PMV Pharmaceuticals is making strides in the development of Rezatapopt, a small molecule p53 reactivator, as a potential treatment for advanced solid tumors and hematologic malignancies harboring TP53 Y220C mutations. The company's third quarter 2024 financial results and corporate update highlight the progress of the PYNNACLE clinical trial and new investigator-initiated studies.
PYNNACLE Trial Update
The Phase 2 monotherapy portion of the PYNNACLE clinical trial is actively enrolling patients with TP53 Y220C and KRAS wild-type advanced solid tumors. This multicenter, single-arm, registrational trial is evaluating Rezatapopt at a dose of 2000 mg once-daily, with the primary endpoint being overall response rate per blinded independent central review. The trial aims to enroll 114 patients across five cohorts at approximately 60 sites.
"The Phase 2 portion of the PYNNACLE trial continues to advance, with site activation and enrollment progressing well," said David Mack, Ph.D., President and Chief Executive Officer of PMV Pharma. Site activation is progressing well, with more than 75% of sites activated across the U.S., Europe, and Asia-Pacific. PMV Pharma plans to provide data from the interim analysis of the Phase 2 monotherapy portion of the PYNNACLE trial by mid-2025 and anticipates a New Drug Application filing by the end of 2026.
Rezatapopt and Azacitidine Combination Study
PMV Pharma is collaborating with MD Anderson Cancer Center and Memorial Sloan Kettering Cancer Center to support an investigator-initiated Phase 1b study. The study is designed to assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of rezatapopt monotherapy and in combination with azacitidine in approximately 25 patients with relapsed or refractory acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) harboring a TP53 Y220C mutation. Enrollment is planned to begin in the first quarter of 2025.
Food Effect on Rezatapopt Exposure
Data presented at the American College of Clinical Pharmacology Annual Conference on September 8, 2024, highlighted the impact of food on Rezatapopt exposure. In the Phase 1 portion of the PYNNACLE study, patients who received Rezatapopt with food showed increased exposure levels at steady state, with AUC 0-24 and C max increasing by 42% and 40%, respectively. Additionally, variability in exposure decreased significantly with food. Rezatapopt was well-tolerated and associated with fewer gastrointestinal (GI) treatment-related adverse events (TRAEs) when administered with food. These data supported the 2000 mg QD dose being recommended to be taken with food within the ongoing PYNNACLE Phase 2 study.
Discontinued Combination Arm
Dose-limiting toxicities were observed in the combination arm of the Phase 1b PYNNACLE trial evaluating rezatapopt and Merck’s anti-PD-1 therapy KEYTRUDA® (pembrolizumab). As a result, rezatapopt 500 mg once-daily in combination with pembrolizumab 200 mg every three weeks was established as the maximum tolerated dose. Due to limited clinical benefit at this dose, PMV Pharma discontinued enrollment in the Phase 1b combination arm.
Financial Status
PMV Pharma ended the third quarter with $197.9 million in cash, cash equivalents, and marketable securities. The company's net loss for the quarter was $19.2 million, primarily due to increased research and development spending.
About Rezatapopt
Rezatapopt (PC14586) is a first-in-class, small molecule p53 reactivator designed to selectively bind to the pocket in the p53 Y220C mutant protein, restoring the wild-type tumor-suppressor function. The U.S. Food and Drug Administration (FDA) granted Fast Track designation to rezatapopt for the treatment of patients with locally advanced or metastatic solid tumors with a TP53 Y220C mutation.
