PRT3789 / Prelude Therap - LARVOL DELTA

Selective SMARCA2 Degradation Promotes Leukemic Differentiation and Synergizes with CDK9 Inhibition to Potently Induce Death in Pre-Clinical Models of Acute Myeloid Leukemia (ASH 2024) - P1 | "PRT2527 is currently being evaluated in Phase I clinical trials for relapsed/refractory hematologic malignancies (NCT05665530). PRT3789 is currently being evaluated in Phase I clinical trials for advanced or metastatic solid tumors with SMARCA4 mutations (NCT05639751)."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Solid Tumor • CD14 • CD34 • CEBPA • DNMT3A • GATA2 • IRF8 • ITGAM • MYC • NDUFA2 • NPM1 • NRAS • SMARCA2 • SMARCA4 • TET2 • TP53 • WT1

Prelude Therapeutics Announces Strategic Business Update (Prelude Therapeutics) - "Prelude...announced it has decided to pause the clinical development of its SMARCA2 degrader program. The decision to pause was based on a comprehensive review of clinical data generated to date and the Company’s assessment of the capital and resource allocation required to advance the SMARCA2 program, versus the JAK2 and KAT6A programs, to key points of value inflection."

Discontinued • Oncology

PRT3789-01: PRT3789 Monotherapy and in Combo w/Docetaxel in Participants w/Advanced or Metastatic Solid Tumors w/SMARCA4 Mutation (clinicaltrials.gov) - P1 | N=135 | Completed | Sponsor: Prelude Therapeutics | Active, not recruiting ➔ Completed | Trial completion date: Mar 2026 ➔ Oct 2025 | Trial primary completion date: Mar 2026 ➔ Oct 2025

Monotherapy • Trial completion • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

PRT3789 is a First-in-Human SMARCA2-Selective Degrader that Induces Synthetic Lethality in SMARCA4-Mutated Cancers. (PubMed, Cancer Res) - "Together, these findings demonstrate the selective targeting of SMARCA2 and the potential for a favorable therapeutic index with PRT3789. Phase I/II clinical trials with PRT3789 are ongoing in biomarker-selected patients with SMARCA4-mutated solid tumors."

First-in-human • Journal • P1 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • SMARCA2 • SMARCA4

KEYNOTE-G02: A Study of PRT3789 in Combination With Pembrolizumab in Patients With Advanced or Metastatic Solid Tumors With a SMARCA4 Mutation (clinicaltrials.gov) - P2 | N=7 | Active, not recruiting | Sponsor: Prelude Therapeutics | Recruiting ➔ Active, not recruiting | N=60 ➔ 7

Enrollment change • Enrollment closed • Esophageal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • SMARCA4

Prelude Therapeutics...Provides Corporate Update (GlobeNewswire) - "'We’ve decided to pause further development of PRT3789, and focus solely on PRT7732 as our go-forward strategy for our SMARCA2 Program.'....PRT3789 has completed Phase 1 clinical development in patients with biomarker selected SMARCA4-mutated cancers. The Company anticipates providing updated data from the Phase 1 study by year-end 2025."

Discontinued • P1 data • Trial completion • Solid Tumor

PRT3789-01: PRT3789 Monotherapy and in Combo w/Docetaxel in Participants w/Advanced or Metastatic Solid Tumors w/SMARCA4 Mutation (clinicaltrials.gov) - P1 | N=135 | Active, not recruiting | Sponsor: Prelude Therapeutics | Recruiting ➔ Active, not recruiting | N=226 ➔ 135

Enrollment change • Enrollment closed • Monotherapy • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

A phase 2 safety and efficacy study of PRT3789 in combination with pembrolizumab in patients with advanced or metastatic solid tumors and a SMARCA4 mutation. (ASCO 2025) - P2 | "This study is actively recruiting. ClinicalTrials.gov ID: NCT06682806."

Clinical • Combination therapy • IO biomarker • Metastases • P2 data • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IFNG • SMARCA2 • SMARCA4

OncoKBTM, MSK's precision oncology knowledge base: 2024 updates (AACR 2025) - "OncoKB promoted BRAF fusions to Level 1 following inclusion as patient eligibility criteria in the FDA drug label for tovorafenib (low-grade glioma). Additionally, OncoKB included KRAS G12C in colorectal cancer and IDH1 mutations in myelodysplastic syndromes as Level 1 following FDA approval of adagrasib + cetuximab and ivosidenib, respectively...Lastly, novel biomarkers including FBXW7 and PPP2R1A alterations (endometrial and ovarian cancer), SMARCA4 mutations (non-small cell lung cancer and esophageal adenocarcinoma) and MTAP deletions (all solid tumors) were included in OncoKB based on compelling preclinical and emerging clinical evidence in association with lunresertib + camonsertib, PRT3789, and AMG193 and MRTX1719, respectively...OncoKB also implemented major software updates to support data integration into the EPIC platform. Future OncoKB efforts are focused on whole genome/exome curation, inclusion of biomarkers for non-NGS-based precision oncology therapies,..."

Tumor mutational burden • Brain Cancer • CNS Tumor • Colorectal Cancer • Endometrial Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Glioma • Hematological Malignancies • Lung Cancer • Microsatellite Instability • Myelodysplastic Syndrome • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Small Intestinal Carcinoma • Solid Tumor • BRAF • FBXW7 • IDH1 • KRAS • MSI • MTAP • POLD1 • PPP2R1A • SMARCA4 • TMB

Elucidating the molecular mechanism of action of the first in human SMARCA2 selective degrader PRT3789 (AACR 2025) - P1 | "Proteomics and mutagenesis studies identified specific lysine residues that were ubiquitinated on the bromodomain of SMARCA2 and SMARCA4, and a unique loop on SMARCA2 that contributed to ternary complex stabilization and ubiquitination. In summary, we describe the systematic characterization of PRT3789 mediated SMARCA2 degradation and illustrate the molecular mechanism of action for how PRT3789 achieves degradation selectivity against SMARCA4."

P1 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • SMARCA2 • SMARCA4

Selective degradation of SMARCA2 and dual degradation of SMARCA2 and SMARCA4 has strong antitumor activity in marginal zone lymphoma (MZL) (AACR 2025) - "PRT3789 is currently in phase 1 as a single agent or in combination with docetaxel for patients with solid tumors with loss of SMARCA4...None of the models had mutations in the coding regions of ARID1A or SMARCA4.Adding individual degraders to the BTK inhibitor ibrutinib, the PI3Kδ inhibitor idelalisib, or to the combination of the PI3K inhibitor copanlisib with the BCL2 inhibitor venetoclax led to additivity/synergism... The single SMARCA2 degrader PRT3789 and the dual SMARCA2/4 degrader showed strong dose-dependent cytotoxic activity in MZL cells, showing activity in the low nM range. Both compounds induced apoptosis as single agents and improved the activity of a BTK inhibitor in the two cell lines tested. Interestingly, the antitumor activity was maintained in MZL cell lines with acquired resistance to BTK, PI3K, and BCL2 inhibitors."

IO biomarker • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Oncology • Solid Tumor • ARID1A • PIK3CD • SMARCA2 • SMARCA4

Discovery of GLR203101, a selective and orally bioavailable PROTAC of SMARCA2 for the treatment of SMARCA4 mutant tumors (AACR 2025) - "Few SMARCA2 selective compounds have entered clinical trials, including PROTAC molecule PRT-3789 administered by intravenous injection in phase 2 clinical trials.Herein, we report the discovery of a selective and orally bioavailable SMARCA2 PROTAC degrader, GLR203101. After 24 hours of oral administration of GLR203101, a robust degradation of SMARCA2 while sparing SMARCA4 was observed in transplanted tumors in the xenograft model. GLR203101 is being evaluated as a preclinical candidate."

Oncology • SMARCA2 • SMARCA4

Interim Phase 1 data presented at the 2025 Japanese Society of Medical Oncology Annual Meeting (GlobeNewswire) - P1 | N=226 | NCT05639751 | Sponsor: Prelude Therapeutics | "As reported by investigators, PRT3789 was generally safe and well-tolerated at doses tested to date....Of the 13 patients with Class 1 mutations treated at doses of 283 mg or higher, 3 had RECIST confirmed partial responses (2 NSCLC, 1 gastric). Tumor shrinkage was observed in patients with both Class 1 and Class 2 SMARCA4 mutations. Additional patients on-study demonstrated clinical benefit as measured by prolonged SD, including one advanced NSCLC patient on study for more than a year....PRT3789 monotherapy dose escalation enrollment is nearing completion and dose escalation in combination with docetaxel continues with plans to present additional results from both cohorts in the second half of 2025."

P1 data • Trial status • Esophageal Cancer • Gastric Cancer • Non Small Cell Lung Cancer

PRT3789, a First-in-Class Intravenous SMARCA2 Degrader, in Advanced Solid Tumors With a SMARCA4 Mutation: Phase 1 Trial (JSMO 2025) - No abstract available

Metastases • P1 data • Oncology • Solid Tumor • SMARCA2 • SMARCA4

KEYNOTE-G02: A Study of PRT3789 in Combination With Pembrolizumab in Patients With Advanced or Metastatic Solid Tumors With a SMARCA4 Mutation (clinicaltrials.gov) - P2 | N=60 | Recruiting | Sponsor: Prelude Therapeutics | Not yet recruiting ➔ Recruiting

Enrollment open • Esophageal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • SMARCA4

A Study of PRT3789 in Combination With Pembrolizumab in Patients With Advanced or Metastatic Solid Tumors With a SMARCA4 Mutation (clinicaltrials.gov) - P2 | N=60 | Not yet recruiting | Sponsor: Prelude Therapeutics

New P2 trial • Esophageal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • SMARCA4

First Clinical Results from A Phase 1 Trial of PRT3789, a First-in-Class Intravenous SMARCA2 Degrader, in Patients with Advanced Solid Tumors with a SMARCA4 Mutation (EORTC-NCI-AACR 2024) - "PRT3789, a first-in-class SMARCA2 degrader, at doses studied to date, appears to be generally well tolerated, with excellent pharmacodynamic effect, and with encouraging anti-tumor activity, even during early dose escalation. This supports the hypothesis that selective SMARCA2 degradation through synthetic lethality with PRT3789 may be an effective therapy for SMARCA4 mutated cancer."

Clinical • Metastases • P1 data • Esophageal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • SMARCA2 • SMARCA4

Prelude Therapeutics Presents New Data from SMARCA Degrader Portfolio at the 36th EORTC-NCI-AACR Symposium (GlobeNewswire) - P1 | N=186 | NCT05639751 | Sponsor: Prelude Therapeutics | "PRT3789 was generally well-tolerated. Treatment emergent adverse events of any grade observed to date consisted of nausea (26.2%), fatigue (21.5%), anemia (20.0%), decreased appetite (20.0%), abdominal pain (18.5%), and constipation (18.5%). No dose limiting toxicities were observed and no study drug-related serious adverse events were reported....Preliminary PK data was available from 24 mg to 376 mg dose cohorts. A general trend of increases in exposure (Cmax, AUC) with dose was observed. Mean concentrations were observed above SMARCA2 plasma DC50 (21 nM) for approximately 8 hours at the 376 mg dose....To date, PRT3789 in combination with docetaxel demonstrated an acceptable safety profile, with no dose limiting toxicities or study drug serious adverse events reported."

P1 data • Esophageal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

The selective SMARCA2 degrader, PRT3789, counteracts the protective cellular stress response to chemotherapy and enhances the efficacy of standard of care chemotherapeutic agents in SMARCA4 mutant NSCLC models (EORTC-NCI-AACR 2024) - "In NSCLC models with SMARCA4 mutations, including cell line-derived xenografts and patient-derived xenografts, PRT3789 significantly improved the efficacy of SoC chemotherapy agents (docetaxel or nab-paclitaxel). In Conclusion, the combination of PRT3789 with NSCLC SoC chemotherapy agents demonstrates significantly enhanced anti-tumor activities in preclinical models of SMARCA4-mutated NSCLC. A Phase I clinical trial investigating the safety and potential therapeutic benefits of the combination of PRT3789 and docetaxel is currently underway in patients with advanced or metastatic solid tumors with SMARCA4 mutations."

Clinical • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CDC45 • CDKN1A • EGF • RAD51 • RAD51AP1 • SMARCA2 • SMARCA4 • TOP2A

Prelude Therapeutics Announces Publication of Abstracts for Presentation at the 36th EORTC-NCI-AACR Symposium (GlobeNewswire) - "Prelude Therapeutics Incorporated...announced the publication of three abstracts regarding its SMARCA Degrader Programs at the 36th EORTC-NCI-AACR Symposium....In addition to the updates we will be providing from our Phase 1 trial of PRT3789, we are looking forward to presenting the first preclinical data from our precision degrader antibody conjugates program. These data demonstrate that a highly potent dual SMARCA2/4 degrader payload can be conjugated to an antibody to specifically target tumor cells and safely induce tumor regressions in preclinical models....PRT3789 is a first-in-class, potent and highly selective SMARCA2 degrader, in Phase 1 clinical development in biomarker selected SMARCA4 mutant patients. Enrollment remains on track, and the Company expects to conclude monotherapy dose escalation by year end 2024 and identify the biologically active dose to advance for future trials."

P1 data • Preclinical • Trial status • Non Small Cell Lung Cancer

Prelude Therapeutics’ SMARCA2 Degrader PRT3789 Demonstrated Promising Initial Clinical Activity and Safety Profile in Phase 1 Trial (GlobeNewswire) - P1 | N=186 | NCT05639751 | Sponsor; Prelude Therapeutics | "Encouraging signs of anti-tumor activity including objective responses observed in patients with SMARCA4-mutated non-small cell lung cancer (NSCLC) and esophageal cancer in early PRT3789 monotherapy dose escalation; At doses studied to date, PRT3789 was generally well-tolerated with no dose-limiting toxicities or study drug-related serious adverse events; Company to host investor conference call and webcast on Friday, September 13, 2024 at 12:00 PM EST."

P1 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

First clinical results from a phase I trial of PRT3789: A first-in-class intravenous SMARCA2 degrader, in patients with advanced solid tumors with a SMARCA4 mutation (ESMO 2024) - P1 | "PRT3789, a first-in-class SMARCA2 degrader, at doses studied to date appears to be well tolerated, with excellent pharmacodynamic effect, and with encouraging signs of anti-tumor activity, even during early dose escalation. Dose escalation and backfill cohorts are ongoing."

Clinical • Metastases • P1 data • Esophageal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • SMARCA2 • SMARCA4

Prelude Therapeutics Announces Publication of Abstract for Presentation at the European Society of Medical Oncology (ESMO) Congress 2024 (GlobeNewswire) - P1 | N=186 | NCT05639751 | Sponsor: Prelude Therapeutics | "Prelude Therapeutics Incorporated...announced the publication of an abstract regarding PRT3789 at the European Society of Medical Oncology (ESMO) Congress 2024 taking place in Barcelona, Spain September 13-17, 2024....No DLTs or study drug-related SAEs have been reported...Dose-related increases in AUC were observed; Dose-dependent decreases in SMARCA2 levels were seen at all doses with a trend for increasing depth and duration with increasing doses; Minimal effects on SMARCA4 levels were seen....Clinical activity of PRT3789 therapy noted to date includes RECIST partial responses, tumor shrinkage and prolonged stable disease (longer than response to most recent therapy) in patients with advanced, heavily pretreated esophageal cancer and NSCLC."

P1 data • Breast Cancer • Esophageal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor

Prelude Therapeutics Reports Second Quarter 2024 Financial Results and Provides Corporate Update (GlobeNewswire) - "Interim Phase 1 data for its first-in-class, highly selective IV SMARCA2 degrader, PRT3789, selected for an oral presentation at the European Society for Medical Oncology (ESMO) Congress 2024 in September....The lead oral candidate, PRT7732, recently was granted IND authorization from the FDA and is expected to enter Phase 1 clinical development in the second half of 2024....PRT2527 is expected to complete monotherapy dose escalation in B-cell malignancies this year. Initiation of dose escalation in myeloid malignancies occurred in the first half of 2024. Interim Phase 1 data is on track for presentation in the fourth quarter of 2024."

IND • New P1 trial • P1 data • Trial status • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lung Cancer • Lymphoma • Mantle Cell Lymphoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • Solid Tumor

Prelude Therapeutics Announces Clinical Collaboration with Merck to Evaluate PRT3789 in Combination with KEYTRUDA (pembrolizumab) in Patients with SMARCA4-Mutated Cancers (GlobeNewswire) - "Prelude Therapeutics Incorporated...today announced that it has entered into a clinical trial collaboration and supply agreement (the 'Agreement') with Merck (known as MSD outside of the US and Canada). Under the terms of the Agreement, the Phase 2 clinical study will evaluate PRT3789, the Company’s investigational, highly selective, first-in-class SMARCA2 degrader in combination with KEYTRUDA (pembrolizumab) Merck’s anti-PD-1 therapy, in patients with SMARCA4-mutated cancers....Enrollment remains on track, and the Company expects to conclude monotherapy dose escalation mid-2024 and identify recommended Phase 2 dose....Under the terms of the Agreement, Merck will provide KEYTRUDA to Prelude, which will be the sponsor of the Phase 2 clinical combination trial."

Licensing / partnership • Trial status • Oncology • Solid Tumor