PRT2527 / Prelude Therap - LARVOL DELTA

PRT2527, a Novel Highly Selective Cyclin-Dependent Kinase 9 (CDK9) Inhibitor, Has Potent Antitumor Activity in Combination with BTK and BCL2 Inhibition in Various Lymphoid Malignancies (ASH 2023) - P1 | "In a similar fashion, Venetoclax-driven BCL2 inhibition also potentiated the anti-tumor activity of PRT2527...Additionally, we demonstrated that PRT2527 potently inhibits growth in Ibrutinib-resistant MCL cell lines. Further work characterizing PRT2527 as monotherapy and in combination with BTKi and BCL2i in in vivo models of BTKi-resistant MCL and CLL is currently ongoing. Altogether these data provide a rationale for evaluating PRT2527 in combination with BTK and BCL2 inhibitors for the treatment of patients with relapsed/refractory hematologic malignancies."

Combination therapy • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2L1 • BMF • CDK9 • MCL1

A Phase 1 Study Evaluating PRT2527, a Potent and Highly Selective CDK9 Inhibitor, As Monotherapy and in Combination with Zanubrutinib in Patients with Select Relapsed/Refractory B-Cell Malignancies (ASH 2023) - P1 | "The study is open to enrollment and registered at ClinicalTrials. gov (NCT05665530)."

Clinical • Combination therapy • Monotherapy • P1 data • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • Solid Tumor • T Cell Non-Hodgkin Lymphoma • BCL2 • BCL2L1 • BCL2L2 • BMF

Results from the Phase 1 Study of PRT2527, a Selective and Potent CDK9 Inhibitor, as Monotherapy and in Combination With Zanubrutinib in Patients with Relapsed/Refractory Lymphoid Malignancies (DGHO 2025) - P1 | "PRT2527 had an acceptable safety profile with activity observed in mono and in combo with zanu, including CR in 2 pts relapsed after CAR-T and responses in CLL/SLL post BTK. Most common TEAE was neutropenia, manageable with growth factor support. Data supports further evaluation of PRT2527 as mono in PTCL and in combo with zanu in aggressive B cell lymphoma."

Clinical • Combination therapy • Monotherapy • P1 data • Anemia • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Cutaneous T-cell Lymphoma • Dermatology • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mycosis Fungoides • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Thrombocytopenia • BCL2 • BCL2L1 • BCL2L2 • BMF

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

Preliminary Results of a Phase 1, Dose-Escalation Study of PRT2527, a Potent and Highly Selective CDK9 Inhibitor, As Monotherapy and in Combination with Zanubrutinib in Patients with Relapsed/Refractory Lymphoid Malignancies (ASH 2024) - P1 | "Neutropenia was the most common TEAE, manageable with growth factor support. Dose finding with PRT2527 as monotherapy or in combo with zanu is ongoing."

Clinical • Combination therapy • IO biomarker • Monotherapy • P1 data • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Cardiovascular • Chronic Lymphocytic Leukemia • Constipation • Diffuse Large B Cell Lymphoma • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • High-grade B-cell lymphoma • Infectious Disease • Leukemia • Lymphoma • Mantle Cell Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • Richter's Syndrome • T Cell Non-Hodgkin Lymphoma • Ventricular Tachycardia • BCL2 • BCL2L1 • BCL2L2 • BMF

PRT2527-02: A Study of PRT2527 as Monotherapy and in Combination With Zanubrutinib or Venetoclax in Participants With R/R Hematologic Malignancies (clinicaltrials.gov) - P1 | N=86 | Active, not recruiting | Sponsor: Prelude Therapeutics | Trial primary completion date: Nov 2025 ➔ Jun 2025

Monotherapy • Trial primary completion date • Acute Myelogenous Leukemia • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Chronic Lymphocytic Leukemia • Chronic Myelomonocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • T Cell Non-Hodgkin Lymphoma

A PHASE 1 STUDY OF PRT2527, A SELECTIVE CDK9 INHIBITOR, AS MONOTHERAPY AND IN COMBINATION WITH ZANUBRUTINIB IN RELAPSED/REFRACTORY LYMPHOID MALIGNANCIES: UPDATED ANALYSIS (ICML 2025) - P1 | "PRT2527 had an acceptable safety profile with activity observed in both mono and in combo with zanu, including CR in 2 pts relapsed after CAR-T and responses in CLL/SLL post BTK. Most common TEAE was neutropenia, manageable with growth factor support. One DLT (grade 3 TLS) was observed in mono (24 mg/m2) and no DLTs in combo."

Combination therapy • IO biomarker • Monotherapy • P1 data • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Cutaneous T-cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mycosis Fungoides • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • BCL2 • BCL2L1 • BCL2L2 • BMF

CDK9 pharmacological inhibition has antitumor activity in marginal zone lymphoma models and can improve the effects of BTK, PI3K, and BCL2 inhibitors (AACR 2025) - P1 | "PRT2527 has shown favorable tolerability, with manageable toxicity in a phase 1 study for solid tumor patients (Patel et al, ENA 2023), and it is now in phase 1 as a single agent and in combination with the BTK inhibitor zanubrutinib for hematological cancers patients (NCT05665530)...The combination of PRT2527 with the PI3K inhibitor idelalisib, with the BTK inhibitor ibrutinib, or triple combination with the PI3K inhibitor copanlisib and the BCL2 inhibitor venetoclax was beneficial in all parental cells, and the benefit was maintained, although reduced, in derivatives with acquired resistance to PI3K and BTK inhibitors. CDK9 inhibition with PRT2527 has in vitro antitumor activity in MZL models, which is maintained in models with acquired resistance to PI3K, BTK, or BCL2 inhibitors. CDK9 inhibition with PRT2527 can improve the sensitivity of MZL cells to BTK, PI3K, and BCL2 inhibitors."

B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • CDK9 • MCL1

PRT2527-02: A Study of PRT2527 as Monotherapy and in Combination With Zanubrutinib or Venetoclax in Participants With R/R Hematologic Malignancies (clinicaltrials.gov) - P1 | N=86 | Active, not recruiting | Sponsor: Prelude Therapeutics | Recruiting ➔ Active, not recruiting | N=274 ➔ 86

Enrollment change • Enrollment closed • Monotherapy • Acute Myelogenous Leukemia • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Chronic Lymphocytic Leukemia • Chronic Myelomonocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • T Cell Non-Hodgkin Lymphoma

Prelude Therapeutics Presents Preliminary Results of Phase 1 Dose-escalation Study of PRT2527 as Monotherapy and in Combination with Zanubrutinib in Patients with Relapsed/Refractory Lymphoid Malignancies (GlobeNewswire) - P1 | N=274 | NCT05665530 | Sponsor: Prelude Therapeutics | "Prelude Therapeutics Incorporated...announced the presentation of the first interim clinical data from its ongoing open-label, dose-escalation trial of PRT2527, a potent and highly selective CDK9 inhibitor, as monotherapy and in combination with zanubrutinib in patients with relapsed/refractory lymphoid malignancies. The data were presented at a poster session of the 66th American Society of Hematology Annual Meeting in San Diego, California....Of the 23 efficacy evaluable patients in the monotherapy cohort, complete responses (CRs) were observed in 1 patient (DLBCL) and 3 partial responses observed (TCL), with an overall response rate (ORR) of 17.4% (4 of 23). Of the 13 patients in the combination cohort who were evaluable for efficacy, complete responses (CRs) were observed in 3 patients (2 DLBCL, 1 MCL) and 2 partial responses (PRs) observed (DLBCL and CLL) with an overall response rate (ORR) of 38.5% (5 of 13)."

P1 data • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Mantle Cell Lymphoma

Prelude Therapeutics Reports Third Quarter 2024 Financial Results and Provides Corporate Update (GlobeNewswire) - "Clinical Program Updates and Upcoming Milestones:...(i) PRT7732 – A potent, highly selective and orally bioavailable SMARCA2 Degrader:...The Company initiated and enrolled our first patients in a phase 1 multi-dose escalation trial of PRT7732 (NCT06560645) in biomarker selected SMARCA4 mutated cancers....(ii) PRT2527 – A potent and highly selective CDK9 Inhibitor:...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 clinical data with potentially best-in-class CDK9 inhibitor, PRT2527 in hematological malignancies will be presented at the American Society of Hematology Annual Meeting in December 2024."

P1 data • Trial status • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Non-Hodgkin’s Lymphoma • Solid Tumor

PRT2527-02: A Study of PRT2527 as Monotherapy and in Combination With Zanubrutinib or Venetoclax in Participants With R/R Hematologic Malignancies (clinicaltrials.gov) - P1 | N=274 | Recruiting | Sponsor: Prelude Therapeutics | N=104 ➔ 274 | Trial completion date: Apr 2025 ➔ Mar 2026 | Trial primary completion date: Apr 2025 ➔ Nov 2025

Combination therapy • Enrollment change • Monotherapy • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Chronic Myelomonocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • T Cell Non-Hodgkin Lymphoma

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 Reports First Quarter 2024 Financial Results and Provides Corporate Update (GlobeNewswire) - "CDK9 inhibitor PRT2527 on track to complete monotherapy dose escalation mid-2024; initiated dosing in combination with zanubrutinib in first quarter of 2024; initial hematological proof-of-concept data expected in second half of 2024....PRT2527 is currently in Phase 1 clinical development and is expected to complete monotherapy dose escalation in B-cell malignancies mid-year. A second cohort of patients with AML is expected to initiate in the first half of 2024."

P1 data • Trial status • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

PRT2527, a novel highly selective cyclin-dependent kinase 9 (CDK9) inhibitor, has potent antitumor activity in combination with BTK and BCL2 inhibition in various lymphoid malignancies (AACR 2024) - P1 | "In similar fashion, Venetoclax-driven BCL2 inhibition also potentiates the anti-tumor activity of PRT2527. In an Ibrutinib-resistant Mino CDX model, we observe increased tumor growth inhibition following treatment with PRT2527 compared to tumors derived from parental Mino cells, suggesting PRT2527 is efficacious in BTKi-resistant MCL. Altogether these data provide a rationale for evaluating PRT2527 in combination with BTK and BCL2 inhibitors for the treatment of patients with relapsed/refractory lymphoid malignancies."

Combination therapy • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2L1 • BMF • CDK9 • MCL1

Prelude Highlights Continued Strength of Discovery Engine at 2024 AACR Annual Meeting (GlobeNewswire) - "PRT2527 is efficacious as monotherapy in preclinical models of DLBCL, CLL and MCL, and combines with both BTK and BCL2 inhibition to improve depth and duration of responses. PRT2527 is currently being evaluated in a Phase I clinical trial in patients with relapsed/refractory hematologic malignancies as monotherapy and in combination with zanubrutinib."

Preclinical • Trial status • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Prelude Announces Acceptance of Multiple Preclinical Abstracts at the 2024 AACR Annual Meeting (GlobeNewswire) - '"We look forward to sharing data on the preclinical characterization of our lead oral SMARCA2 degrader, PRT7732, which is on track to advance into Phase 1 clinical development in the second half of this year, and to presenting additional preclinical data for our highly selective and potent CDK9 inhibitor, PRT2527, that supports its potential therapeutic value in combination with BTK and BCL2 inhibitors in lymphoid malignancies. For our next generation CDK4/6 inhibitor, PRT3645, we will present preclinical data supporting its potential therapeutic value in combination with other targeted therapies for a range of tumor types in addition to breast cancer.'"

New P1 trial • Preclinical • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Hematological Malignancies • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

PBRM1 loss is associated with increased sensitivity to MCL1 and CDK9 inhibition in clear cell renal cancer. (PubMed, Front Oncol) - "Increased MCL1 activity has been described as a resistance mechanism to Sunitinib and Everolimus, two approved agents for ccRCC. PRT2527, a potent CDK9 inhibitor which depletes MCL1, was similarly efficacious in monotherapy and in combination with Sunitinib in PBRM1-loss cells. Taken together, these findings suggest PBRM1 loss is associated with MCL1i sensitivity in ccRCC and provide rationale for the evaluation of PRT1419 and PRT2527 for the treatment for PBRM1-deficient ccRCC."

IO biomarker • Journal • Clear Cell Renal Cell Carcinoma • Hematological Disorders • Hematological Malignancies • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • BCL2 • PBRM1

Prelude Therapeutics Reports Full Year 2023 Financial Results and Outlines Key Objectives for 2024 (GlobeNewswire) - "SMARCA2 degrader PRT3789 on track to complete monotherapy dose escalation mid-year and initiate combination with docetaxel in first half of 2024; initial proof-of concept data expected in second half of 2024....CDK9 inhibitor PRT2527 on track to complete monotherapy dose escalation mid-2024; initiate dosing in combination with zanubrutinib in first quarter of 2024; initial hematological proof-of-concept data expected in second half of 2024....The lead oral molecule, PRT7732, is currently in investigational new drug (IND) enabling studies and on track to enter Phase 1 clinical development in the second half of 2024."

New P1 trial • P1 data • Trial status • Chronic Lymphocytic Leukemia • Mantle Cell Lymphoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Richter's Syndrome • Small Lymphocytic Lymphoma

A Study of PRT2527 in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=30 | Completed | Sponsor: Prelude Therapeutics | Active, not recruiting ➔ Completed

Metastases • Trial completion • Trial completion date • Trial primary completion date • Breast Cancer • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Prostate Cancer • Sarcoma • Solid Tumor • HER-2 • MYC

Prelude Announces Strategic Pipeline Progress and Updates, including its Partnership with AbCellera, and Reports Third Quarter Financial Results (GlobeNewswire) - "PRT2527 in hematologic malignancies (NCT05665530)...this study is currently ongoing with initial clinical data expected in mid 2024."

P1 data • Chronic Lymphocytic Leukemia • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Richter's Syndrome • Small Lymphocytic Lymphoma

Prelude Announces Multiple Clinical and Preclinical Poster Presentations at AACR-NCI-EORTC International Conference (GlobeNewswire) - "Prelude Therapeutics Incorporated...announces multiple clinical and preclinical posters at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics....'This additional data from our solid tumor trial investigating our potent and selective CDK9 inhibitor, PRT2527, continues to support a best-in-class safety and target engagement profile for the molecule'....A second Phase 1 clinical trial in patients with hematological cancers is also underway, with initial data expected in 1H 2024....The overall safety profile observed in this study supports further development of PRT2527 in combination with other targeted therapies in hematological malignancies."

P1 data • Solid Tumor

A phase 1 study evaluating PRT2527, a potent and highly selective CDK9 inhibitor, in patients with select relapsed/refractory B-cell malignancies (IWCLL 2023) - P1 | "Secondary endpoints include objective response rate, duration of response, duration of complete response, and pharmacokinetic profile of PRT2527. The study is open to enrollment and registered at ClinicalTrials.gov, NCT05665530."

Clinical • P1 data • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • CASP3

A phase 1 dose-escalation study of PRT2527, a cyclin-dependent kinase 9 (CDK9) inhibitor, in adult patients with advanced solid tumors: an updated analysis. (AACR-NCI-EORTC 2023) - No abstract available

Clinical • Metastases • P1 data • Oncology • Solid Tumor • CDK9

A Study of PRT2527 as Monotherapy and in Combination With Zanubrutinib in Participants With R/R Hematologic Malignancies (clinicaltrials.gov) - P1 | N=104 | Recruiting | Sponsor: Prelude Therapeutics | N=51 ➔ 104

Combination therapy • Enrollment change • Monotherapy • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • T Cell Non-Hodgkin Lymphoma