VT3989 / Vivace Therap - LARVOL DELTA

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

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

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

Identification of small molecule Pan-TEAD inhibitors disrupting YAP-TEAD protein-protein interaction and targeting gastric cancer cells (AACR 2024) - P1 | "Aberrant overexpression of YAP/TAZ-TEAD promotes tumorigenesis and is therefore considered oncogenes in many solid tumors...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

Harnessing the power of endogenous metabolite-protein interactions for allosteric modulation (ACS-Sp 2024) - "Allosteric metabolite binding sites on these targets have been successfully used to generate new medicines (e.g.: Asciminib for BCR-ABL) and investigational cancer therapies (e.g.: IK-930, VT3989 for TEAD). Atavistik Bio has developed the AMPS (Atavistik Metabolite Protein Screening) platform that enables systematic and scalable screening of metabolites against proteins or protein complexes of interest. In this oral presentation, it will be highlighted how the AMPS platform can identify allosteric protein-metabolite interactions to advance small molecule drug discovery efforts."

Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • BCR

Study to Evaluate VT3989 in Patients With Metastatic Solid Tumors Enriched for Tumors With NF2 Gene Mutations (clinicaltrials.gov) - P1 | N=188 | Recruiting | Sponsor: Vivace Therapeutics, Inc | Trial completion date: Feb 2024 ➔ Dec 2024 | Trial primary completion date: Feb 2024 ➔ Nov 2024

Metastases • Trial completion date • Trial primary completion date • Mesothelioma • Oncology • Solid Tumor • NF2

First-in-Human Phase 1 Trial of VT3989, a First-in-Class YAP/TEAD Inhibitor in Patients with Advanced Mesothelioma (IASLC-WCLC 2023) - "The 44 mesothelioma patients had a median age of 65 (range 21-83), ECOG PS of 0 (n=7) or 1 (n=37), median of 3 prior regimens (range 1-8); all had received prior platinum and pemetrexed, 43/44 (98%) had prior immune checkpoint inhibitors and 16/44 (36%) had VEGF antibodies; 33 had epithelioid, 7 biphasic and 4 sarcomatoid histology. VT3989 is well tolerated with durable responses in patients with refractory mesothelioma. This study provides the first clinical proof-of-concept for drugging the Hippo-YAP-TEAD pathway. RP2D optimization including further schedule evaluation and expansion are ongoing in mesothelioma patients evaluating different intermittent schedules."

Clinical • IO biomarker • Metastases • P1 data • Cardiomyopathy • Cardiovascular • Fatigue • Glomerulonephritis • Hypotension • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Nephrology • Oncology • Pulmonary Disease • Renal Disease • Sarcoma • Solid Tumor • NF2

VT3989, the first-in-class and first-in-human TEAD auto-palmitoylation inhibitor, enhances the efficacy and durability of multiple targeted therapies of the MAPK and P13K/AKT/mTOR pathways. (AACR-NCI-EORTC 2023) - No abstract available

Clinical • P1 data • Oncology

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

Study to Evaluate VT3989 in Patients With Metastatic Solid Tumors Enriched for Tumors With NF2 Gene Mutations (clinicaltrials.gov) - P1 | N=188 | Recruiting | Sponsor: Vivace Therapeutics, Inc | N=80 ➔ 188

Enrollment change • Lung Cancer • Mesothelioma • Oncology • Solid Tumor

TY-0584: A potent, orally available small molecule YAP/TEAD inhibitor, exhibits anti-tumor effects in vitro and in vivo (AACR 2023) - P1, P3 | "Therefore, small molecules that target palmitoylation of TEAD have been explored and VT3989 (NCT04665206) and IK-930 (NCT05228015) have success to enter the clinical trials...In line with the results of the in-vitro experiments, another YAP/TEAD inhibitor TY-0536 in combination with TY-9591 significantly delay the tumor regrowth in the PC9 CDX mouse model...[Shengli Dong and Apeng Liang contributed equally to this work. Jun Li, Shengli Dong, and Apeng Liang are the corresponding authors.]"

Preclinical • Brain Cancer • CNS Tumor • Head and Neck Cancer • Lung Cancer • Melanoma • Meningioma • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • NF2

Researchers Report Clinical Proof-of-Concept Data for Vivace Therapeutics' VT3989, a First for a Cancer Drug Targeting the Hippo Pathway, in Oral Presentation at AACR 2023 (PRNewswire) - P1 | N=80 | NCT04665206 | Sponsor: Vivace Therapeutics | "Vivace Therapeutics...announced that the first clinical data for a cancer treatment targeting the Hippo pathway was presented at the American Association for Cancer Research (AACR) Annual Meeting 2023. Results from the company's Phase 1 clinical study of its first-in-class transcriptional enhanced associate domain (TEAD) autopalmitoylation inhibitor, VT3989, showed the compound to be well tolerated with durable antitumor responses in patients with advanced malignant mesothelioma and other tumors with neurofibromatosis 2 (NF2) mutations."

P1 data • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor

Vivace Therapeutics to Unveil First Clinical Data for a Cancer Drug Targeting the Hippo Pathway (PRNewswire) - "Vivace Therapeutics, Inc...announced that the first clinical data for a cancer treatment targeting the Hippo pathway will be presented at the American Association for Cancer Research (AACR) Annual Meeting 2022. Results from the company's Phase 1 clinical study of its first-in-class transcriptional enhanced associate domain (TEAD) autopalmitoylation inhibitor, VT3989, will be presented by Timothy A. Yap, Ph.D., of the University of Texas, M.D. Anderson Cancer Center, during an oral plenary session at the conference. The AACR conference is being held April 14-19, 2023, in Orange, Florida."

P1 data • Mesothelioma • Oncology • Solid Tumor

Vivace Therapeutics Presents New Preclinical Data Highlighting Strong Synergistic Activity for Combination of VT3989 and Osimertinib at American Association for Cancer Research (AACR) Annual Meeting 2022 (PRNewswire) - "Data reported in the poster presentation demonstrated that VT3989 exhibits strong synergistic activity with osimertinib. This was highlighted by the ability of the combination to enhance the blocking of tumor growth in EGFR mutant, non-small cell lung cancer (NSCLC) cell-line derived xenograft models, including the HCC827 model that is already known to be particularly sensitive to osimertinib. Furthermore, the combination of VT3989 and osimertinib significantly increased the life span of mice in an NCI-H1975 NSCLC CDX model as compared to osimertinib monotherapy. Additionally, researchers showed similar synergistic activity in blocking tumor regrowth in human patient-derived xenograft models of EGFR mutant NSCLC."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology

The TEAD autopalmitoylation inhibitor VT3989 improves efficacy and increases durability of efficacy of osimertinib in preclinical EGFR mutant tumor models (AACR 2022) - "In vivo, we observed strong VT3989 and osimertinib combination effect in NCI-H1975 and HCC827 cell line-derived xenograft models. We also tested the combination in several EGFR mutant NSCLC patient-derived xenograft models and demonstrated that the addition of VT3989 enhanced the efficacy of osimertinib and delayed tumor regrowth compared to osimertinib alone."

Preclinical • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • EGFR • KRAS

Vivace Therapeutics to Present New Data from Preclinical Combination Studies of VT3989 and Osimertinib at American Association for Cancer Research (AACR) Annual Meeting 2022 (PRNewswire) - "Vivace Therapeutics...announced that new preclinical data on the company's transcriptional enhanced associate domain (TEAD) autopalmitoylation inhibitor, VT3989, will be presented at the American Association for Cancer Research (AACR) Annual Meeting 2022. Presented findings will highlight results of research evaluating the combination of VT3989 and osimertinib (Tagrisso®), an epidermal growth factor receptor (EGFR) inhibitor, in preclinical EGFR mutant tumor models. Study data demonstrated strong synergistic activity for the treatment combination as compared to osimertinib alone, as evidenced by enhanced efficacy and delayed tumor regrowth."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

Vivace Therapeutics Announces Issuance of New U.S. Composition of Matter Patents (PRNewswire) - "Vivace Therapeutics, Inc...announced that the United States Patent and Trademark Office (USPTO) has issued the company two new composition of matter patents. The newly issued patents, U.S. No. 11,186,554 and U.S. No. 11,192,865, are directed at novel, first-in-class, anti-cancer compounds discovered by Vivace that target the Hippo pathway....The company's clinical candidate, VT3989, is currently in Phase 1 clinical trials. "

Patent • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor

Study to Evaluate VT3989 in Patients With Metastatic Solid Tumors Enriched for Tumors With NF2 Gene Mutations (clinicaltrials.gov) - P1; N=80; Recruiting; Sponsor: Vivace Therapeutics, Inc; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Lung Cancer • Mesothelioma • Oncology • Solid Tumor