rezatapopt (PC14586) / PMV Pharma - LARVOL DELTA

Restoring p53 wild-type conformation in TP53-Y220C-mutant acute myeloid leukemia. (PubMed, Blood) - P1 | "Pharmacological inhibition of the BCL-2/BAX interaction with venetoclax fully compensates for this deficiency, induces massive cell death in AML cells and stem/progenitor cells in vitro and prolongs survival of TP53-Y220C AML xenografts in vivo. Collectively, we identified transcription-dependent and -independent mechanisms that limit the apoptogenic activities of reactivated conformational p53-WT and suggest approaches to optimize apoptosis induction in TP53-mutant leukemia. A clinical trial of PC14586 in TP53-Y220C AML/myelodysplastic syndromes has recently been initiated (NCT06616636)."

IO biomarker • Journal • P53WT • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • BCL2 • BCL2L1 • MCL1 • TP53

Rezatapopt: A promising small-molecule "refolder" specific for TP53Y220C mutant tumors. (PubMed, Neoplasia) - P1/2 | "achieve to enhance our understanding of the mechanisms and effects of p53-Y220C reactivator compounds and underscore the potential of targeting p53 mutants in cancer therapy [3]. Through this spotlight article, we aim to summarize the findings and emphasize the clinical implications of the study by Puzio-Kutler et al."

Journal • Oncology • Solid Tumor • TP53

TP53 genomic alterations including targetable TP53 Y220C mutation in clinically advanced breast cancer. (ASCO 2025) - "Funded by No funding sources reported Background: Recent studies demonstrating the ability of drugs such as Rezatapopt to target the TP53 Y220C mutation motivated us to assess the TP53 mutation landscape in clinically advanced breast cancer (CABC)... TP53 Y220C is a relatively rare event in CABC. The TP53 mutant group was associated with GA in tumor suppressor genes, including BRCA1, PTEN, and RB1, whereas the TP53wt group was associated with GA in pathways associated with endocrine resistance, including PIK3CA and ESR1. †Benjamini/Hochberg adjustment."

Clinical • IO biomarker • Metastases • Tumor mutational burden • Breast Cancer • HER2 Breast Cancer • Microsatellite Instability • Oncology • Solid Tumor • BRCA1 • BRCA2 • CCND1 • CDH1 • ER • HER-2 • HRD • MSI • PD-L1 • PIK3CA • PTEN • RB1 • TMB • TP53

PYNNACLE phase 2 clinical trial of rezatapopt in patients with advanced solid tumors harboring a TP53 Y220C mutation. (ASCO 2025) - P1/2 | "PYNNACLE Phase 1/2 basket study (NCT04585750).* Defined as no KRAS single nucleotide variant. BICR, blinded independent central review; ORR, objective response rate; RECIST v1.1, Response Evaluation Criteria in Solid Tumors Version 1.1."

Clinical • Metastases • P2 data • Brain Cancer • CNS Tumor • Oncology • Solid Tumor • KRAS • TP53

PMV Pharmaceuticals Reports First Quarter 2025 Financial Results and Corporate Highlights (GlobeNewswire) - "Enrollment on track in Phase 2 pivotal portion of PYNNACLE clinical trial evaluating rezatapopt as monotherapy in patients with TP53 Y220C and KRAS wild-type advanced solid tumors....PMV Pharma plans to provide interim analysis data from the Phase 2 PYNNACLE trial in the middle of 2025. This interim analysis will include data for approximately 50 patients, of which approximately 40% are in the ovarian cancer cohort, who have been followed for at least 18 weeks."

Enrollment status • P2 data • Solid Tumor

PYNNACLE Phase 2 Study of Rezatapopt in Patients with Advanced Solid Tumors, including Breast Cancers, and a TP53 Y220C mutation (ESMO-BC 2025) - P1/2 | "Patients are followed until death, lost to follow-up, two years after last patient discontinuation, or end of study. Table: 150TiP PYNNACLE phase II study BICR, blinded independent central review; ORR, objective response rate; RECIST v1.1, Response Evaluation Criteria in Solid Tumors Version 1.1."

Clinical • Metastases • P2 data • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • KRAS • TP53

Clinical resistance to Y220C-mutant p53 reactivators (AACR 2025) - "Furthermore, we observe a complete lack of p53 reactivation upon treatment of these p53 double mutant cells with rezatapopt, as target gene expression remains unaffected.This work provides the first insightful characterization of clinical acquired resistance to p53 Y220C reactivators. Future studies will elucidate whether more potent covalent Y220C reactivators manage to overcome the resistance mechanisms identified in this study."

Clinical • Late-breaking abstract • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • 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

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