Novartis halted enrollment in its Phase 1 trial of IAG933, a TEAD inhibitor being studied for mesothelioma. A Novartis spokesperson said the decision was “not caused by any safety concerns, and was based on the project’s tolerability and antitumour activity.” The asset was subsequently removed from the company’s pipeline presentation. The move leaves Vivace Therapeutics’ VT3989 as the leading drug in this class, which targets a key vulnerability in mesothelioma cells.
What Are TEAD Inhibitors?
The Hippo Pathway
TEAD inhibitors target a cellular pathway critical to many mesotheliomas:
| Pathway Component | Role | In Mesothelioma |
|---|---|---|
| Hippo pathway | Controls cell growth | Often disrupted |
| NF2/Merlin | Tumor suppressor | Lost in 40-50% of cases |
| YAP/TAZ | Growth signals | Overactive when NF2 lost |
| TEAD | Final effector | Drug target |
When the tumor suppressor NF2 is lost (common in mesothelioma), TEAD proteins drive uncontrolled cell growth. Blocking TEAD can stop this growth.
Why TEAD Is Attractive
| Advantage | Explanation |
|---|---|
| Mesothelioma-specific | High rates of pathway disruption |
| Novel mechanism | Different from chemo and immunotherapy |
| Oral dosing | Convenient for patients |
| Clear biomarker | NF2 status may predict response |
The Novartis Decision
What Happened
| Timeline | Event |
|---|---|
| 2020s | Novartis develops IAG933 |
| 2024 | Phase 1 trial (NCT04857372) underway |
| ESMO 2025 | Phase 1 data reported |
| Late 2025 | Enrollment halted; asset removed from pipeline |
| Stated reason | Tolerability and antitumor activity |
At ESMO 2025, Phase 1 data showed a 19% objective response rate across 37 people with Hippo-altered tumors overall, and roughly 13% to 17% ORR across 30 people with pleural mesothelioma at 300 mg to 400 mg daily doses. Dose-limiting toxicities included QTc prolongation in four people (at 400 mg and 600 mg doses) and grade 2 proteinuria in one person.
Industry Context
IAG933 is not the first TEAD inhibitor to hit a wall:
| Company | Drug | Status |
|---|---|---|
| Novartis | IAG933 | Enrollment halted (late 2025) |
| Ikena | IK-930 | Discontinued May 2024 |
| Vivace | VT3989 | Advancing to Phase 3 |
The challenges highlight the difficulty of developing TEAD inhibitors, and make VT3989’s results at ESMO 2025 more significant for the class.
Multiple TEAD inhibitor programs have struggled, but VT3989’s success validates the target. For patients seeking TEAD inhibitor access, ask your oncologist about VT3989 clinical trials and consider NF2 testing. This biomarker may predict response.
VT3989: Now the Leader
Strong Clinical Data
With Novartis out, VT3989 from Vivace Therapeutics is now the most advanced TEAD inhibitor for mesothelioma:
| VT3989 Results | Data |
|---|---|
| Overall response rate | 32% |
| Disease control rate | 86% |
| Median PFS | 40 weeks (vs 15 weeks historical) |
| FDA designation | Fast Track |
| Next step | Phase 3 trial planned |
Why VT3989 May Have Succeeded
| Factor | Possible Advantage |
|---|---|
| Drug design | Different binding characteristics |
| Patient selection | Focused on NF2-mutant tumors |
| Dosing strategy | Optimized regimen |
| Company focus | Mesothelioma as priority indication |
What This Means for Patients
Current Treatment Landscape
| Treatment | Setting | Status |
|---|---|---|
| Chemotherapy | First-line | Standard of care |
| Opdivo + Yervoy | First-line | FDA approved |
| Nivolumab alone | Relapsed | CONFIRM trial data |
| TEAD inhibitors | Relapsed | In development |
TEAD inhibitors represent a potential new option for patients who have exhausted standard treatments.
Timeline Expectations
| Milestone | Expected Timeframe |
|---|---|
| VT3989 Phase 3 starts | 2026 |
| Phase 3 results | 2028-2029 |
| Potential FDA approval | 2029-2030 |
Patients seeking TEAD inhibitor access should ask about clinical trials.
Finding TEAD Inhibitor Trials
- Ask your oncologist about VT3989 and other TEAD trials
- Search ClinicalTrials.gov for “TEAD mesothelioma”
- Consider NF2 testing: May help determine eligibility
- Contact Vivace Therapeutics: For trial information
The Broader Drug Development Lesson
High Failure Rates
The IAG933 discontinuation illustrates drug development challenges:
| Stage | Historical Success Rate |
|---|---|
| Phase 1 to approval | ~10% |
| Phase 2 to approval | ~30% |
| Phase 3 to approval | ~60% |
Many promising drugs fail. The key is having multiple options in development.
Mesothelioma Pipeline Status
| Drug Class | Drugs in Development |
|---|---|
| Checkpoint inhibitors | Multiple approved and in trials |
| TEAD inhibitors | VT3989 leading |
| Arginine depletion | Pegargiminase |
| Bispecific antibodies | BNT327 and others |
| Targeted therapies | Various |
The pipeline is more robust than ever, offering hope despite individual setbacks.
Key Takeaways
One drug’s failure does not doom a class: VT3989, another TEAD inhibitor, continues to show promise in NF2-mutated mesothelioma. Mesothelioma research is advancing, with multiple novel approaches (checkpoint inhibitors, arginine depletion, bispecific antibodies, and targeted agents) in development at once. Biomarkers matter, and NF2 status in particular may predict TEAD inhibitor response. Clinical trials remain the primary route through which patients access new drugs. And drug development takes years, so individual setbacks have to be read against longer timelines.
Related Articles
- VT3989 TEAD Inhibitor Breakthrough
- BioNTech BNT327 ASCO 2025 Data
- ATOMIC-Meso Arginine Depletion Results
- Mesothelioma Clinical Trials
What happened to Novartis IAG933?▼
Novartis halted enrollment in its Phase 1 trial of IAG933 in late 2025 and removed the asset from its pipeline presentation. A company spokesperson said the decision was based on the project’s tolerability and antitumor activity, and not on safety concerns. At ESMO 2025, IAG933 had shown a 19% overall response rate across 37 people with Hippo-altered tumors and roughly 13% to 17% in 30 people with pleural mesothelioma. This leaves VT3989 as the leading TEAD inhibitor for mesothelioma.
What are TEAD inhibitors?▼
TEAD inhibitors target a key pathway in mesothelioma. When the tumor suppressor NF2 is lost (40-50% of cases), TEAD proteins drive uncontrolled cell growth. Blocking TEAD can stop this growth. The approach is mesothelioma-specific, oral, and has a clear biomarker (NF2 status).
How is VT3989 performing?▼
VT3989 has shown 32% response rate, 86% disease control, and 40-week median progression-free survival (vs 15 weeks historical). It has received FDA Fast Track designation and is advancing to Phase 3 trials starting in 2026, with potential approval around 2029-2030.
How can I access TEAD inhibitor trials?▼
Ask your oncologist about VT3989 trials, search ClinicalTrials.gov for “TEAD mesothelioma,” consider NF2 testing to determine eligibility, and contact Vivace Therapeutics directly for trial information.