation for developing innovative CRC therapies."

Journal • Review • CNS Disorders • Colorectal Cancer • Oncology • Psychiatry • Solid Tumor • TAFAZZIN

The selective Yap/Tead inhibitor TY-1054 re-sensitizes acquired resistance to multiple tyrosine kinase-based targeted therapies (AACR 2025) - P1 | "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

Study to Evaluate VT3989 in Patients with Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=336 | Recruiting | Sponsor: Vivace Therapeutics, Inc | Phase classification: P1/2 ➔ P1 | N=250 ➔ 336

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

Vivace Therapeutics Raises $35 Million in Series D Financing to Support Clinical Development of First-in-Class Cancer Drug Targeting the Hippo Pathway (PRNewswire) - "Vivace Therapeutics, Inc...announced the closing of a $35 million Series D financing. The round was led by RA Capital Management, an existing investor, and included investment from other existing investors Canaan Partners and Cenova Capital. Proceeds will support the continued clinical development of the company's first-in-class and best-in-class transcriptional enhanced associate domain (TEAD) autopalmitoylation inhibitor, VT3989, with an initial focus on mesothelioma....Clinical findings for VT3989 have been particularly notable in patients with mesothelioma who have failed chemotherapy and immuno-oncology combination regimens, which represent the only approved therapies in this indication. These results will be presented at a major medical conference in the second half of 2025. Based on these data, Vivace is working to advance VT3989 toward a randomized registrational Phase 3 clinical trial in patients with mesothelioma and intends to discuss its plans with the..."

FDA event • Financing • P1 data • Mesothelioma • Solid Tumor

Evaluating the Use of Merlin-YAP Dual-label Immunohistochemistry for Predicting Response to TEAD Inhibitor VT3989 (EORTC-NCI-AACR 2024) - P1/2 | "The Merlin/YAP duplex IHC assay is ready for clinical application in an ongoing VT3989 trial where clinical activity is being observed in mesothelioma and will provide novel insights on the YAP/TAZ-TEAD pathway."

Mesothelioma • Oncology • Solid Tumor • NF2

Advances in Targeted Therapy for Malignant Pleural Mesothelioma (PubMed, Zhongguo Fei Ai Za Zhi) - "At present, it has been found the following types of targets: gene mutation targets such as BRCA associated protein 1 (BAP1) and cyclin-dependent kinase 2A (CDKN2A); epigenetic targets such as lysine (K)-specific demethylase 4A (KDM4A) and lysine-specific demethylase 1 (LSD1), and signal protein targets such as glucose-regulated protein 78 (GRP78) and signal transducer and activator of transcription 3 (STAT3). So far, available clinical trials include phase II clinical trials of histone methyltransferase inhibitor Tazemetostat, poly (ADP-ribose) polymerase (PARP) inhibitor Rucaparib and cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor Abemaciclib, as well as phase I clinical trials of mesothelin-targeting chimeric antigen receptor T-cell immunotherapy (CAR-T) cell injection in the thoracic cavity and TEA domain family member (TEAD) inhibitor VT3989 and IK-930, and the results of these trials have showed certain clinical efficacy.."

IO biomarker • Journal • Review • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor • BAP1 • BRCA • CDKN2A • HSPA5 • KDM4A • MSLN • STAT3

Study to Evaluate VT3989 in Patients With Metastatic Solid Tumors Enriched for Tumors With NF2 or mNF2 Gene Mutations (clinicaltrials.gov) - P1/2 | N=250 | Recruiting | Sponsor: Vivace Therapeutics, Inc | Phase classification: P1 ➔ P1/2 | N=188 ➔ 250 | Trial completion date: Dec 2024 ➔ Jun 2027 | Trial primary completion date: Nov 2024 ➔ Dec 2026

Enrollment change • Metastases • Phase classification • Trial completion date • Trial primary completion date • Fibrosis • Genetic Disorders • Mesothelioma • Neurofibromatosis • Oncology • Solid Tumor • NF2

Comparing TEAD palmitoylation inhibitors with differential TEAD selectivity in combination efficacy with targeted therapies and in renal safety (AACR 2024) - "We have discovered and developed highly potent and selective TEAD auto-palmitoylation inhibitors that interact directly with TEAD by occupying the central palmitate pocket, disrupt YAP/TAZ-TEAD protein interaction, suppress TEAD transcriptional activity, and selectively block NF2-deficient mesothelioma proliferation in vitro and inhibit NF2 mutant tumor growth in vivo. 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..."

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

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