IAG933 / Novartis - LARVOL DELTA

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