Ezharmia (valemetostat) / Daiichi Sankyo - LARVOL DELTA

EMBRYONIC ECTODERM DEVELOPMENT (EED) INHIBITOR APG-5918 EXHIBITS POTENT ANTITUMOR ACTIVITY AND SYNERGIZES WITH HISTONE DEACETYLASE INHIBITOR TUCIDINOSTAT IN PRECLINICAL T-CELL LYMPHOMA (TCL) MODELS (EHA 2025) - "A subcutaneous HuT102 cell line-derived xenograft (CDX) model was established to assess in vivo antitumor efficacy.APG-5918 exhibited potent antiproliferative activity in vitro, with IC50 values ranging from 0.1 to 7.2 μM, outperforming dual EZH1/2i valemetostat and EZH2i tazemetostat. APG-5918 exhibited potent antitumor activity alone and synergized with tucidinostat in preclinical TCL models. Mechanistically, it modulated PRC2 complex and induced apoptosis and cell cycle arrest. Combination with tucidinostat further enhanced these effects."

Epigenetic controller • Preclinical • Hematological Malignancies • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • CASP3 • CDK6 • EZH2

THE CORRELATION OF MUTATIONAL PROFILES AND VALEMETOSTAT EFFICACY IN PATIENTS WITH R/R PTCL IN THE PHASE 2 VALENTINE-PTCL01 TRIAL (ICML 2025) - "While valemetostat is efficacious in PTCL irrespective of pathologic subtypes, our study indicated that the BL molecular profile could be associated with a difference in clinical response to valemetostat. Further understanding of the heterogeneity of PTCL biology and valemetostat response may provide supportive information for treatment-decision making."

Clinical • P2 data • Adult T-Cell Leukemia-Lymphoma • Leukemia • Lymphoma • Peripheral T-cell Lymphoma • ALK • DNMT3A • EZH2 • IDH2 • RHOA • TET2 • TP53

Valemetostat monotherapy in patients with relapsed or refractory follicular lymphoma: primary results of the phase 2 VALYM study from the LYSA group (ICML 2025) - No abstract available

Clinical • Monotherapy • P2 data • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Oncology

DS3201 and Ipilimumab for the Treatment of Metastatic Prostate, Urothelial and Renal Cell Cancers (clinicaltrials.gov) - P1 | N=65 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Recruiting ➔ Active, not recruiting

Enrollment closed • Castration-Resistant Prostate Cancer • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • Urothelial Cancer • PD-L1 • PTEN • RB1 • TP53

EZH1 deficiency promotes ferroptosis resistance by activating NRF2 in sepsis-associated liver injury. (PubMed, Clin Epigenetics) - "In the in vitro, LPS-induced ferroptosis model, EZH1 inhibitor DS3201 exhibited an anti-ferroptosis effect, which was reversed NRF2 inhibitor ML385. These findings indicate that EZH1 deficiency or inhibition with DS3201 alleviates ferroptosis in the liver by activating the NRF2, and it is suggested that targeting EZH1 may be a new therapeutic strategy in SALI."

Journal • Hepatology • Infectious Disease • Inflammation • Liver Failure • Septic Shock • EZH2

Safety and efficacy of the EZH1/2 inhibitor valemetostat tosylate (DS-3201b) in pediatric patients with malignant solid tumors (NCCH1904): A multicenter phase I trial. (ASCO 2025) - P | "Valemetostat was safe in Japanese pediatric patients, demonstrating antitumor activity against INI1-negative tumors, such as AT/RT. These findings support further exploration of valemetosat in combination therapies targeting SMARCB1/INI1-deficient tumors. Additionally, the durable control of tumor observed in NB suggests potential efficacy of valemetostat against this malignancy."

Clinical • P1 data • Acute Lymphocytic Leukemia • Adult T-Cell Leukemia-Lymphoma • Anemia • Brain Cancer • Chordoma • Glioma • Hematological Malignancies • Infectious Disease • Leukemia • Lymphoma • Neuroblastoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Pediatrics • Peripheral T-cell Lymphoma • Pneumonia • Respiratory Diseases • Rhabdoid Tumor • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • T Cell Non-Hodgkin Lymphoma • EZH2 • SMARCB1

Precision diagnostics in prostate cancer treatment (PREDICT): A phase 2 multi-arm biomarker based study (Alliance A032102). (ASCO 2025) - P2 | "Patients with Rb loss (DNA), Rb functional loss signature (RNA), NEPC signature (RNA) will be allocated to treatment with the EZH1/2 inhibitor valemetostat. Patients with at least 2 of 3 tumor suppressor gene DNA alterations (TP53, RB1, PTEN), FANC alteration (DNA), or SLFN11 overexpression (RNA) will be allocated to cabazitaxel plus carboplatin. Patients without any study-defined alterations will be allocated to physician choice treatment with either cabazitaxel, ARPI, or 177Lu-PSMA-617...A Simon two-stage minimax design per arm was used to determine whether the response rate for measurable disease patients was greater than 0.20. This design has a type 1 error equal to 0.05 and has power equal to 0.90 if the probability of response is 0.37."

Biomarker • P2 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • EZH2 • PTEN • RB1 • SLFN11 • TP53

Epigenetic Regulation of Tollip by Cigarette Smoke Exposure Impairs Human Lung Defense: Unlocking the Mystery of Viral Infection (ATS 2025) - "EZH1/EZH2 siRNA or their pharmacological inhibitor valemetostat tosylate in part restored TOLLIP expression and reduced IAV levels in CS-exposed airway epithelial cells and PCLS... The present study reveals, for the first time, that repeated CS exposure reduces TOLLIP expression in part through EZH1/EZH2-H3K27me3-mediated epigenetic mechanisms. Targeting EZH1 and EZH2 may serve as a promising therapeutic strategy to restore TOLLIP expression and host defense against viral infections in COPD patients. Keywords: Cigarette smoke, COPD, IAV, TOLLIP, Histone methylation Acknowledgments: The authors acknowledge BioRender for providing the figure template."

Chronic Obstructive Pulmonary Disease • Immunology • Infectious Disease • Influenza • Pulmonary Disease • Respiratory Diseases • EZH2

Additional Data and Trials-in-Progress Across Daiichi Sankyo’s Oncology Portfolio at ASCO (Daiichi Sankyo Press Release) - "Oral presentations also will highlight initial results from the TUXEDO-3 phase 2 trial (#2005) evaluating patritumab deruxtecan in patients with metastatic breast cancer or advanced NSCLC and active brain metastases and in patients with leptomeningeal carcinomatosis/disease from advanced solid tumors, as well as results from a phase 1 trial (#10003) evaluating valemetostat, a dual EZH1 and EZH2 inhibitor, in pediatric patients with malignant solid tumors...Additional DXd ADC trials-in-progress poster presentations include the REJOICE-PanTumor01 phase 2 trial (TPS3158) evaluating raludotatug deruxtecan (R-DXd) in patients with locally advanced or metastatic gynecologic or genitourinary cancers, IDeate-PanTumor02 phase 1b/2 trial (TPS3157) evaluating ifinatamab deruxtecan in patients with recurrent or metastatic solid tumors and a substudy of KEYMAKER-U06, a phase 1/2 trial (TPS4209) evaluating ifinatamab deruxtecan in combination with pembrolizumab..."

Clinical data • Trial status • Acute Myelogenous Leukemia • Esophageal Squamous Cell Carcinoma • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Non Small Cell Lung Cancer • Triple Negative Breast Cancer

Effect of Mild to Moderate Hepatic Impairment on Valemetostat Pharmacokinetics: An Open-Label, Phase I Study. (PubMed, Clin Pharmacol Drug Dev) - "No treatment-related adverse events were reported. Based on the result of this trial, no dosing adjustments are recommended for patients with mild to moderate HI receiving valemetostat."

Journal • P1 data • PK/PD data • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Hepatology • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • EZH2

Upregulation of YY1/EZH2 and MLH1 as Therapeutic Targets for Adult T-Cell Leukemia/Lymphoma. (PubMed, Cancer Sci) - "Notably, lentiviral YY1 knockdown and the EZH1/2 inhibitor valemetostat downregulated MLH1 in ATLL cell lines and primary ATLL cells. Finally, knockdown of YY1 or MLH1 suppressed the proliferation of ATLL cells. Our findings suggest that YY1/EZH2 overexpression in the ATLL subpopulation defines aggressiveness and that MLH1 downregulation through YY1/EZH2 inhibition may be an effective treatment for aggressive ATLL."

IO biomarker • Journal • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CADM1 • CCR4 • CD48 • EZH2 • MLH1 • MSH2 • YY1

Enhancer of zeste homolog 1/2 dual inhibitor valemetostat outperforms enhancer of zeste homolog 2-selective inhibitors in reactivating latent HIV-1 reservoirs ex vivo. (PubMed, Front Microbiol) - "ACH2 cells were treated with valemetostat for 7-14 days and with suberoylanilide hydroxamic acid (SAHA)...Valemetostat reversed latently HIV-l-infected CD4+ T cells isolated from patients with HIV-1 and induced HIV-1 mRNA expression more potently than GSK126 and E7438...Kyoto Encyclopedia of Genes and Genomes enrichment pathway analysis showed that these 21 hub genes contributed to various signaling pathways, including the JAK-STAT signaling pathway. This study provides novel insights for the development of treatments to reactivate latently HIV-1-infected cells."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease • CD4 • EZH2

Reduced EZH1/2 expression in imipridone-treated cells correlates with synergy following combinations with EZH1/2 or HDAC inhibitors in diffuse glioma and other tumors. (PubMed, Am J Cancer Res) - "Small molecule imipridones including ONC201, ONC206 and ONC212 have anti-cancer activity mediated in part through the integrated stress response, induction of TRAIL and its receptor DR5, and activation of mitochondrial caseinolytic protease ClpP with impaired oxidative phosphorylation...RNA-seq showed ONC201 and EHZ2i tazemetostat-treated cells have similar transcriptional profiles and share overlap of top regulated genes...ONC201 and EZH2i share similar targets and actions on tumors. Synergistic combinations of imipridones plus EZH1/2i or imipridones, EZH2i and HDACi merit further investigation."

Journal • Brain Cancer • Breast Cancer • CNS Tumor • Gastric Cancer • Gene Therapies • Genito-urinary Cancer • Glioma • Lung Cancer • Oncology • Prostate Cancer • Small Cell Lung Cancer • Solid Tumor • EZH2

Enhancing TIL efficacy in NSCLC through epigenetic reprogramming and computational modeling (AACR 2025) - "Thus, we further hypothesize that modern sequencing data and mathematical biology can discover alternative mechanisms of T cell suppression that will suggest novel targets for TIL-combination treatment.To test these hypotheses, we have tested the EZH2 inhibitor valemetostat with anti-PD1 in a murine model of non-small cell lung cancer...Our blending of classic bench science with bio-informatics has the potential to deepen our understanding of TIL therapy and to identify new way to improve therapeutic responses. Funding: T32 CA165990 (DRP), R01 CA237643 (CFB), R01 HL170193 (CFB), P30 CA177558 (Markey Shared Resources)."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IFNG • IL2

Targeting heterogeneity to improve non-small cell lung cancer treatments (AACR 2025) - "Using a syngeneic lung cancer model, we observed that the EZH2 inhibitor valemetostat combined with anti-PD1 immunotherapy drives tumor regression, increased activated T cells and increased antigen expression on the tumor cells...Our previous studies showed that dietary MR improved carboplatin response and slowed tumor progression in an aggressive KRAS/Lkb1 mouse model1...Together these studies show that modulating EZH2 or methionine levels in NSCLC are effective ways to increase treatment efficacy. We also demonstrate use of cutting edge "multi-culture" experiments that can successfully model in vivo environments to better predict cancer response to treatment."

Heterogeneity • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD8 • KRAS • STK11

Drug screens identify new therapeutic targets that synergize with EZH1/2 inhibition in adult T-cell leukemia/lymphoma (AACR 2025) - "In light of these mechanisms, a phase II clinical trial evaluated the efficacy of Valemetostat (VAL), a dual EZH1/2 inhibitor, in ATLL patients...Finally, we tested these nine hits in 6x6 combination matrices to precisely determine the optimal dosing with VAL.Currently, we are expanding our validation across additional ATLL cell lines and optimizing dosage schedules for in vivo testing on our established ATLL models to ensure synergistic effective.This research aims to identify novel targets that will sensitize resistant ATLL to epigenetic therapies. These findings may contribute to developing strategies to address drug resistance and offer additional treatment opportunities for this difficult-to-treat disease."

Clinical • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • EZH2

Targeting mesenchymal cells with epigenetic therapy in lung cancer and lung disease (AACR 2025) - "Several EZH2 inhibitors (tazemetostat and valemetostat) provide a reliable and therapeutically tolerable treatment option for diseased patients...In vivo, we have observed that EZH2 inhibition attenuates the fibrosis that occurs after exposure to bleomycin...Our preliminary results suggest that EZH2 inhibition can alter cells to be more susceptible to anti-PD1, and we are now examining the contributions of mesenchymal cells to these phenotypes. Together our results suggest that targeting EZH2 may improve aspects of both pulmonary fibrosis and lung cancer, and be a way to target these co-occurring diseases to improve patient outcomes."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • TGFB1

Exploring epigenetic control of immunogenicity in small cell lung cancer through multi-omics analyses (AACR 2025) - "In SCLC cell lines treated with EZH1/2 dual inhibitor valemetostat, we examine changes in chromatin accessibility (ATAC-seq), three-dimensional chromatin organization (micro-C profile), and gene expression (RNA-seq).Key Findings: Gene set enrichment analysis of RNA-seq data revealed upregulation of genes involved in antigen processing, presentation, and inflammatory response pathways following EZH1/2 dual inhibition in SCLC cell line H146... Our integrative multi-omics approach reveals a comprehensive model of EZH1/2 contribution to SCLC pathogenesis, highlighting its role in chromatin reorganization and gene expression regulation. Future work will focus on identifying additional therapeutically relevant genes within the EZH1/2-regulated network for potential intervention strategies."

Epigenetic controller • Endocrine Cancer • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • EZH2 • HLA-B • HLA-C

Preclinical assessment of valemetostat, a dual inhibitor of EZH2 and EZH1, combined with trastuzumab deruxtecan and datopotamab deruxtecan for multiple solid tumors (AACR 2025) - P1 | "Results from in vitro and in vivo analyses suggest that valemetostat potentiates the antitumor effect of DXd-ADCs via multiple cellular mechanisms, including increased expression of SLFN11, neoantigen presenting molecules (eg, MHC), ADC targets (eg, HER2), and reduced expression of genes involved in the DDR. A phase 1b, open-label, Master Protocol trial is currently investigating the clinical safety, tolerability, and preliminary efficacy of valemetostat in combination with T-DXd and Dato-DXd in patients with various solid tumors (NCT06244485)."

Preclinical • Breast Cancer • Gastric Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EZH2 • SLFN11

Pharmacokinetics, metabolism, and excretion of [14C]-valemetostat in healthy male participants, and in vitro plasma protein binding. (PubMed, Cancer Chemother Pharmacol) - "Valemetostat was rapidly absorbed into the systemic circulation, mainly excreted via the biliary/fecal route, primarily metabolized by CYP3A enzymes to CALZ-1809a, and highly bound to plasma proteins, with a greater affinity to AAG than HSA in vitro."

Journal • PK/PD data • Preclinical • EZH2

Targeted Treatment for Metastatic Prostate Cancer, The PREDICT Trial (clinicaltrials.gov) - P2 | N=474 | Recruiting | Sponsor: Alliance for Clinical Trials in Oncology | Not yet recruiting ➔ Recruiting

Enrollment open • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Clinical and therapeutic significance of genetic profiling in adult T-cell leukemia/lymphoma. (PubMed, Leuk Res) - "Furthermore, genetic and epigenetic events influencing response to molecularly targeted therapies, such as mogamulizumab and valemetostat, have also been identified. Collectively, these insights underscore the clinical importance of assessing genetic alterations. This review highlights the latest insights into the genetic landscape of ATLL and their clinical implications, which will facilitate the development of future strategies for targeted and personalized therapy."

IO biomarker • Journal • Review • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • PD-L1 • PRKCB

TOLLIP downregulation by cigarette smoke exposure impairs human lung defense against Influenza A virus infection. (PubMed, Am J Pathol) - "EZH1/2 siRNA or their pharmacological inhibitor valemetostat tosylate in part restored TOLLIP and reduced IAV levels in CS-exposed airway epithelial cells and PCLS. Our findings suggest that repeated CS exposure during viral infection reduced TOLLIP levels and increased viral load in part through EZH1/EZH2-H3K27me3-mediated epigenetic mechanisms. Targeting EZH1 and EZH2 may serve as one of the potential therapeutic strategies to restore TOLLIP expression and host defense against viral infections in COPD patients."

Journal • Chronic Obstructive Pulmonary Disease • Immunology • Infectious Disease • Influenza • Pulmonary Disease • Respiratory Diseases • EZH2

Polycomb repressive complex 2 (PRC2) pathway's role in cancer cell plasticity and drug resistance. (PubMed, Funct Integr Genomics) - "Inhibitors like MAK683 and EED226 disrupt EED's ability to maintain PRC2 activity, thereby reducing H3K27me3 levels and reactivating tumor suppressor genes. Valemetostat, a dual inhibitor of both EZH2 and EED, has shown promising results in aggressive cancers like diffuse large B-cell lymphoma and small-cell lung cancer, underlining the therapeutic potential of targeting multiple PRC2 components...Tazemetostat, a selective EZH2 inhibitor, has demonstrated significant clinical efficacy in EZH2-mutant cancers, such as non-Hodgkin lymphomas and epithelioid sarcoma. However, the compensatory function of enhancer of zeste homolog 1 (EZH1) in some cancers requires dual inhibition strategies, as seen with agents like UNC1999 and Tulmimetostat, which target both EZH1 and EZH2. Given PRC2's multifaceted role in cancer biology, its inhibition represents a promising avenue for therapeutic intervention. The continued development of PRC2 inhibitors and exploration of their..."

IO biomarker • Journal • Review • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Genito-urinary Cancer • Hematological Malignancies • Lung Cancer • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Prostate Cancer • Sarcoma • Small Cell Lung Cancer • Soft Tissue Sarcoma • Solid Tumor • EZH2

Valemetostat Plus Trastuzumab Deruxtecan (T-DXd) or Datopotamab Deruxtecan (Dato-DXd) in Patients With Solid Tumors (JSMO 2025) - No abstract available

Clinical • Oncology • Solid Tumor