P-500 / Prelude Therap, Pathos - LARVOL DELTA

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

Characterization of splicing aberrations induced by PRMT5 inhibition in Glioblastoma (SNO 2024) - "Here, we characterized the effects of pharmacological inhibition of PRMT5 by the brain-penetrant, orally bioavailable inhibitors, PRT811 and PRT808 on treatment-induced splicing aberrations using a panel of patient-derived glioma stem cells (GSC) and organotypic human glioma slice cultures...Additional analysis is ongoing to determine which of the aberrant transcripts are translated to yield tumor specific neoantigens that can be potential targets for tumor specific immune strategies. These results underscore the efficacy of pharmacological PRMT5 inhibition in genetically and epigenetically diverse GSCs, and highlight its potential for developing novel immune and non-immune therapeutic strategies against GBM."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • MTAP • PRMT5

Pathos AI Closes $62M Oversubscribed Series C Round of Financing to Accelerate its Platform Approach to Drug Development (GlobeNewswire) - "Pathos AI...announced the closing of an oversubscribed $62M Series C funding round. The Series C financing round was led by New Enterprise Associates (NEA) with participation from Revolution Growth and other existing insiders....In the last 12 months, Pathos has acquired two clinical-stage precision oncology assets with plans to launch the next clinical trials in 2025. For both therapeutics, P-300 and P-500, the PATHOS platform is fueling its patient selection strategy and clinical trial design to improve the likelihood of success."

Financing • Glioma

5-methylthioadenosine phosphorylase (MTAP) loss in clinically advanced uveal melanoma (CAUM): A comprehensive genomic profiling (CGP) study (ESMO 2024) - "Treatment options are limited to Tebentafusp in patients with HLA-A*02:01 mutation with immunotherapy and chemotherapy yielding poor results...In a recent phase I trial of a PRMT5 inhibitor, PRT811, clinical activity was described in cases of CAUM. 676 CAUM and 9666 CASM patients underwent hybrid capture based CGP to evaluate genomic alterations (GA)... Although MTAP loss is less frequent in CAUM than in CASM, the recent evidence that this genomic alteration predicts responsiveness to PRMT5 inhibition is noteworthy. This highlights the importance of further investigating this biomarker for patients with this rare and clinically aggressive type of cancer."

Clinical • IO biomarker • Metastases • Tumor mutational burden • Eye Cancer • Melanoma • Microsatellite Instability • Oncology • Solid Tumor • Uveal Melanoma • BAP1 • BRAF • CDKN2A • CDKN2B • GNA11 • GNAQ • HLA-A • MSI • MTAP • NF1 • PD-L1 • TMB

Pathos Expands Pipeline With Worldwide License of Phase 2-ready Brain-penetrant, PRMT5 Inhibitor (GlobeNewswire) - "Pathos AI, Inc...announced today the world-wide license of PRT811, a potent, selective, and orally bioavailable brain penetrant SAM-competitive PRMT5 inhibitor from Prelude Therapeutics."

Licensing / partnership • Brain Cancer • CNS Tumor • Glioma • Melanoma • Oncology • Solid Tumor • Uveal Melanoma

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

PRT811 Showcases Early Signals of Efficacy in IDH-Mutant Glioma and Uveal Melanoma (OncLive) - P1 | N=86 | NCT04089449 | Sponsor: Prelude Therapeutics | "At the 2023 ASCO Annual Meeting, Monga presented findings from a phase 1 trial...investigating PRT811 in these populations. In this trial, 2 patients in the glioma cohort (n = 38) responded to treatment, and both patients had IDH-positive disease. One of these patients achieved a complete response (CR) with a duration of response (DOR) of 31.0 months and was still receiving treatment at the data cutoff date, and the other patient had a CR with a DOR of 7.5 months and subsequently developed progressive disease (PD). In the uveal melanoma cohort (n = 23), 1 patient with splicing mutation–positive disease responded to the agent, achieving a partial response (PR) with a DOR of 10.0 months followed by PD."

P1 data • Brain Cancer • CNS Tumor • Glioma • Melanoma • Ocular Melanoma • Oncology • Solid Tumor • Uveal Melanoma

A phase 1 study of the protein arginine methyltransferase 5 (PRMT5) brain-penetrant inhibitor PRT811 in patients (pts) with recurrent high-grade glioma or uveal melanoma (UM). (ASCO 2023) - P1 | "PRT811 demonstrated an acceptable safety profile and clinical activity in pts with glioma and MUM. Clinical trial information: NCT04089449."

Clinical • P1 data • Anemia • Brain Cancer • CNS Lymphoma • CNS Tumor • Constipation • Eye Cancer • Fatigue • Gastroenterology • Gastrointestinal Disorder • Glioma • Hematological Disorders • Hematological Malignancies • Lymphoma • Melanoma • Oncology • Solid Tumor • Thrombocytopenia • Uveal Melanoma • IDH1 • IDH2 • PRMT5

PRT811 Yields Early Anti-Tumor Activity in Uveal Melanoma/Advanced Glioma (Cancer Network) - P1 | N=86 | NCT04089449 | Sponsor: Prelude Therapeutics | "The overall response rate (ORR) among patients treated with PRT811 in the glioma cohort was 5.3%, with the best overall response being a complete response. Moreover, 2.6% of patients in the cohort had unconfirmed partial responses (PRs), 28.9% achieved stable disease (SD), 52.6% had progressive disease (PD), and 22% were not evaluable. Patients in the uveal melanoma arm had an ORR of 4.4%. In this cohort, the best response was a PR, and all were unconfirmed. SD was seen in 34.8% of the patients with uveal melanoma, 43.5% had PD, and 13.0% of patients were not evaluable."

P1 data • Brain Cancer • CNS Tumor • Eye Cancer • Glioma • Melanoma • Ocular Melanoma • Oncology • Solid Tumor • Uveal Melanoma

A Study of PRT811 in Participants With Advanced Solid Tumors, CNS Lymphoma and Gliomas (clinicaltrials.gov) - P1 | N=86 | Completed | Sponsor: Prelude Therapeutics | Active, not recruiting ➔ Completed | N=145 ➔ 86

Enrollment change • Metastases • Trial completion • Brain Cancer • CNS Lymphoma • CNS Tumor • Glioma • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor

[VIRTUAL] A phase 1 dose escalation study of protein arginine methyltransferase 5 (PRMT5) brain penetrant inhibitor PRT811 in patients with advanced solid tumors, including recurrent high- grade gliomas (AACR-NCI-EORTC 2021) - No abstract available

Clinical • P1 data • Brain Cancer • Glioma • Oncology • Solid Tumor • PRMT5

[VIRTUAL] Discovery of PRT811, a potent, selective, and orally bioavailable brain penetrant PRMT5 Inhibitor for the treatment of brain tumors (AACR-II 2020) - P1 | "In a panel of brain cancer cell lines of varied histology, PRT811 reduced SDMA levels and inhibited cell proliferation with IC50 values in the range of 7-40 nM and 29-134 nM, respectively, regardless of expression levels of methylguanine methyltransferase (MGMT), the expression of which is associated with temozolomide (TMZ) resistance. Moreover, in a U-87 MG subcutaneous xenograft model in nude rats, once daily oral dosing of PRT811 at 20 and 30 mg/kg resulted in 91% and 100% tumor growth inhibition, respectively. PRT811 and related analogues are being studied across a panel of primary human and murine brain tumors ex vivo, and in vivo in primary orthotopic models of CNS lymphoma, a rare and aggressive subset of non-Hodgkins lymphomas.PRT811 is currently under evaluation in a Phase I clinical trial in patients with advanced solid tumors, gliomas, and myelofibrosis (NCT04089449)."

Brain Cancer • CNS Tumor • Glioblastoma • Hematological Malignancies • Lymphoma • Myelofibrosis • Non-Hodgkin’s Lymphoma • Oncology

A Study of PRT811 in Participants With Advanced Solid Tumors, CNS Lymphoma and Gliomas (clinicaltrials.gov) - P1 | N=145 | Active, not recruiting | Sponsor: Prelude Therapeutics | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Brain Cancer • CNS Lymphoma • CNS Tumor • Glioma • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor

A Study of PRT811 in Participants With Advanced Solid Tumors, CNS Lymphoma and Gliomas (clinicaltrials.gov) - P1 | N=145 | Recruiting | Sponsor: Prelude Therapeutics | Trial completion date: Oct 2022 ➔ Feb 2023 | Trial primary completion date: Oct 2022 ➔ Feb 2023

Trial completion date • Trial primary completion date • Brain Cancer • CNS Lymphoma • CNS Tumor • Glioma • Hematological Malignancies • 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

"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

Prelude Therapeutics Announces First Quarter 2022 Financial Results and Operations Update (GlobeNewswire) - "As previously announced, Prelude has prioritized PRT811 for clinical development in select expansion cohorts. Prelude intends to complete the data analyses of the ongoing expansion cohorts and expects to announce next steps for the PRMT5 program in 2H2022; Prelude continues to expect to file an IND application mid-year, with the initiation of a Phase 1 trial of PRT3645 to follow in 2H2022."

Clinical • IND • New P1 trial • Oncology

Characterization of factors affecting sensitivity and resistance to PRMT5 inhibition in glioblastoma (AACR 2022) - "MATERIALS AND Using pharmacological inhibition of PRMT5 using with the highly specific inhibitors PRT808 and PRT811, we examined their effects on apoptosis, cell proliferation, cell cycle distribution, and methylation markers in patient-derived glioma stem-like cells (GSC) with epigenetic and genetic signaling... Our results demonstrate pharmacological PRMT5 inhibition induced SDMA reduction and late apoptosis in genetically and epigenetically heterogeneous patient-derived GSC lines and that mutant p53 lines are less sensitive to PRMT5 inhibition. Additional studies related to splicing defects upon PRMT5 inhibition are ongoing and will be presented at the meeting."

Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • MTAP • PRMT5

Prelude Therapeutics Provides Clinical Update and Announces Presentation of New Preclinical Data at the Upcoming 2022 AACR Annual Meeting (GlobeNewswire) - "'For the PRMT5 program, which includes PRT543 and PRT811, we are concentrating our efforts on PRT811 because of its superior safety profile, higher level of target engagement, and unique brain penetrant properties. Our development efforts for PRT811 are focused on specific indications, including splicing mutated myeloid malignancies and solid tumors, including uveal melanoma, and IDH1 mutated high grade glioma. We anticipate reporting data from the ongoing dose expansion cohorts in 2H/2022'...'we believe PRT1419 has the potential to be a best-in-class MCL1 inhibitor. We look forward to reporting data from the combination study in 2H/2022.'....'An IND submission for PRT3645 is planned for mid-year, with a second IND submission for our SMARCA2/BRM candidate by year-end 2022.'"

IND • New trial • CNS Lymphoma • Glioma • Hematological Malignancies • Melanoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Prelude Therapeutics Announces Third Quarter 2021 Financial Results and Operations Update (GlobeNewswire) - “PRT811: Phase 1 Dose Escalation Study Data Presented at the AACR-NCI-EORTC Annual Meeting; Dose Expansion Portion of Phase 1 Trial to Commence 4Q21...Prelude will shortly commence the dose expansion portion of the Phase 1 trial in selected patients with central nervous system cancers (CNS) and non-CNS cancers. The Company expects to present data from the expansion cohorts in 2022....Phase 1 Dose Escalation Portion of Oral and Intravenous (IV) PRT1419 Trial Ongoing...The Company expects to add dose expansion and combination cohorts to the Phase 1 clinical trial in the first half of 2022.”

P1 data • Trial status • Acute Myelogenous Leukemia • Brain Cancer • CNS Tumor • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Solid Tumor

A Study of PRT811 in Participants With Advanced Solid Tumors, CNS Lymphoma and Gliomas (clinicaltrials.gov) - P1; N=145; Recruiting; Sponsor: Prelude Therapeutics; N=75 ➔ 145; Trial primary completion date: Oct 2021 ➔ Oct 2022

Clinical • Enrollment change • Trial primary completion date • Brain Cancer • CNS Lymphoma • CNS Tumor • Glioma • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor

Prelude Therapeutics Announces Presentation of Encouraging Data from Multiple Programs at the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics (GlobeNewswire) - P1, N=75; NCT04089449; Sponsor: Prelude Therapeutics; "PRT811 demonstrated dose dependent inhibition of PRMT5 activity as evidenced by an 83% reduction in serum sDMA at a dose of 600 mg daily (QD). In addition, PRT811 demonstrated signs of preliminary clinical activity, including an IDH1 mutated GBM patient who experienced a partial response (PR) that evolved into a durable CR for more than 13 months and remains on treatment....the Company expects to commence enrollment in the expansion portion of the trial in the fourth quarter. Data from the expansion cohorts are expected to be presented at medical meetings throughout 2022."

P1 data • Breast Cancer • Glioblastoma • Melanoma • Oncology • Solid Tumor • Triple Negative Breast Cancer

Prelude Therapeutics Announces Second Quarter 2021 Financial Results and Operations Update (GlobeNewswire) - "Research and Development (R&D) Expenses: For the second quarter of 2021, R&D expense increased by $12.6 million to $22.4 million for the three months ended June 30, 2021 from $9.8 million for the three months ended June 30, 2020. The increase was mainly due to increased clinical research costs for the PRT543, PRT811 and PRT1419 (Oral and IV) programs, and increased chemistry, manufacturing and other costs for those trials."

Commercial • Oncology

Prelude Therapeutics Announces Second Quarter 2021 Financial Results and Operations Update (GlobeNewswire) - “PRT543…The Company expects to present data from the expansion cohorts at medical meetings throughout 2022…PRT811; Dose Expansion Portion of Phase 1 Trial Expected to Commence in 3Q21; Data from Dose Escalation Portion to be Presented at the AACR-NCI-EORTC Annual Meeting…PRT1419…The Company expects to add dose expansion and combination cohorts to the Phase 1 clinical trial in the second half of 2021…The Company remains on track to submit an Investigational New Drug (IND) application in 2021 for PRT2527, which is designed to be a potent and selective CDK9 inhibitor. In addition, the Company continues to expect to initiate IND-enabling studies for PRT-SCA2, which is designed to be a SMARCA2 protein degrader, by the end of the year.”

IND • P1 data • Trial status • Acute Myelogenous Leukemia • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Solid Tumor