The HIPPO pathway, a cellular signaling system that prevents uncontrolled cell growth, has long been seen as a promising target for treating mesothelioma. However, multiple drug companies that have pursued this approach have quietly discontinued their efforts.
Tolerability Issues and Limited Effectiveness Halts Mesothelioma Drug Development
Mesothelioma tumors have specific genetic mutations affecting the HIPPO pathway. These mutations cause the HIPPO pathway to malfunction, allowing the rare cancer’s cells to multiply unchecked. Believing that blocking the proteins involved in this dysregulated pathway could stop mesothelioma tumor growth, researchers from multiple pharmaceutical companies have worked to design targeted inhibitors, but the approach has proven to be more difficult than anticipated.
Among the growing list of pharmaceutical companies with failed TEAD inhibitors is Novartis, which has quietly halted development of IAG933, a mesothelioma drug targeting the HIPPO pathway. The treatment disappeared from the company’s pipeline in its third-quarter earnings presentation, and Novartis has confirmed that it had stopped enrolling patients in the phase 1 trial, stating that the decision wasn’t caused by safety concerns, but that the drug had demonstrated concerning tolerability issues and limited antitumor activity.
Mesothelioma Drug Shows Disappointing Results
Recent data presented at the European Society for Medical Oncology (ESMO) conference revealed underwhelming mesothelioma treatment results from IAG933. Among 30 pleural mesothelioma patients receiving higher doses, only four achieved confirmed responses—a 13% response rate, and of that group, two required dose reductions due to the development of a potentially dangerous heart rhythm abnormality. Five patients experienced dose-limiting toxicities, highlighting the treatment’s tolerability challenges.
In dropping its pursuit of the drug, Novartis joins Ikena Oncology, which shelved its mesothelioma TEAD inhibitor IK-930 last year after reporting zero responses in clinical trials. Currently, the most promising TEAD inhibitor for mesothelioma treatment is being pursued by Vivace Therapeutics, which continues advancing VT3989. Updated mesothelioma trial results from Vivace showed a 32% response rate in 22 mesothelioma patients after optimizing dosing—substantially better than the results that Novartis reported. Vivace plans to launch a registrational phase 3 mesothelioma trial in early 2026, though VT3989 also causes concerning side effects, including proteinuria and elevated liver enzymes.
Despite ongoing challenges in developing effective treatments for this aggressive asbestos-related cancer, several other companies, including Orion, BridGene Biosciences, Insilico Medicine, and Merck KGaA, are developing mesothelioma treatments targeting the HIPPO pathway, though none have reported clinical results yet.
If you or someone you love has been diagnosed with mesothelioma, research into the HIPPO pathway represents significant hope. For information on other resources, contact the Patient Advocates at Mesothelioma.net at 1-800-692-8608.
