PRT543 / Prelude Therap - LARVOL DELTA

Phase Ib Study of PRT543, an Oral Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor, in Patients with Relapsed or Refractory, Splicing Factor-Mutant Myeloid Malignancies (ASH 2024) - P1 | "Pts with higher-risk MDS, AML, or MDS/MPN overlap had a splicing factor mutation and R/R disease after prior HMA +/- venetoclax, ≥2 cycles of intensive induction chemotherapy, or any other therapies. In summary, monotherapy with PRT543 is safe in pts with R/R splicing mutant myeloid malignancies and demonstrated clear target engagement and splicing changes with objective responses in 5 out of 40 pts including 1 AML pt with a CRi and a HR-MDS pt with trilineage HI. Additional preclinical data including the PRT543 structure will be presented."

Clinical • P1 data • Acute Myelogenous Leukemia • Anemia • Myelodysplastic Syndrome • Neutropenia • Respiratory Diseases • Thrombocytopenia • PRMT5 • SF3B1 • SRSF2 • U2AF1

Phase Ib study of PRT543, an oral protein arginine methyltransferase 5 (PRMT5) inhibitor, in patients with advanced splicing factor-mutant myeloid malignancies. (PubMed, Leukemia) - No abstract available

Journal • P1 data • Hematological Malignancies • Oncology

PRMT5 inhibition has a potent anti-tumor activity against adenoid cystic carcinoma of salivary glands. (PubMed, J Exp Clin Cancer Res) - "Taken together, our study underscores the role of PRMT5 in ACC oncogenesis and provides a strong rationale for the clinical development of PRMT5 inhibitors as a targeted monotherapy or combination therapy for treatment of patients with this rare disease, based on the analysis of their underlying molecular profile."

Journal • Adenoid Cystic Carcinoma • Oncology • Rare Diseases • Salivary Gland Cancer

PRMT5 inhibition has a potent anti-tumor activity against adenoid cystic carcinoma of salivary glands (AHNS-COSM 2024) - "Identifying PRMT5 as a putative candidate, we next determined the applicability of PRMT5 inhibitors (PRT543 and PRT811) using ACC cell lines, organoids, and patient derived xenograft (PDX) models. Our study underscores the role of PRMT5 in ACC and supports PRMT5 blockade as a promising strategy for treating this rare disease."

Adenoid Cystic Carcinoma • Oncology • Rare Diseases • Salivary Gland Cancer

PRT543, a protein arginine methyltransferase 5 inhibitor, in patients with advanced adenoid cystic carcinoma: An open-label, phase I dose-expansion study. (PubMed, Oral Oncol) - P1 | "In this analysis, PRT543 was tolerable, and the observed efficacy was limited in patients with R/M ACC."

Journal • Metastases • P1 data • Adenoid Cystic Carcinoma • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor • NOTCH1

PRMT5 Inhibitors Regulate DNA Damage Repair Pathways in Cancer Cells and Improve Response to PARP Inhibition and Chemotherapies. (PubMed, Cancer Res Commun) - "Combining C220 or PRT543 with olaparib or chemotherapeutic agents such as cisplatin demonstrates a potent synergistic interaction in breast and ovarian cancer cells in vitro. Furthermore, PRT543 treatment significantly inhibits growth of Olaparib resistant tumors in vivo. These studies reveal a novel mechanism of PRMT5 inhibition and suggest beneficial combinatorial effects with other therapies, particularly in patients with tumors that are resistant to therapies dependent on DNA damage as their mechanism of action."

Journal • Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • BRCA1 • BRCA2 • FANCA • PNKP • PRMT5 • RAD51

PRMT5 Inhibitors Regulate DNA Damage Repair Pathways in Cancer Cells and Improve Response to PARP Inhibition and Chemotherapies (Cancer Res Commun) - "Combining C220 or PRT543 with Olaparib or chemotherapeutic agents such as cisplatin demonstrates a potent synergistic interaction in breast and ovarian cancer cells in vitro. Moreover, combination of PRT543 with Olaparib effectively inhibits the growth of patient-derived breast and ovarian cancer xenografts. Furthermore, PRT543 treatment significantly inhibits growth of Olaparib resistant tumors in vivo."

Preclinical • Breast Cancer • Ovarian Cancer

PRT543, a methyl transferase inhibitor, has potent anti-tumor activity against adenoid cystic carcinoma of salivary glands (AACR 2023) - "Further, based on these observations, we have sequenced a collection of 50 ACC tumor samples to identify the subset of patients who may potentially benefit from PRT543 treatment based on their underlying genetic signatures. This study provides evidence underscoring the role of PRMT5 signaling in ACC and supports the clinical development of PRMT5 inhibitors for this indication."

Adenoid Cystic Carcinoma • Oncology • Salivary Gland Cancer • Solid Tumor • MYB • PRMT5

[VIRTUAL] Preclinical characterization of PRT543,a potent and selective inhibitor of protein arginine methyltransferase 5 (PRMT5), with broad antitumor activity in in vitro and in vivomodels (AACR-II 2020) - P1 | "Combining PRT543 with the BCL2 inhibitor, venetoclax, revealed a potent synergistic interaction in models of leukemia and lymphoma. Further ex vivo testing in genetically-defined primary patient tumor samples is ongoing. PRT543 is currently under evaluation in a Phase I clinical trial in patients with advanced solid tumors and hematological malignancies (NCT03886831)."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Bladder Cancer • Genito-urinary Cancer • Hematological Malignancies • Leukemia • Lung Cancer • Lymphoma • Mantle Cell Lymphoma • Oncology • Small Cell Lung Cancer • Thoracic Cancer • Urothelial Cancer

PRMT5 Inhibition Drives Therapeutic Vulnerability to BCL-2 Inhibition with Venetoclax and Provides Rationale for Combination Therapy in Mantle Cell Lymphoma (ASH 2019) - P1; "The average overall survival of patients with MCL is 5 years and for the majority of patients who progress on targeted agents like ibrutinib, survival remains at a dismal 3-8 months. This preclinical data provides mechanistic rationale while demonstrating therapeutic synergy and lack of toxicity in this preclinical study and justifies further consideration of this combination strategy targeting PRMT5 and BCL2 in MCL in the clinical setting. PRT543, a selective PRMT5 inhibitor, has been advanced into clinical studies for the treatment of patients with solid tumors and hematologic malignancies, including MCL (NCT03886831)."

Combination therapy • IO biomarker • Hematological Disorders • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Transplantation • BAX • FOXO1

PRMT5 Inhibition Modulates E2F1 and P53 to Restore Cell Cycle Regulation and Drive DNA Damage Response in Ibrutinib-Resistant Mantle Cell Lymphoma (ASH 2021) - P1 | "Western blot analysis confirmed E2F target gene repression (TK1, CCNA2, CHK1, CDK1) and accumulation of DNA damage response proteins (cleaved PARP, cleaved CASP3, p-H2AX) that are further enhanced with combination of doxorubicin. Pharmacologic inhibition of PRMT5 with the clinical-grade, novel small molecule inhibitor (PRT543, Prelude Therapeutics) merits further investigation in ongoing clinical trials (NCT03886831, clinicaltrials.gov), specifically for the treatment of IR-MCL with deletion of MTAP and prior to the genomic mutation of TP53 . We are currently exploring novel combinations to maximize the therapeutic potential of PRMT5 inhibition in this disease."

Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • CASP3 • CCNA2 • CD19 • CDK1 • CDKN1A • CDKN2A • CHEK1 • E2F1 • MTAP • PRMT5

PRMT5 Inhibition Modulates E2F1 Methylation and Gene Regulatory Networks Leading to Therapeutic Efficacy in JAK2VF Mutant MPN (ASH 2019) - P1; "These data demonstrate a novel link between PRMT5, E2F1 gene regulatory function, and the survival of MPN cells and provide a strong mechanism-based rationale for therapeutic studies of PRMT5 inhibitors in MPN. Based on these studies and others, PRT543, a novel and selective PRMT5 inhibitor, is currently being evaluated in a Phase I clinical trial in advanced cancers, including myelofibrosis (NCT03886831)."

Clinical • CCL3 • CCL4 • CCL5 • CD34 • CD71 • E2F1 • ENG • IL1B • JAK2 • MIP-2

[VIRTUAL] A phase 1 dose escalation study of protein arginine methyltransferase 5 (PRMT5) inhibitor PRT543 in patients with advanced solid tumors and lymphoma (AACR-NCI-EORTC 2021) - No abstract available

Clinical • P1 data • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor • PRMT5

PRMT5 inhibitor PRT543 displays potent antitumor activity in U2AF1S34F and RBM10LOF spliceosome-mutant non-small cell lung cancer in vitro and in vivo (AACR 2022) - P1 | "Efficacy studies in patient-derived xenograft (PDX) models, as well as genomic profiling of spliceosome-mutant cellular models in response to PRT543 are ongoing. PRT543 is currently under evaluation in a Phase I clinical trial in patients with advanced solid tumors and hematological malignancies (NCT03886831)."

Preclinical • Eye Cancer • Hematological Malignancies • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Uveal Melanoma • BRCA1 • FANCA • FANCL • PRMT5 • RAD51 • RBM10 • U2AF1

[VIRTUAL] PRMT5 inhibition epigenetically regulates DNA damage response pathways in cancer cells and sensitizes to chemotherapy and PARP inhibition (AACR 2021) - P1 | "These studies not only reveal a novel mechanism of PRMT5 inhibition, but also suggest beneficial combination effects with other therapies, particularly in patients with tumors that are resistant to therapies that are dependent on DNA damage as their mechanism of action. PRT543 is currently under evaluation in a Phase I clinical trial in patients with advanced solid tumors and hematological malignancies (NCT03886831)."

Breast Cancer • Hematological Malignancies • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • ATR • BRCA1 • BRCA2 • CHEK1 • POLD1 • PRMT5 • RAD51

[VIRTUAL] PRMT5 inhibition downregulates MYB and NOTCH1 signaling, key molecular drivers of adenoid cystic carcinoma (AACR 2021) - P1 | "Collectively, these findings provide a strong molecular rationale for exploring PRT543 as a potential therapeutic option for ACC tumors. PRT543 is currently under evaluation in a Phase I clinical trial in patients with advanced solid tumors and hematological malignancies (NCT03886831)."

Adenoid Cystic Carcinoma • Head and Neck Cancer • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • FOXM1 • GATA3 • MYB • NFIB • NOTCH1 • PRMT5 • SOX4

[VIRTUAL] PRMT5 inhibition regulates alternative splicing and DNA damage repair pathways in SF3B1 R625G expressing uveal melanoma cells (AACR 2021) - P1 | "In summary, our results suggest that PRMT5 inhibition regulates cancer-associated RNA splicing machinery and the DNA damage response, resulting in synergistic antitumor activity when combined with chemotherapy and/or PARP inhibitors, particularly in cancers with spliceosomal mutations. PRT543 is currently under evaluation in a Phase I clinical trial in patients with advanced solid tumors and hematological malignancies (NCT03886831)."

Eye Cancer • Hematological Malignancies • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • ATM • MBD4 • POLD1 • PRMT5 • SF3B1

PRMT5 Inhibition Alters Mitochondrial Dynamics in Mantle Cell Lymphoma Creating Vulnerability to BH3 Mimetic Compounds (ASH 2022) - "Selectively inhibiting PRMT5 has shown significant anti-tumor activity in preclinical MCL models, and a Phase 1 clinical trial with PRT543 (Prelude), a novel PRMT5 inhibitor, is underway...Combinatorial treatment was tested in vivo using the PDX.AA.MCL model of ibrutinib resistant MCL...Navitoclax and PRT808 single agent as well as PRT808+PRT1419 regimens significantly slowed disease progression...Of note, navitoclax dosing alone or in combination did not induce additional platelet loss. Our results provide rationale for combining BH3 mimetics and PRMT5 inhibition in clinical trials as a novel treatment strategy for MCL."

IO biomarker • Hematological Disorders • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Thrombocytopenia • BBC3 • BCL2 • BCL2L1 • BCL2L2 • E2F1 • PRMT5 • RELA

A Study of PRT543 in Participants With Advanced Solid Tumors and Hematologic Malignancies (clinicaltrials.gov) - P1 | N=232 | Completed | Sponsor: Prelude Therapeutics | Active, not recruiting ➔ Completed

Trial completion • Acute Myelogenous Leukemia • Adenoid Cystic Carcinoma • Chronic Myeloid Leukemia • Chronic Myelomonocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Myelodysplastic Syndrome • Myelofibrosis • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Prelude Therapeutics Announces Third Quarter 2022 Financial Results and Provides Business Update (GlobeNewswire) - “Brain Penetrant CDK4/6: Phase 1 clinical trial is being initiated for PRT3645 in biomarker enriched patients with select tumor types including sarcomas, mesothelioma, gliomas, head and neck cancers and non-small cell lung cancer, in addition to breast cancer with or without brain metastases. Present initial clinical results at a medical conference in 2H 2023. RP2D in solid tumors in 2H 2024...SMARCA2/BRM Protein Degrader Program: Prelude received IND clearance in October for PRT3879. Prelude plans to dose the first patient in Q1 2023. SMARCA2 inhibition has the greatest potential in patients with SMARCA4 deficient cancers, including up to 10% of all non-small cell lung cancers. Provide Clinical update 2H 2023....In the Phase 1 trials for PRT543 and PRT811, both molecules were generally well tolerated....Full results from the two clinical trials will be shared in the first half of 2023."

P1 data • Trial status • Breast Cancer • CNS Tumor • Glioblastoma • Glioma • Head and Neck Cancer • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Sarcoma • Solid Tumor

A Phase 1 Dose Escalation Study of Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor PRT543 in Patients with Myeloid Malignancies (ASH 2021) - P1 | "PRT543 was well tolerated with a favorable safety profile. Dose-dependent inhibition of target engagement and functional activity of PRMT5 were observed. PRT543 treatment demonstrated reduction in inflammatory markers and improvement in symptoms and anemia in select patients."

Clinical • P1 data • Acute Myelogenous Leukemia • Anemia • Fatigue • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Myelodysplastic Syndrome • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Pruritus • Solid Tumor • Thrombocytopenia • CRP • CXCL8 • IL6 • PRMT5 • SF3B1

A Study of PRT543 in Participants With Advanced Solid Tumors and Hematologic Malignancies (clinicaltrials.gov) - P1 | N=227 | Active, not recruiting | Sponsor: Prelude Therapeutics | Trial primary completion date: Aug 2022 ➔ Dec 2022

Trial primary completion date • Acute Myelogenous Leukemia • Adenoid Cystic Carcinoma • Chronic Myeloid Leukemia • Chronic Myelomonocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Myelodysplastic Syndrome • Myelofibrosis • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

"Select projects targeting synthetic lethality TNG908 MRTX1719 SKL27969 AMG 193 AG-270 IDE397 JNJ-64619178 PRT543 PRT811 RP-6306 GSK3326595 GSK3368715 PF-06939999 JBI-778 TNG462 ISM020 AGX323 AT101/ AT201 @JacobPlieth @evaluatepharma https://t.co/74gBPzNLcn https://t.co/5Um0uV9GAB" (@BRAINCURES)

Synthetic lethality

Protein Arginine Methyltransferase 5 (PRMT5) Inhibitors in Oncology Clinical Trials: A review. (PubMed, J Immunother Precis Oncol) - "Partial response has been seen in adenoid cystic carcinoma from both GSK3326595 and JNJ-64619178, with four cases of stable disease seen with PRT543. Highly significant is a durable complete response in isocitrate dehydrogenase 1-mutated glioblastoma multiforme with PRT811...Further studies are warranted, and there are clinical trials to come whose data will be telling of the efficacy of PRMT5 inhibitors in both hematologic and solid malignancies. The aim of this study is to compile available results of PRMT5 inhibitors in oncology clinical trials."

IO biomarker • Journal • Review • Adenoid Cystic Carcinoma • Brain Cancer • Glioblastoma • Hematological Disorders • Oncology • Solid Tumor • IDH1 • PRMT5

A Study of PRT543 in Participants With Advanced Solid Tumors and Hematologic Malignancies (clinicaltrials.gov) - P1 | N=227 | Active, not recruiting | Sponsor: Prelude Therapeutics | Recruiting ➔ Active, not recruiting | Trial completion date: Aug 2022 ➔ Dec 2022 | Trial primary completion date: Apr 2022 ➔ Aug 2022

Enrollment closed • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Adenoid Cystic Carcinoma • Chronic Myeloid Leukemia • Chronic Myelomonocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Myelodysplastic Syndrome • Myelofibrosis • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor