IAG933 / Novartis - LARVOL DELTA

A first-in-human study of oral IAG933 in adult patients with advanced mesothelioma and other solid tumours (ESMO 2025) - P1 | "Conclusions IAG933 is a direct inhibitor of the YAP-TEAD protein-protein interaction. In the dose escalation phase of this trial, IAG933 was well-tolerated and demonstrated clinical efficacy."

Clinical • First-in-human • Metastases • P1 data • Brain Cancer • Malignant Pleural Mesothelioma • Meningioma • Mesothelioma • Oncology • Peritoneal Mesothelioma • Pleural Mesothelioma • Solid Tumor • LATS1

COMBINED TEAD AND TYROSINE KINASE INHIBITOR THERAPY STRONGLY EXTENDS SURVIVAL IN HEPATOCELLULAR CARCINOMA (AASLD 2025) - "The combination of TKI lenvatinib and panTEADi IAG933 significantly extended median OS (>18 wks/ongoing IAG933+lenvatinib vs 10.5 wks IAG933, 9.9 wks lenvatinib, 5.9 wks vehicle) in MET+CCNTB1-driven HCC. The unique HCC-promoting functions of each TEAD family member provide the basis for potent anti-tumor effects of panTEADi in HCC. Owing to strong synergies, the combination of panTEADi and TKI may represent a potent and clinically applicable tumor cell-targeted therapy for HCC that could be combined with current TME-directed therapies."

Hepatocellular Cancer • Oncology • Solid Tumor • NRAS

COMBINED TEAD AND RAS INHIBITOR THERAPY ACHIEVES LONG-TERM SURVIVAL IN KRAS-MUTANT CHOLANGIOCARCINOMA (AASLD 2025) - " Bulk and scRNA-seq analysis in mouse CCA models, the TCGA and Fu-iCCA cohorts and human scRNA-seq data revealed a consistent upregulation of YAP/TAZ/TEAD pathway members...VT104 or IAG933 plus KRASG12D-specific inhibitor MTRX1133 or panRAS inhibitors RMC-7977 and RMC-6236 blocked compensatory YAP/TAZ pathway activation, achieved strong synergies in vitro and extended median survival from 2.3 weeks to 9.7 weeks (VT104 + MRTX1133, p<0.0001) and 14.4 weeks (VT104 + RMC7977, p<0.0001) in KRASG12D-driven CCA... Collectively, our study identified TEAD and RAS signaling as convergent and druggable vulnerabilities that can be targeted to prolong CCA survival and delay the development of resistance."

IO biomarker • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • CAFs • KRAS • NICD

TEAD INHIBITION BY IAG933 AS A NOVEL THERAPEUTIC STRATEGY FOR CHOLANGIOCARCINOMA (AASLD 2025) - "Cells were treated with IAG933 alone or in combination with either standard chemotherapy (gemcitabine/cisplatin; GemCis) or a pan-KRAS inhibitor (RMC-6236)... IAG933 robustly inhibits TEAD-driven transcription and suppresses CCA growth in vitro and in vivo. Its synergy with GemCis and RMC-6236 supports its potential as a therapeutic candidate for CCA, including KRAS-mutated subtypes. Notably, SOD2 upregulation as a response to TEAD inhibition may represent a general resistance mechanism in CCA."

Biliary Cancer • Cholangiocarcinoma • Liver Cancer • Oncology • Solid Tumor • CCN1 • CTGF • KRAS • SOD2

Discovery of a Potent and Selective TEAD Degrader with Durable Degradation Activity. (PubMed, Adv Sci (Weinh)) - "KG-FP-003 exhibits superior activity compared to the lipid-binding pocket (LBP) inhibitor MYF-03-176 and the TEAD-YAP protein-protein interaction (PPI) inhibitor IAG933, efficiently degrading all TEAD isoforms at low nanomolar concentrations in a ubiquitin-proteasome system (UPS)-dependent manner. Furthermore, barcoded cell line screening revealed elevated sensitivity in several cancer types, including endometrial carcinoma, glioblastoma, ovarian epithelial tumors, and osteosarcoma. These findings position KG-FP-003 as a compelling lead candidate for TEAD isoform-selective therapies and underscore its potential utility beyond Hippo-dysregulated mesothelioma."

Journal • Brain Cancer • Endometrial Cancer • Glioblastoma • Mesothelioma • Oncology • Osteosarcoma • Ovarian Cancer • Sarcoma • Solid Tumor • Targeted Protein Degradation

A Phase I Study of IAG933 in Patients With Advanced Mesothelioma and Other Solid Tumors (clinicaltrials.gov) - P1 | N=137 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting

Enrollment closed • Mesothelioma • Oncology • Solid Tumor • LATS1 • LATS2

Identification of pyrazolo-piperidinone derivatives targeting YAP-TEAD interface 3 as anticancer agents through integrated virtual screening and mass spectrometry proteomics. (PubMed, Eur J Med Chem) - "They demonstrated efficacy against colorectal cancer cells resistant to the KRAS-dependent clinical candidate IAG933 and confirmed the ability to inhibit TEAD4 target genes expression. Bioinformatic metabolic pathway analysis further differentiated the mechanism of action of the 6a analogs from verteporfin, a known indirect modulator of the Y:T complex. These findings establish the pyrazolo-piperidinone class as novel Y:T disruptors and provide insights into their metabolic impact on downstream effectors, offering a valuable framework for future hit-to-lead optimization and mechanism of action studies."

Journal • Colorectal Cancer • Oncology • Ovarian Cancer • Solid Tumor • CTGF • KRAS • TEAD4 • TGFB1

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

Combination therapy with YAP/TEAD and RAS inhibitors overcomes phenotypic cell plasticity-driven resistance in NRAS-mutated melanoma (EACR 2025) - "Material and Loss-of-function approaches using RMC-6236, IAG933 (a YAP-TEAD interaction inhibitor), or siRNAs were employed to evaluate the impact of NRAS inhibition on phenotypic adaptation (RNA-seq, RT-qPCR, western blot analyses) as well as cell proliferation and survival (colony formation assay, flow cytometry) in human and murine NRAS-mutant cell line models. NRAS inhibition in melanoma cells induces a mesenchymal phenotypic transition linked to YAP pathway activation. YAP/TEAD inhibition can overcome resistance to NRAS inhibition by preventing adaptive phenotype switching and inducing tumor cell death. This work provides a scientific rationale for treating NRAS-mutant melanomas with a combination of RAS and YAP-TEAD inhibitors."

Combination therapy • IO biomarker • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • NRAS

Determination of the MYC- and TEAD-dependent transcriptome in pancreatic cancer (AACR 2025) - "We recently reported MYC amplification and TEAD-dependent transcriptional activation by YAP as drivers of resistance to the multi-RAS inhibitor RMC-7977 (RASmulti), the preclinical analog of RMC-6236...To determine the TEAD-dependent transcriptome, we treated a panel of three sets of paired naïve and RASmulti-resistant KPC cell lines, derived from an autochthonous mouse model of PDAC, and of six human KRAS-mutant PDAC cell lines with the TEAD inhibitor IAG933, with RMC-7977, or with the combination...Proteomic profiling of PDAC cell lines with acquired resistance to RMC-7977 showed upregulation of TEAD-dependent gene products, supporting TEAD activation as a non-genetic mechanism of acquired resistance. Together, our findings expand the role of MYC and TEAD in supporting PDAC cell growth and resistance to RAS inhibition and provide rationale for further evaluation of combination therapeutic strategies to limit resistance."

Late-breaking abstract • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • KRAS • MYC

A Role for the Hippo/YAP1 Pathway in the Regulation of In Vitro Vasculogenic Mimicry in Glioblastoma Cells. (PubMed, J Cell Mol Med) - "All three Hippo pathway inhibitors tested, GNE7883, VT107 and IAG933 effectively inhibited U87 and U251 cell migration and in vitro VM as assessed on Cultrex matrix...SiRNA-mediated transient silencing of YAP1 repressed cell migration, VM formation and CTGF and Cyr61 transcription. In conclusion, targeting of VM using Hippo pathway inhibitors could help circumvent GBM chemoresistance and effectively complement other brain cancer treatments."

Journal • Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CCN1 • CTGF • TEAD1 • YAP1

A Phase I Study of IAG933 in Patients With Advanced Mesothelioma and Other Solid Tumors (clinicaltrials.gov) - P1 | N=156 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Jan 2026 ➔ Sep 2026 | Trial primary completion date: Jan 2026 ➔ Sep 2026

Metastases • Trial completion date • Trial primary completion date • Mesothelioma • Oncology • Solid Tumor • LATS1 • LATS2

A Phase I Study of IAG933 in Patients With Advanced Mesothelioma and Other Solid Tumors (clinicaltrials.gov) - P1 | N=156 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Oct 2025 ➔ Jan 2026 | Trial primary completion date: Oct 2025 ➔ Jan 2026

Metastases • Trial completion date • Trial primary completion date • Mesothelioma • Oncology • Solid Tumor • LATS1 • LATS2

Direct inhibition of the YAP:TEAD interaction: an unprecedented drug discovery challenge. (PubMed, ChemMedChem) - "The identification of inhibitors of the YAP:TEAD interaction is one approach to develop novel anticancer drugs: the first clinical candidate (IAG933) preventing the association between these two proteins by direct competition has just been reported...The most critical of these involves an omega-loop (Ω-loop), a secondary structure element rarely found in protein-protein interactions. This review summarizes how the knowledge gained from structure-function studies of the interaction between the Ω-loop of YAP and TEAD was used to devise the strategy to identify potent low-molecular weight compounds that show a pronounced anti-tumor effect."

Journal • Oncology

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

Direct and selective pharmacological disruption of the YAP-TEAD interface by IAG933 inhibits Hippo-dependent and RAS-MAPK-altered cancers. (PubMed, Nat Cancer) - "Importantly this also extended to larger tumor indications, such as lung, pancreatic and colorectal cancer, in combination with RTK, KRAS-mutant selective and MAPK inhibitors, leading to more efficacious and durable responses. Clinical evaluation of IAG933 is underway."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Mesothelioma • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

A Phase I Study of IAG933 in Patients With Advanced Mesothelioma and Other Solid Tumors (clinicaltrials.gov) - P1 | N=156 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: May 2025 ➔ Oct 2025 | Trial primary completion date: May 2025 ➔ Oct 2025

Metastases • Trial completion date • Trial primary completion date • Mesothelioma • Oncology • Solid Tumor • LATS1 • LATS2

A Phase I Study of IAG933 in Patients With Advanced Mesothelioma and Other Solid Tumors (clinicaltrials.gov) - P1 | N=156 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Sep 2024 ➔ May 2025 | Trial primary completion date: Sep 2024 ➔ May 2025

Metastases • Trial completion date • Trial primary completion date • Lung Cancer • Mesothelioma • Oncology • Solid Tumor • LATS1 • LATS2

Leveraging Hot Spots of TEAD-Coregulator Interactions in the Design of Direct Small Molecule Protein-Protein Interaction Disruptors Targeting Hippo Pathway Signaling. (PubMed, Pharmaceuticals (Basel)) - "One direct YAP-TEAD PPID (IAG933) that targets interface 3 has entered a clinical trial in 2021. However, in general, strategically designing effective small molecules PPIDs targeting TEAD interfaces 2 and 3 has been challenging compared with allosteric inhibitor development. This review focuses on the development of direct surface disruptors and discusses the challenges and opportunities for developing potent YAP/TAZ-TEAD inhibitors for the treatment of cancer."

Journal • Review • Oncology • TEAD1

IAG933, a selective and orally efficacious YAP1/WWTR1(TAZ)-panTEAD protein-protein interaction inhibitor with pre-clinical activity in monotherapy and combinations (AACR 2023) - "Here we report the identification of IAG933, the first molecule able to potently and directly disrupt the YAP/TAZ-TEADs PPI with suitable properties to enter in clinical trial. Moreover, we provide evidence for combination benefits of IAG933 with several MAPK/KRAS inhibitors, both in vitro and in vivo, in non-Hippo altered models including lung, pancreatic and colorectal cancer. Overall, our results provide a rationale of progressing IAG933 as a monotherapy in patients with Hippo-mutated cancers, and as a combination partner in MAPK-dependent cancers, with the potential to treat patient populations of high unmet medical need."

Late-breaking abstract • Monotherapy • Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pancreatic Cancer • Solid Tumor • KRAS • NF2 • TAFAZZIN • VGLL4 • WWTR1 • YAP1