rezatapopt (PC14586) / PMV Pharma - LARVOL DELTA

PYNNACLE phase 2 clinical trial of rezatapopt in patients with advanced solid tumors harboring a TP53 Y220C mutation. (ASCO 2025) - P1/2 | "Clinical Trial Registration Number: NCT04585750 The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

Clinical • Metastases • P2 data • Oncology • Solid Tumor • TP53

Restoring the function of the guardian of the genome: FMC-220 a highly potent and selective covalent activator of p53 Y220C (AACR 2025) - "In contrast to reversible Y220C binders including rezatapopt, covalent engagement of Y220C results in persistent activation of p53 following drug washout that leads to enhanced Y220C mutant cancer cell senescence and death. In addition, FMC-220 is very well tolerated in vivo. Together, these data demonstrate the promise of FMC-220, a first-in-class covalent activator of p53 Y220C, with the potential to deliver improved outcomes for patients with Y220C mutation positive tumors."

Oncology • KRAS • TP53

PYNNACLE Phase 2 Study of Rezatapopt in Patients with Advanced Solid Tumors, including Breast Cancers, and a TP53 Y220C mutation (ESMO-BC 2025) - No abstract available

Clinical • Metastases • P2 data • Breast Cancer • Oncology • Solid Tumor • TP53

Rezatapopt (PC14586): A First-in-Class Small Molecule p53 Y220C Mutant Protein Stabilizer in Clinical Trials. (PubMed, J Med Chem) - No abstract available

Journal

PYNNACLE phase II assessing rezatapopt in patients with advanced solid tumors, including lung cancer, harboring a TP53 Y220C mutation (ELCC 2025) - P1/2 | "The primary endpoint is objective response rate as assessed by blinded independent central review; key secondary endpoints include time to response, duration of response, disease control rate, progression-free and overall survival, adverse events, pharmacokinetic parameters, and patient-reported outcomes. Patients will be followed until death, lost to follow-up, 2 years after last patient discontinuation, or end of study."

Clinical • Metastases • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • KRAS • TP53

The PYNNACLE Phase 2 trial assessing rezatapopt (PC14586), a selective p53 reactivator, in patients with locally advanced or metastatic solid tumors (including ovarian and endometrial cancers) harboring a TP53 Y220C mutation (SGO 2025) - No abstract available

Clinical • Metastases • P2 data • Endometrial Cancer • Oncology • Ovarian Cancer • Solid Tumor • TP53

PMV Pharmaceuticals Reports Full Year 2024 Financial Results and Corporate Highlights (GlobeNewswire) - "Enrollment is on track in the Phase 2 monotherapy portion of the PYNNACLE clinical trial....PMV Pharma plans to provide data from the interim analysis of the Phase 2 monotherapy portion of PYNNACLE in the middle of 2025 and anticipates a New Drug Application submission by the end of 2026....Enrollment commenced in the MD Anderson Cancer Center investigator-initiated Phase 1b study evaluating rezatapopt monotherapy and in combination with azacitidine in patients with relapsed or refractory AML/MDS harboring a TP53 Y220C mutation."

Enrollment status • FDA filing • P2 data • Acute Myelogenous Leukemia • Myelodysplastic Syndrome • Solid Tumor

Restoration of the Tumor Suppressor Function of Y220C-Mutant p53 by Rezatapopt, a Small Molecule Reactivator. (PubMed, Cancer Discov) - "These compounds demonstrate potent anti-tumor activity in preclinical models as single agents and in combination with immunotherapy. Currently, rezatapopt is being evaluated in a registrational Phase 2 clinical trial for patients with advanced solid tumors harboring the TP53 Y220C mutation."

IO biomarker • Journal • Oncology • Solid Tumor • TP53

A Phase Ib Study of Rezatapopt in Combination With Azacitidine or Azacitidine and Venetoclax in Patients With TP53Y220C Mutant Myeloid Malignancies (Acute Myeloid Leukemia or Myelodysplastic Syndrome) (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Not yet recruiting ➔ Recruiting

Enrollment open • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Discovery of Rezatapopt (PC14586), a First-in-Class, Small-Molecule Reactivator of p53 Y220C Mutant in Development. (PubMed, ACS Med Chem Lett) - "In mouse models with established human tumor xenografts harboring the TP53 Y220C mutation, rezatapopt demonstrated tumor inhibition and regression at well-tolerated doses. In Phase 1 clinical trials, rezatapopt demonstrated a favorable safety profile within the efficacious dose range and showed single-agent efficacy in heavily pretreated patients with various TP53 Y220C mutant solid tumors."

Journal • Oncology • Solid Tumor • TP53

Reactivation of p53 in TP53-Y220C Mutant AML: Mechanism of Action and Mechanism-Based Drug Combinations (ASH 2024) - "PC14586, in combination with venetoclax (VEN), can activate Bax and synergistically induced cell death in TP53-Y220C Molm13, primary patient samples, and PDX cells that did not respond to PC14586 as a single agent, and prolonged survival in Molm13 TP53-Y220C xenografted mice (p=0.0026). Both contribute to the diminished apoptogenic activity of PC14586 in TP53-Y220C AML cells, which can be overcome by combinations of PC14586 with MDM2 or/and Bcl-2 inhibitors. Clinical trials of PC14586 with VEN or VEN/HMA combinations are planned in TP53-Y220C AML/MDS."

IO biomarker • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Lymphoma • Oncology • BCL2L1 • CDKN1A • MCL1 • TP53

Phase 1 Analysis from the PYNNACLE Phase 1/2 Study of Rezatapopt in the Subgroup of Patients with Advanced Breast Cancer Harboring a TP53 Y220C Mutation (SABCS 2024) - P1/2 | "Rezatapopt had a favorable safety profile in the efficacious dose range with improvements in gastrointestinal adverse events observed when administered with food. The PYNNACLE tumor-agnostic registrational Phase 2 trial, which includes a breast cancer cohort, will assess rezatapopt as monotherapy at the recommended Phase 2 dose of 2000 mg QD with food in patients with TP53 Y220C-mutated and KRAS wild-type advanced solid tumors."

Clinical • Metastases • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • BRCA1 • BRCA2 • HER-2 • KRAS • PIK3CA • TP53

A Study to Investigate the Effects of Acid Reducing Agents on Pharmacokinetics of PC14586 in Healthy Participants (clinicaltrials.gov) - P1 | N=28 | Completed | Sponsor: PMV Pharmaceuticals, Inc | Active, not recruiting ➔ Completed | Trial completion date: Jun 2024 ➔ Feb 2024

Trial completion • Trial completion date

A Study to Investigate the Effects of Itraconazole on the Pharmacokinetics of PC14586 in Healthy Participants (clinicaltrials.gov) - P1 | N=12 | Completed | Sponsor: PMV Pharmaceuticals, Inc | Recruiting ➔ Completed

Trial completion

PMV Pharmaceuticals Reports Third Quarter 2024 Financial Results (GlobeNewswire) - P1/2 | N=230 | PYNNACLE (NCT04585750) | Sponsor: PMV Pharmaceuticals, Inc | "Rezatapopt food effect data were presented on September 8, 2024 during a poster session at the American College of Clinical Pharmacology Annual Conference. Key data are...In the Phase 1 portion of the PYNNACLE study, 13 patients received rezatapopt in a fasted state, while 12 patients received rezatapopt after eating. When taken with food, exposure levels at steady state as measured by AUC0-24 and Cmax increased by 42% and 40%, respectively. Additionally, variability in exposure decreased significantly with food...These data supported the 2000 mg QD dose being recommended to be taken with food within the ongoing PYNNACLE Phase 2 study...Net loss for the quarter ended September 30, 2024, was $19.2 million compared....The net loss increase was a result of increased research and development (R&D) spending associated with advancing our lead product candidate through the PYNNACLE Phase 1/2 clinical trial."

Commercial • P1 data • Trial status • Oncology • Solid Tumor

MD Anderson Cancer Center and Memorial Sloan Kettering Cancer Center to Initiate a Phase 1b Study in Recurrent/Refractory AML/MDS (GlobeNewswire) - "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 recurrent or refractory acute myeloid leukemia (AML)/myelodysplastic syndromes (MDS) harboring a TP53 Y220C mutation. Enrollment is planned to begin in the first quarter of 2025 across two sites."

Trial status • Acute Myelogenous Leukemia • Myelodysplastic Syndrome

PYNNACLE Phase 2 Monotherapy Update (GlobeNewswire) - "Enrollment is on track in the Phase 2 monotherapy portion of the PYNNACLE clinical trial. The multicenter, single-arm, registrational, tumor-agnostic Phase 2 trial is assessing rezatapopt as monotherapy at a dose of 2000 mg once-daily in patients with TP53 Y220C and KRAS wild-type advanced solid tumors....The trial is designed to enroll 114 patients across five cohorts at approximately 60 sites. More than 75% of sites have been activated across the U.S., Europe, and Asia-Pacific. PMV plans to provide data from the interim analysis of the Phase 2 monotherapy portion of the PYNNACLE trial by mid-2025 and anticipates submitting a New Drug Application by the end of 2026."

FDA filing • P2 data • Trial status • Breast Cancer • Colorectal Cancer • Endometrial Cancer • Head and Neck Cancer • Lung Cancer • Ovarian Cancer • Prostate Cancer

PYNNACLE Phase 1b Rezatapopt in Combination with Pembrolizumab Update (GlobeNewswire) - "PMV has decided to discontinue enrollment in the Phase 1b combination arm of the PYNNACLE trial evaluating rezatapopt in combination with Merck’s anti-PD-1 therapy KEYTRUDA (pembrolizumab) in patients with advanced solid tumors harboring a TP53 Y220C mutation. Nineteen patients were enrolled in the combination arm of the trial. This decision was driven by dose-limiting toxicities (DLTs) observed at the 1000 mg dose of rezatapopt once-daily plus pembrolizumab 200 mg every three weeks....Per protocol, these observations established rezatapopt 500 mg once-daily in combination with pembrolizumab 200 mg every three weeks as the maximum tolerated dose. Patients dosed with rezatapopt 500 mg once-daily in combination with pembrolizumab did not experience a clinically meaningful benefit, informing the decision to discontinue enrollment in the combination arm of the PYNNACLE trial."

Trial status • Breast Cancer • Colorectal Cancer • Endometrial Cancer • Head and Neck Cancer • Lung Cancer • Ovarian Cancer • Prostate Cancer

Discovery of NTS071, an orally bioavailable, highly potent and selective small molecule p53 Y220C reactivator (EORTC-NCI-AACR 2024) - "NTS071 is a highly potent and selective p53 Y220C reactivator that possesses desirable preclinical characteristics and shows promise in treating solid tumors harboring a TP53 Y220C mutation."

Oncology • Solid Tumor • BAX • CDKN1A

A Phase Ib Study of Rezatapopt in Combination with Azacitidine or Azacitidine and Venetoclax in Patients with TP53Y220C Mutant Myeloid Malignancies (Acute Myeloid Leukemia or Myelodysplastic Syndrome) (clinicaltrials.gov) - P1 | N=25 | Not yet recruiting | Sponsor: M.D. Anderson Cancer Center

Combination therapy • New P1 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

PYNNACLE phase II trial of rezatapopt (PC14586) in solid tumors with a TP53 Y220C mutation (ESMO 2024) - P1/2 | "Primary endpoint is objective response rate (ORR) assessed per BICR in the ovarian cancer cohort and across cohorts; key secondary endpoints include ORR per investigator, time to and duration of response, disease control rate, progression-free and overall survival, adverse event incidence, pharmacokinetic parameters, and pt-reported outcomes. Pts followed until lost to follow-up, death, two yrs after last pt discontinuation, or end of study."

P2 data • Brain Cancer • CNS Tumor • Oncology • Ovarian Cancer • Solid Tumor • KRAS • TP53

PMV Pharmaceuticals Reports Second Quarter 2024 Financial Results and Provides a Progress Update on PYNNACLE Clinical Trial (GlobeNewswire) - "Enrollment is on track in the Phase 2 monotherapy portion of the PYNNACLE clinical trial...Site activation is progressing well, with more than 60% of sites activated across the U.S., Europe, and Asia-Pacific. PMV 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 (NDA) filing by the end of 2026...Enrollment continues in the Phase 1b combination arm of the PYNNACLE trial evaluating rezatapopt in combination with pembrolizumab (200 mg every three weeks) in patients with advanced solid tumors harboring a TP53 Y220C mutation."

FDA filing • P1/2 data • Trial status • Oncology • Solid Tumor

ENHANCING THE EFFICACY OF P53-Y220C REACTIVATOR PC14586 BY COMBINATION WITH MDM2 OR BCL-2 INHIBITORS IN TP53-Y220C AML (EHA 2024) - " Isogenic TP53-Y220C, TP53-knockout, and various TP53 mutant AML cell lines and primary AML cells withTP53-Y220C mutations were treated with PC586, nutlin3a (MDM2 inhibitor), venetoclax (VEN, BCL2 inhibitor),or PC586 in combination with each agent. PC586 restored WT-p53 activity and induced target gene expression in TP53-Y220C expressing AML. Mechanism-based combinations with MDM2 or BCL-2 inhibitors enhanced the apoptogenic activity of PC586. A clinical trial of PC586 in combination with VEN is in preparation."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor • ANXA5 • CD34 • CDKN1A • MDM2

Foundation Medicine and PMV Pharma Announce Collaboration to Develop Companion Diagnostic for Rezatapopt, a First-In-Class, Investigational, Selective p53 Y220C Reactivator (GlobeNewswire) - "Foundation Medicine, Inc. and PMV Pharmaceuticals, Inc...announced a partnership to develop Foundation Medicine’s tissue-based comprehensive genomic profiling test, FoundationOneCDx, as a companion diagnostic for PMV Pharma’s rezatapopt, a first-in-class, investigational therapy for patients with locally advanced or metastatic solid tumors that have a TP53 Y220C mutation."

Diagnostic • Licensing / partnership • Oncology • Solid Tumor

GS-P-328, a brain-penetrant small molecule p53 Y220C reactivator for tumors harboring p53 Y220C mutation (AACR 2024) - "The initial clinical evaluation of PC14586 that can restore missense-mutant p53 protein has seen efficacy in patients harboring p53 Y220C mutation even though there is still room for improvement. GS-P-328 has a favorable ADME profile in rodents, dogs and NHPs, as well as a much better safety profile. GS-P-328 is now under IND-enabling study and P1 study is planned in early 2025."

Lung Cancer • Oncology • Solid Tumor • CDKN1A • MDM2