IPN60210 / Ipsen - LARVOL DELTA

The Impact of SETD2 Loss on Radiosensitivity and Survival in High-Grade Gliomas (ASTRO 2026) - "Functional validation was conducted in U87MG glioblastoma cell lines and patient-derived tumorspheres using shRNA-mediated knockdown and pharmacologic inhibition with EZM0414... SETD2 deficiency is associated with improved survival and enhanced radiosensitivity in high-grade gliomas, particularly in IDH-wildtype glioblastoma. Contrary to its traditional tumor suppressor role in other malignancies, SETD2 loss in HGG appears to define a biologically distinct and radiation-responsive subgroup. These findings suggest that SETD2 loss may serve as a predictive biomarker of radiation response and represent a potential therapeutic vulnerability for radiosensitization strategies."

Brain Cancer • Glioblastoma • Glioma • High Grade Glioma • Oncology • Solid Tumor • SETD2

Blocking SETD2 Enhances the Therapeutic Efficiency of Menin Inhibitor in MLL-Fusion Leukemia. (PubMed, Cancer Sci) - "Next, we show that inhibitors of SETD2 (EZM0414) and menin (Revumenib) have synergistic efficacy against MLL-fusion and NPM1-mut leukemia and make prominent induction of cell cycle arrest, differentiation, and apoptosis. Finally, we clarify that the combined-drug treatment delays MLL-fusion leukemia progression in vivo. Taken together, these findings establish the simultaneously blocking of transcription elongation and initiation by epigenetic inhibitors as a promising therapeutic strategy for these aggressive leukemias."

Journal • Hematological Malignancies • Leukemia • Oncology • NPM1 • SETD2

The histone methyltransferase SETD2 regulates the PI3K/AKT signaling pathway to affect the in vitro fertilization of yak oocytes. (PubMed, Anim Reprod Sci) - "Pharmacological inhibition of SETD2 using EZM0414 significantly increased ROS levels and reduced GSH levels in yak oocytes...Collectively, these findings demonstrate that SETD2 is essential for maintaining PI3K/AKT signaling, preventing apoptosis, and preserving fertilization competence in yak oocytes. This work provides new mechanistic insight into the epigenetic regulation of fertilization and offers a potential strategy for improving assisted reproductive efficiency in livestock."

IO biomarker • Journal • Preclinical • Gynecology • AKT2 • BCL2 • CASP3 • CREB5 • MCL1 • PIK3C2B • PIK3R1 • SETD2

Targeting SETD2 in Combination with Radiotherapy in Rectal Cancer (AACR-NCI-EORTC 2025) - "Both genetic and pharmacologic abrogation of SETD2 resulted in a marked enhancement of radiation-induced DNA damage compared to radiation treatment alone. A significant increase in γH2AX foci was observed in cells treated with EZM0414 in combination with ionizing radiation, indicating an elevated accumulation of double-strand breaks. Furthermore, clonogenic assays revealed that inhibition of SETD2 substantially impaired cell survival following radiation exposure."

Combination therapy • Colorectal Cancer • Oncology • Rectal Cancer • Solid Tumor • KRAS • SETD2

SETD2 and EZH2: Two epigenetic drivers of prostate cancer. (PubMed, J Cancer) - "Although inhibitors targeting SETD2 (e.g., EZM0414) and EZH2 (e.g., tazemetostat) demonstrate antitumor activity in preclinical models, their clinical efficacy remains constrained by drug resistance and tumor microenvironment heterogeneity. Emerging evidence suggests that combining epigenetic therapies with immunotherapy may enhance therapeutic outcomes. This review comprehensively systematically examines the molecular mechanisms underlying the SETD2/EZH2 axis in prostate cancer, providing a theoretical foundation for developing precision therapies based on SETD2- or EZH2-mediated epigenetic modifications."

IO biomarker • Journal • Review • Castration-Resistant Prostate Cancer • Gene Therapies • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • EZH2 • SETD2

Chromatin Rewiring by SETD2 Drives Lipotoxic Injury in Cardiometabolic HFpEF. (PubMed, Circ Res) - "Finally, SETD2 was upregulated in left ventricle specimens from patients with cHFpEF while EZM0414 attenuated cardiomyocyte stiffness. Targeting SETD2 might prevent lipotoxic injury in cHFpEF."

Journal • Cardiovascular • Congestive Heart Failure • Genetic Disorders • Heart Failure • Metabolic Disorders • Respiratory Diseases • SETD2

SETD2 regulates oocytes in vitro maturation through histone methylation and maternal mRNA degradation in yak. (PubMed, Theriogenology) - "To determine the role of SETD2 in oocytes, we employed the SETD2 inhibitor EZM0414 during oocyte maturation...Furthermore, suppression of SETD2 markedly reduced the expression of oocyte secretion-related proteins (TSG6 and GDF9) and cumulus expansion-related protein (PTGS2), demonstrating that oocyte secretion and cumulus expansion were positively correlated with SETD2. Overall, our findings establish SETD2 as an essential regulator of yak oocyte maturation via histone methylation and maternal mRNAs degradation."

Journal • Preclinical • PACERR • PTGS2 • SETD2

C6TSEDRVAJZ, a combination of small-molecule compounds, induces differentiation of human placental fibroblasts into epithelioid cells in vitro (PubMed, Nan Fang Yi Ke Da Xue Xue Bao) - "The small-molecule compound combination C6TSEDRVAJZ is capable of inducing HPFs into ciEP-Ls under hypoxic conditions with a high induction efficiency."

Journal • Preclinical • CD34 • CDH1 • COL1A1 • GLI3 • KRT18 • KRT18 • KRT19 • PAX8 • S100A4 • SMAD3 • VIM • WT1

SET-101: A Study of the Safety, Tolerability and Effectiveness of EZM0414 Investigative Product in Participants With Relapsed/Refractory Multiple Myeloma and Relapsed/Refractory Diffuse Large B Cell Lymphoma (clinicaltrials.gov) - P1 | N=13 | Terminated | Sponsor: Epizyme, Inc. | N=96 ➔ 13 | Trial completion date: Jun 2025 ➔ Apr 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Dec 2024 ➔ Apr 2024; Strategic business decision

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

SET-101: A Study of the Safety, Tolerability and Effectiveness of EZM0414 Investigative Product in Participants With Relapsed/Refractory Multiple Myeloma and Relapsed/Refractory Diffuse Large B Cell Lymphoma (clinicaltrials.gov) - P1 | N=96 | Active, not recruiting | Sponsor: Epizyme, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

Targeting Tri-Methyl-Histone H3 (Lys27) in Rectal Cancer: A Novel Strategy to Enhance Radiosensitivity and Predict Response to Neoadjuvant Therapy (ASTRO 2023) - "In vitro treatment with a novel SETD2 inhibitor, EZM0414, led to a 2-fold increase in DNA damage following IR (5 Gy) as measured by ?H2aX foci staining... Our study uncovers a new biomarker, Tri-Methyl-Histone H3 (Lys27), that could be used to predict response to neoadjuvant chemoradiation in rectal cancer patients. Our preclinical data indicates that targeting SETD2 to reduce Tri-Methyl-Histone H3 (Lys27) mediated DNA repair could improve the efficacy of radiation therapy for rectal cancer patients."

Clinical • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Rectal Cancer • Solid Tumor • SETD2

Targeting Tri-Methyl-Histone H3 (Lys27) in Rectal Cancer: A Novel Strategy to Enhance Radiosensitivity and Predict Response to Neoadjuvant Therapy. (PubMed, Int J Radiat Oncol Biol Phys) - "Our study uncovers a new biomarker, Tri-Methyl-Histone H3 (Lys27), that could be used to predict response to neoadjuvant chemoradiation in rectal cancer patients. Our preclinical data indicates that targeting SETD2 to reduce Tri-Methyl-Histone H3 (Lys27) mediated DNA repair could improve the efficacy of radiation therapy for rectal cancer patients."

Journal • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Rectal Cancer • Solid Tumor • SETD2

A Phase 1/1b Open-Label, Multicenter, Two-Part Study of SETD2 Inhibitor EZM0414 in Patients with Relapsed/Refractory Multiple Myeloma or Diffuse Large B-Cell Lymphoma (ASH 2021) - "Study Design and Methods : This first-in-human, 2-part, multicenter, open-label study will enroll patients aged ≥18 years with R/R MM who have received prior treatment with immune modulators, proteasome inhibitors, and anti-CD38 therapy, or who are intolerant to established therapies known to provide clinical benefit in MM, or with R/R DLBCL who have received at least 2 prior lines of therapy, including treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH); rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-hyper CVAD); or other standard of care therapies. Exploratory endpoints include a pharmacokinetic/pharmacodynamic profile analysis and the determination of mechanism of action biomarkers, such as histones and histone methylation. The study design will include a futility assessment in the phase 1b part of the..."

Clinical • IO biomarker • P1 data • Bone Marrow Transplantation • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Immune Modulation • Inflammation • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Transplantation • FGFR3 • IGH • SETD2

Ipsen Completes Acquisition of Epizyme Expanding Its Portfolio in Oncology (Businesswire) - "Ipsen...announced the closing of the definitive merger agreement under which Ipsen has acquired Epizyme, Inc. (Epizyme). Pursuant to the transaction, Ipsen acquires all outstanding shares of Epizyme for $1.45 per share plus a contingent value right (CVR) of $1.00 per share....As part of the transaction, Ipsen acquires Epizyme’s lead medicine, Tazverik® (tazemetostat), a first-in-class, chemotherapy-free EZH2a inhibitor, which was granted Accelerated Approval by the U.S. Food and Drug Administration (FDA) in 2020....Ipsen also acquires Epizyme’s first-in-class, oral SETD2 inhibitor development candidate, EZM0414..."

M&A • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

Conformational-Design-Driven Discovery of EZM0414: A Selective, Potent SETD2 Inhibitor for Clinical Studies. (PubMed, ACS Med Chem Lett) - "Herein we describe the conformational-design-driven evolution of the advanced chemistry lead, which resulted in compounds appropriate for clinical evaluation. Further optimization of this chemical series led to the discovery of EZM0414, which is a potent, selective, and orally bioavailable inhibitor of SETD2 with good pharmacokinetic properties and robust pharmacodynamic activity in a mouse xenograft model."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • SETD2

Ipsen to acquire Epizyme, expanding its portfolio in oncology (Businesswire) - "Financial highlights: The acquisition of Epizyme will immediately provide incremental sales and will leverage the U.S. commercial infrastructure....Transaction details: Under the terms of the agreement and plan of merger, Ipsen, through a subsidiary, will initiate a tender offer to acquire all outstanding shares of Epizyme at a price of $1.45 per share in cash at the closing of the transaction, for an initial estimated aggregate consideration of $247 million plus one contingent value right (CVR) per share."

M&A • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

Ipsen to acquire Epizyme, expanding its portfolio in oncology (Businesswire) - "Ipsen...and Epizyme...announced that they have entered into a definitive merger agreement under which Ipsen will acquire Epizyme. The primary focus of the acquisition is on the lead medicine, Tazverik® (tazemetostat)...It is currently indicated for adults with relapsed or refractory follicular lymphoma (FL)....Initial results from the Phase III randomized portion of this study are planned to read out in 2026. As part of the transaction, Ipsen will also acquire Epizyme’s first-in-class, oral SETD2 inhibitor development candidate, EZM0414,..."

M&A • P3 data • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

SET-101: A Study in Subjects With Relapsed/Refractory Multiple Myeloma and Relapsed/Refractory Diffuse Large B-Cell Lymphoma (clinicaltrials.gov) - P1 | N=96 | Recruiting | Sponsor: Epizyme, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

Discovery and First Structural Disclosure of EZM0414: A potent and selective small molecule inhibitor of the histone methyltransferase SETD2 (AACR 2022) - "Because H3K36me2 is the substrate of SETD2, we hypothesized that inhibiting SETD2 could target the underlying oncogenic mechanism driven by the dysregulated H3K36 methylation from MMSET overexpression in t(4;14) MM patients, and would establish proof of concept in this and other B cell malignancies (e.g. DLBCL) that may demonstrate dysregulated H3K36me3 or a dependency on SETD2. In this presentation, we will describe the discovery and structure of our clinical candidate EZM0414, a first-in-class, potent, selective, orally bioavailable small molecule inhibitor of the enzymatic activity of SETD2; robust anti-tumor effects of SETD2 inhibition with EZM0414 in MM (including t(4;14) MM) and DLBCL preclinical studies; and the outline of the ongoing first-in-human Ph1/1b open-label, multicenter study of EZM0414 in patients with relapsed/refractory MM or DLBCL."

Epigenetic controller • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • NSD2 • SETD2

"MM/DLBCL CDX models and response to EZM0414 in vivo, treatments were well tolerated, minimal effects on body weight #AACR22" (,@gerlach_d)

Preclinical • Diffuse Large B Cell Lymphoma • Oncology

"EZM0414, Histone Methyltransferase SETD2 inhibitor. >10k fold selectivity over other HMT. Impairs growth in MM, DLBCL lines. Decreases H3K36me3 levels. Reduces tumor growth in xeno-models. #AACR22" (,@itsvenu_)

Epigenetic controller • Diffuse Large B Cell Lymphoma • Oncology • SETD2

Epizyme Reports Fourth Quarter and Full Year 2021 Financial Results and Provides Business Update (Businesswire) - "During the fourth quarter of 2021, Epizyme initiated the SET-101 study, a first-in-human Phase 1/1b study of EZM0414, Epizyme’s novel, first-in-class, oral SETD2 inhibitor, in adult patients with R/R multiple myeloma (MM) and R/R DLBCL. The Company expects to enroll between 30-36 patients in the Phase 1 dose escalation portion of the study....Epizyme plans to provide updates as the study reaches key enrollment milestones, along with preliminary data from SET-101 in 2022."

P1 data • Trial initiation date • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

Epizyme Announces Pricing of Public Offering of Common Stock (Businesswire) - "Epizyme, Inc...today announced the pricing of an underwritten public offering of 56,666,667 shares of its common stock at a price to the public of $1.50 per share....Epizyme anticipates using the net proceeds...to fund global development and commercialization costs of tazemetostat outside of Japan, including the costs of conducting the Company’s ongoing and planned clinical trials of tazemetostat...to fund the Company’s Phase 1/1b trial of its SETD2 inhibitor, EZM0414 and the discovery and identification of additional product candidates to expand the Company’s pipeline of novel epigenetic therapies..."

Financing • Chordoma • Colorectal Cancer • Diffuse Large B Cell Lymphoma • Endometrial Cancer • Follicular Lymphoma • Giant Cell Tumor of Bone • Gynecologic Cancers • Hematological Malignancies • Lymphoma • Malignant Pleural Mesothelioma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Melanoma • Mesothelioma • Multiple Myeloma • Neuroendocrine Tumor • Neurofibrosarcoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Ovarian Cancer • Pancreatic Adenocarcinoma • Prostate Cancer • Rhabdoid Tumor • Sarcoma • Skin Cancer • Soft Tissue Sarcoma • Squamous Cell Carcinoma of Head and Neck • Synovial Sarcoma • Uterine Cancer

Epizyme multiple myeloma candidate granted FDA Orphan Drug Designation (SeekingAlpha) - "The FDA has granted Orphan Drug Designation to Epizyme (EPZM +1.4%) for a small molecule inhibitor of the enzymatic activity of Su(var) for the treatment of multiple myeloma....The full generic name of the candidate is small molecule inhibitor of the enzymatic activity of Su(var), Enhancer-of-zeste, Trithorax domain containing 2 (SETD2)"

Orphan drug • Hematological Malignancies • Multiple Myeloma • Oncology

Pharmacologic Inhibition of the Histone Methyltransferase SETD2 with EZM0414 As a Novel Therapeutic Strategy in Relapsed or Refractory Multiple Myeloma and Diffuse Large B-Cell Lymphoma (ASH 2021) - "Targeting SETD2 with a small molecule inhibitor results in significantly reduced growth of t(4;14) MM, as well as non-t(4;14) MM and DLBCL cell lines, in both in vitro and in vivo preclinical studies. In addition, in vitro synergy was observed with EZM0414 and certain SOC agents commonly used in MM and DLBCL, supporting the combination of SETD2 inhibition with current MM and DLBCL therapies. This work provides the rationale for targeting SETD2 in B cell malignancies such as MM, especially t(4;14) MM, as well as DLBCL, and forms the basis for conducting Phase 1/1b clinical studies to evaluate the safety and activity of EZM0414 in patients with R/R MM and DLBCL."

Epigenetic controller • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • SETD2