onametostat (JNJ-64619178) / J&J - LARVOL DELTA

Screening NSCLC Patient Organoids With Epigenetic Compound Library Identifies a Therapeutic Vulnerability to PRMT5 Inhibition (IASLC-WCLC 2026) - "In contrast, the substrate-competitive PRMT5 inhibitor GSK591 showed activity in fewer models (4/33)...Limited testing with the clinically relevant SAM-competitive PRMT5 inhibitor Onametostat demonstrated concordant responses in LLY283 sensitive models...Distinct baseline alternative splicing patterns further differentiate sensitive vs resistant models, indicating coordinated transcriptional and splicing programs linked to proliferation and metabolism. These findings provide a framework for further development of SAM-competitive PRMT5 inhibitors."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • EGFR • FGFR1 • IL2 • KRAS • PIK3CA • PRMT5 • STAT5

Inhibition of PRMT5 sensitizes B-cell non-Hodgkin lymphoma cells to both intrinsic and extrinsic apoptotic cell death. (PubMed, Blood Neoplasia) - "Interestingly, JNJ-64619178 upregulated death receptor 4 (DR4) and death receptor 5 (DR5) expression on the cell membrane of B-NHL cell lines, thereby sensitizing them, including the less BCL-2-dependent cell lines, to recombinant TRAIL-induced extrinsic apoptotic cell death. These findings highlight a role of PRMT5 in regulating both intrinsic and extrinsic apoptosis and suggest potential combination partners with PRMT5 inhibitors for potential clinical application in B-NHL."

IO biomarker • Journal • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • TNFRSF10B

PRMT5-mediated methylation of LKB1 controls PD-L1 expression in NSCLC. (PubMed, Biomed J) - "These findings identify a PRMT5-LKB1-AMPK regulatory axis controlling PD-L1 expression in a cell-context-dependent manner and suggest that LKB1 status may serve as a predictive biomarker for combining PRMT5 inhibitors with ICB in NSCLC. This strategy offers a potential therapeutic avenue to overcome immunotherapy resistance in LKB1-proficient NSCLC."

IO biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD4 • CD8 • PD-L1 • PRMT5 • STK11

Development and Validation of an LC-MS/MS Method for the Quantitation of JNJ-64619178 (JNJ) in Mouse Plasma: Characterization of In Vitro and In Vivo Pharmacokinetic Properties. (PubMed, Molecules) - "Oral bioavailability was low (15%). The validated method was successfully applied to in vitro and in vivo studies and will guide dosing in animal models of medulloblastoma."

Journal • PK/PD data • Preclinical • Brain Cancer • Hematological Malignancies • Lung Cancer • Lymphoma • Medulloblastoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Emerging role of protein arginine methyltransferase 5 in gastrointestinal cancer (Review). (PubMed, Oncol Lett) - "However, PRMT5 inhibitors (e.g., GSK3326595 and JNJ-64619178) demonstrate antitumor effects in preclinical models and methylthioadenosine phosphorylase (MTAP) deletion may serve as a potential biomarker for patient selection. The clinical translation of PRMT5 inhibitors is limited by hematological toxicity, lack of robust predictive biomarkers beyond MTAP and potential resistance from compensatory PRMT family members. It is key to clarify GI cancer-specific PRMT5 mechanisms and potentially develop optimized combination therapies in the future."

Journal • Review • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Hematological Disorders • Hepatocellular Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CTNNB1 • CXCL8 • EGFR • GPX4 • MTAP • MYC • PRMT5 • SLC7A11 • SMAD4 • TGFB1

A Rollover Study for Continued Study Treatment and Ongoing Safety Monitoring (clinicaltrials.gov) - P1 | N=120 | Enrolling by invitation | Sponsor: Janssen Research & Development, LLC | N=52 ➔ 120

Enrollment change • Acute Myelogenous Leukemia • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Prostate Cancer • Solid Tumor

Targeting the PLK1-PRMT5 axis enhances radiosensitivity in prostate cancer (AACR 2026) - "Importantly, both PLK1 inhibition (Onvansertib) and PRMT5 inhibition (Onametostat) synergized with ionizing radiation (IR) to suppress tumor growth in vitro and in vivo. These findings highlight a previously unrecognized role of PLK1-mediated PRMT5 phosphorylation in cell cycle control and radiosensitivity, suggesting that targeting the PLK1-PRMT5 axis may serve as a promising therapeutic strategy to enhance radiotherapy efficacy in prostate cancer."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • PLK1 • PRMT5

Comprehensive assay approaches for PRMT5 targeted drug discovery (AACR 2026) - "Here, we established comprehensive assay platforms for PRMT5-targeted drug discovery and validated them using five known inhibitors (LLY-283, JNJ-64619178, GSK591, EPZ015666, and GSK33326595). NanoBRET target engagement intracellular assay results indicated that the PRMT5 inhibitors engaged with the PRMT5/MEP50 complex within one hour of incubation in live HEK293 cells, and Western blot confirmed inhibition of histone H4R3me2s methylation, a key substrate of PRMT5, in MV4-11, Jeko-1, 22RV1, and PC3 cancer cell lines. Collectively, these platforms enable identification, optimization, and mechanistic characterization of PRMT5 inhibitors, accelerating development of selective and potent therapeutic candidates."

Hematological Malignancies • Oncology

Combination of MTA-cooperative PRMT5 inhibitor and direct mutant-selective KRAS inhibitors as a novel therapeutic approach for MTAP-deficient pancreatic cancer (AACR 2024) - "We found that suppression of PRMT5 activity using two distinct first-generation clinical candidate small molecule inhibitors (JNJ-64619178 and GSK3326595) demonstrated single agent activity and reduced PDAC cell growth...In support of our hypothesis, we demonstrated that combination treatment with MRTX1719 and mutant selective KRAS inhibitors (G12Ci/MRTX849 and G12Di/MRTX1133) further sensitized KRASG12C/D-mutant PDAC cells to KRAS inhibition in short- and long-term growth assays as well as in vivo xenograft studies. Our ongoing studies are evaluating the consequences of co-targeting PRMT5 and KRAS on gene expression changes using RNA-Seq and cancer cell signaling pathways using RPPA analyses. In summary, our data support concurrent inhibition of PRMT5 and KRAS as a promising therapeutic strategy for MTAP-deficient KRAS-mutant pancreatic cancer."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • MTAP

A Rollover Study for Continued Study Treatment and Ongoing Safety Monitoring (clinicaltrials.gov) - P1 | N=52 | Enrolling by invitation | Sponsor: Janssen Research & Development, LLC | N=35 ➔ 52

Enrollment change • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Rollover Study for Continued Study Treatment and Ongoing Safety Monitoring (clinicaltrials.gov) - P1 | N=120 | Enrolling by invitation | Sponsor: Janssen Research & Development, LLC | N=80 ➔ 120

Enrollment change • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Potential novel interventions of oncohistones, epigenetic modifications, and RNA processing machinery in betel-nuts related HNSCC in Taiwan (AACR 2025) - "PI3K/AKT/mTOR interventions, ALK/IGF1R inhibitor, CDK4/6 inhibitor, BCl2 inhibitor, WEE1 inhibitor, ATR inhibitor, DNA-PK inhibitor, AT2AR inhibitor, Mcl-1 inhibitor, MEK1/2 inhibitor, JAK2 inhibitor, CXCR4 inhibitor, FAK inhibitor, p53 reactivator, MDM2 inhibitor, SHP2 inhibitor, PARP7 inhibitor, IAP inhibitor, GLS1 inhibitor, eribulin, & VEGFR2/ PDGFR/FGFR or VEGFR2/c-MET/Axl triple blockage might be effective on TW2.6 and reverse treatment refractoriness, through the inhibition of mesenchymal transformation, pRB, & PI3K/AKT /mTOR signaling and modulation of stemness & PD1/PDL1 pathway...Disrupting NSD1 in HNSCC cell lines led to CpG hypomethylation & enhanced cisplatin sensitivity. TW2.6 used to test (1)in vitro drug sensitivity to (a)Chemical Modulators of Splicing; (b)PRMT5 inhibitor; (c)CDK9 inhibitor, EZH2i, DNMT3i, BRD/BET4i, and HDACi; (d)NSD1/SETD2 inhibitor; (e)METTL3 inhibitor; (2)synergistic effects with other therapies by MTT assay, colony..."

IO biomarker • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma of Head and Neck • AKT1 • ALK • ARID1B • ATM • AXL • BRD4 • CCND3 • CDK12 • CXCR4 • DDR2 • EPHB1 • FAT1 • FGF10 • FGFR • FLCN • HRAS • KDM5A • KDR • METTL3 • MITF • NSD1 • PDGFRB • PIK3CA • RICTOR • RPS6KB1 • SDHA • SETD2 • SOX9 • STK11 • TERT • TIPARP • TMB • TNFAIP3

A Rollover Study for Continued Study Treatment and Ongoing Safety Monitoring (clinicaltrials.gov) - P1 | N=80 | Enrolling by invitation | Sponsor: Janssen Research & Development, LLC | Trial completion date: Jan 2028 ➔ Oct 2028

Trial completion date • Acute Myelogenous Leukemia • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Prostate Cancer • Solid Tumor

PRMT5 as a target in CRC interception: Synthetic lethal dependency identified in APC-LOF preclinical models of FAP disease (AACR 2025) - "JNJ-64619178 (JNJ-9178), a potent clinical PRMT5 inhibitor, demonstrated an >800-fold window in growth inhibition of engineered APCKO organoids compared to wild-type (WT). To address these dose-limiting toxicities, we have developed a GI-restricted approach and discovered new compounds that only inhibit PRMT5 activity locally in the intestinal tract. This strategy is detailed in a second abstract."

Preclinical • Synthetic lethality • Colorectal Cancer • Oncology • Solid Tumor • APC

CR108485: A Study of JNJ-64619178, an Inhibitor of PRMT5 in Participants With Advanced Solid Tumors, NHL, and Lower Risk MDS (clinicaltrials.gov) - P1 | N=114 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Dec 2022 ➔ Dec 2023 | Trial primary completion date: Jul 2022 ➔ Dec 2023

First-in-human • Trial completion date • Trial primary completion date • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

CR108485: A Study of JNJ-64619178, an Inhibitor of PRMT5 in Participants With Advanced Solid Tumors, NHL, and Lower Risk MDS (clinicaltrials.gov) - P1 | N=120 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Dec 2021 ➔ Jul 2022

First-in-human • Trial completion date • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

CR108485: A Study of JNJ-64619178, an Inhibitor of PRMT5 in Participants With Advanced Solid Tumors, NHL, and Lower Risk MDS (clinicaltrials.gov) - P1 | N=113 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Recruiting ➔ Active, not recruiting | N=190 ➔ 113

Enrollment change • Enrollment closed • First-in-human • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

CR108485: A Study of JNJ-64619178, an Inhibitor of PRMT5 in Participants With Advanced Solid Tumors, NHL, and Lower Risk MDS (clinicaltrials.gov) - P1 | N=114 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Dec 2023 ➔ Dec 2024 | Trial primary completion date: Dec 2023 ➔ Dec 2024

First-in-human • Trial completion date • Trial primary completion date • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

CR108485: A Study of JNJ-64619178, an Inhibitor of PRMT5 in Participants With Advanced Solid Tumors, NHL, and Lower Risk MDS (clinicaltrials.gov) - P1 | N=138 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial primary completion date: Dec 2021 ➔ Jul 2022

First-in-human • Trial primary completion date • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

CR108485: A Study of JNJ-64619178, an Inhibitor of PRMT5 in Participants With Advanced Solid Tumors, NHL, and Lower Risk MDS (clinicaltrials.gov) - P1 | N=114 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Jul 2022 ➔ Dec 2022

First-in-human • Trial completion date • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

CR108485: A Study of JNJ-64619178, an Inhibitor of PRMT5 in Participants With Advanced Solid Tumors, NHL, and Lower Risk MDS (clinicaltrials.gov) - P1 | N=70 | Recruiting | Sponsor: Janssen Research & Development, LLC | Not yet recruiting ➔ Recruiting

Enrollment open • First-in-human • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

CR108485: A Study of JNJ-64619178, an Inhibitor of PRMT5 in Participants With Advanced Solid Tumors, NHL, and Lower Risk MDS (clinicaltrials.gov) - P1 | N=190 | Recruiting | Sponsor: Janssen Research & Development, LLC | N=138 ➔ 190

Enrollment change • First-in-human • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

CR108485: A Study of JNJ-64619178, an Inhibitor of PRMT5 in Participants With Advanced Solid Tumors, NHL, and Lower Risk MDS (clinicaltrials.gov) - P1 | N=70 | Not yet recruiting | Sponsor: Janssen Research & Development, LLC

First-in-human • New P1 trial • B Cell Non-Hodgkin Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Solid Tumor

CR108485: A Study of JNJ-64619178, an Inhibitor of PRMT5 in Participants With Advanced Solid Tumors, NHL, and Lower Risk MDS (clinicaltrials.gov) - P1 | N=120 | Recruiting | Sponsor: Janssen Research & Development, LLC | N=70 ➔ 120

Enrollment change • First-in-human • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

CR108485: A Study of JNJ-64619178, an Inhibitor of PRMT5 in Participants With Advanced Solid Tumors, NHL, and Lower Risk MDS (clinicaltrials.gov) - P1 | N=114 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Dec 2024 ➔ Dec 2025 | Trial primary completion date: Dec 2024 ➔ Dec 2025

First-in-human • Trial completion date • Trial primary completion date • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor