VT3989 Receives FDA Orphan Drug Designation for Mesothelioma

The FDA has granted orphan drug designation to VT3989, the company's first-in-class and best-in-class transcriptional enhanced associate domain (TEAD) autopalmitoylation inhibitor, for the treatment of patients with mesothelioma.1

This novel investigational small molecule was designed to target the Hippo pathway by inhibiting palmitoylation of members of the TEAD protein family.1,2 Dysregulation of this pathway through NF2 mutations can lead to unchecked proliferation and impaired cellular differentiation.2

VT3989 is the first and only TEAD autopalmitoylation inhibitor to show compelling clinical efficacy and a positive safety profile in an ongoing phase 1 open-label trial (NCT04665206) and has been evaluated in over 200 patients to date, according to the drug’s developer, Vivace Therapeutics.1

"The granting of orphan drug designation to VT3989 underscores the critical need for new, effective therapies for mesothelioma, an aggressive cancer with limited treatment options. The benefits provided by this important designation will support our continued advancement of VT3989, which has already generated compelling clinical trial data, a first for this promising therapeutic class," Sofie Qiao, PhD, president and chief executive officer of Vivace Therapeutics, stated in a news release. "We are committed to continuing clinical development of VT3989 and discussing a move into a registrational phase 3 study in mesothelioma with [the] FDA by the end of 2025."

The agent has demonstrated notable clinical outcomes among patients with mesothelioma previously treated with chemotherapy and immune checkpoint inhibitors, which are the only currently approved therapies for this indication. These data are expected to be presented at a major medical conference in the second half of 2025.

Phase 1 Study Overview

This multicenter, open-label phase 1 trial was designed to evaluate the safety, tolerability, pharmacokinetics, and biological activity of VT3989 in patients with advanced, refractory solid tumors, including both pleural and non-pleural malignant mesothelioma.2

The study is enrolling patients with an ECOG performance status of 0 to 2 and is enriched for those with malignant pleural mesothelioma or tumors harboring NF2 mutations. The dose-escalation phase followed a standard 3+3 design, with patients receiving continuous daily dosing of VT3989 at 25 mg (n = 5), 50 mg (n = 6), 100 mg (n = 6), 150 mg (n = 6), or 200 mg (n = 4) in 3- or 4-week cycles. Tumor response assessments were performed approximately every 8 to 9 weeks.

Several intermittent dosing schedules were subsequently explored, including: 50 mg daily for 15 days followed by weekly dosing (n = 6); 100 mg daily for 15 days followed by weekly dosing (n = 6); 150 mg on a 1-week-on/3-weeks-off schedule (n = 6); 100 mg on a 2-weeks-on/2-weeks-off schedule (n = 7); and 200 mg given either on a 2-weeks-on/2-weeks-off (n = 5), 1-week-on/2-weeks-off (n = 6), or 2-weeks-on/1-week-off (n = 6) schedule.

The dose-expansion portion will include 3 cohorts, one of which is pending determination. In cohort 1 (n = 10–27), patients with mesothelioma, regardless of NF2 mutation status, will receive 100 mg daily on a 2-weeks-on/2-weeks-off schedule. In cohort 2 (n = 10–27), patients will receive 50 mg daily for 15 days, followed by 100 mg weekly.

The study’s primary end points include safety/tolerability, maximum tolerated dose, and recommended phase 2 dose. Preliminary antitumor activity in NF2-mutant tumors, pharmacokinetics, time to response, and duration of response serve as key secondary end points. Exploratory analyses will assess Hippo/YAP signaling through serial biopsies, changes in circulating tumor DNA, and expression of YAP and Merlin by immunohistochemistry.

Early Efficacy and Safety Data With VT3989

Findings from this phase 1 trial, which were presented at the 2023 AACR Annual Meeting, showed durable antitumor activity and tolerability in patients with malignant mesothelioma and other solid tumors harboring NF2 mutations. Of the 69 patients with measurable disease, 7 experienced a reduction in tumor size and achieved partial responses (PRs) by RECIST 1.1 criteria; this included 6 confirmed PRs, and 1 unconfirmed PR. Moreover, 34 patients with measurable disease had stable disease as their best response to treatment.

VT3989 was also found to be well tolerated, with no dose-limiting toxicities or grade 5 adverse effects (AEs) observed. Most AEs with this agent were grade 1/2. Grade 3 AEs included albuminuria (4.3%), peripheral edema (1.4%), fatigue (1.4%), increased alanine transaminase levels (1.4%), and increased aspartate transaminase levels (1.4%).

References

1. Vivace Therapeutics announces receipt of orphan drug designation for VT3989 for treatment of mesothelioma. News Release. Vivace Therapeutics. July 31, 2025. Accessed August 1, 2025. https://www.prnewswire.com/news-releases/vivace-therapeutics-announces-receipt-of-orphan-drug-designation-for-vt3989-for-treatment-of-mesothelioma-302516783.html
2. Yap TA, Kwiatkowski DJ, Desai, et al. 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. Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract CT006.