E7820 / Eisai - LARVOL DELTA

E7820, an Anti-Cancer Sulfonamide, in Combination with Venetoclax in Patients with Splicing Factor Mutant Myeloid Malignancies: A Phase II Clinical Trial (ASH 2023) - P2 | "Secondary endpoints include overall and event-free survival. Correlative biomarker and pharmacodynamic parameters will be assessed as exploratory endpoints including effects on RBM39 protein levels, changes in global and key target splicing events, and evaluation of DCAF15 mRNA levels and response to therapy."

Clinical • Combination therapy • IO biomarker • P2 data • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • BCL2 • MCL1 • RBM39 • SF3B1 • SRSF2 • U2AF1 • ZRSR2

Targeting Poly(U) Binding Splicing Factor 60 (PUF60): A Small-Molecule Inhibitor Shows Anti-Leukemic Activity and Impacts Cell Cycle in Leukemia Models (ASH 2024) - "In comparison, E7820, an RBM39 degrader, increased G2/M phase in both NKM-1 and K562...Upregulation of cholesterol biosynthesis may be a feedback loop to counteract the inhibition of PUF60 by SF2-69. Further optimization of SF2-69 will allow us to develop more effective and selective chemical probes for studying the role of PUF60 overexpression in leukemia and the potential use of PUF60 inhibitors in MDS and AML cells carrying splicing factor mutations."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Solid Tumor • CDC25C • GNRP • PLK1 • RASGRF1 • RBM39 • SF3B1 • SRSF2 • U2AF1

The integrin α2-osteoclast axis: a key driver of bone destruction and therapeutic target in osteosarcoma. (PubMed, J Transl Med) - "This study uncovered that ITGA2 drives osteosarcoma progression and aggravates osteolysis via the "ITGA2-osteoclast axis", with high expression predicting poor outcomes. Mechanistically, ITGA2 promoted tumor invasion and bone metabolism imbalance by regulating osteoclastogenic signaling, while its targeted inhibition synergistically suppresses tumor growth and restores bone homeostasis, highlighting ITGA2 as a pivotal therapeutic target for osteosarcoma."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • ITGA2 • MMP9

Targeting Integrin α2 to Overcome Imatinib Resistance in Chronic Myeloid Leukemia Cells. (PubMed, Biomolecules) - "Our findings showed that ITGA2 is overexpressed in K562R cells and ITGA2 inhibitor E7820 (2.5 µM) treatment significantly decreased cell viability and induced apoptosis in both sensitive and resistant cells. Flow cytometry confirmed ITGA2 inhibition at the protein level, and rhodamine assays revealed reduced MDR1 activity in treated cells. These results demonstrate that targeting ITGA2 may overcome imatinib resistance and offer a novel therapeutic strategy for CML."

IO biomarker • Journal • Chronic Myeloid Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • ABCB1 • ABL1 • BAX • BCL2 • BCR • ITGA2

ITGA2 Mediates the Resistance of Hepatocellular Carcinoma to Lenvatinib by Activating the AKT/FOXO3A Signaling Pathway. (PubMed, Cancers (Basel)) - "The global incidence of primary liver cancer ranks sixth among malignant tumors, while its mortality rate ranks third and is the second leading cause of cancer-related deaths in China [...]."

Journal • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • ITGA2

Advancing treatment in high-grade serous ovarian cancer through targeting of RNA splicing (EACR 2025) - "Introduction: The RNA binding protein RBM39 regulates alternative splicing and is targeted by the small aryl sulphonamides E7070 (indisulam) and E7820. An increase in antigen-presenting cells (APCs) such as cDCs may reflect a rise in neoantigens available for identification, aligning with our hypothesis. Overall, these results could suggest a complex immunomodulatory effect following RBM39 depletion, which could potentially benefit patients receiving immunotherapies."

High Grade Serous Ovarian Cancer • Neuroblastoma • Oncology • Ovarian Cancer • Solid Tumor • Targeted Protein Degradation • RBM39

A Study of E7820 in People With Bone Marrow (Myeloid) Cancers (clinicaltrials.gov) - P2 | N=12 | Completed | Sponsor: Memorial Sloan Kettering Cancer Center | Active, not recruiting ➔ Completed

Trial completion • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • FLT3 • IDH1 • SF3B1 • SRSF2 • U2AF1 • ZRSR2

Targeting RBM39 suppresses tumor growth and sensitizes osteosarcoma cells to cisplatin. (PubMed, Oncogene) - "Importantly, our results reveal that the pharmacological depletion of RBM39 by using the anti-cancer aryl sulfonamide (E7820), a drug known for its oral bioavailability and safe administration, effectively represses osteosarcoma growth and sensitizes osteosarcoma cells to cisplatin treatment both in vitro and in vivo. Our findings unveil the crucial role of RBM39 in modulating tumor growth and cisplatin sensitivity in osteosarcoma cells, suggesting that the combination of aryl sulfonamides with cisplatin may benefit patients with osteosarcoma."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • DKK1 • RBM39

Recent advances in anticancer mechanisms of molecular glue degraders: focus on RBM39-dgrading synthetic sulfonamide such as indisulam, E7820, tasisulam, and chloroquinoxaline sulfonamide. (PubMed, Genes Genomics) - "Recent research on tasisulam reveals its potential in cancer therapy by targeting RBM39 degradation through DCAF15-mediated pathways. Understanding these mechanisms could lead to new treatments that affect alternative splicing and improve cancer therapies Overall, although these drugs exhibit promising mechanisms of action, further research is required to optimize their clinical efficacy and safety."

Journal • Review • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Hematological Malignancies • Metabolic Disorders • Neuroblastoma • Oncology • Solid Tumor • Targeted Protein Degradation • RBM39

Investigator-initiated clinical studies to be launched following confirmation of tumor shrinkage induced by the targeted protein degrader E7820 using J-PDX (Japanese cancer patient-derived tissue transplantation models) (Eisai Press Release) - "Tumor-agnostic efficacy evaluation of Eisai's targeted protein degrader E7820 was performed using patient-derived xenograft (PDX) models created by transplanting tumor tissue derived from patients into immunodeficient mice (pancreatic cancer, bile duct cancer, gastric cancer, and uterine cancer), which observed tumor shrinkage in 38.1% for overall, 58.3% for bile duct cancer, and 55.6% for uterine cancer....Based on the cancer types and predictive biomarkers associated with E7820 efficacy revealed by this study, an investigator-initiated clinical study will be launched at the National Cancer Center Hospital and the National Cancer Center Hospital East for the purposes of safety evaluation including the tolerability in Japanese patients, and exploratory efficacy evaluation."

New trial • Preclinical • Cholangiocarcinoma • Gastric Cancer • Pancreatic Cancer • Uterine Cancer

A Study of E7820 in People With Bone Marrow (Myeloid) Cancers (clinicaltrials.gov) - P2 | N=12 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Aug 2024 ➔ Aug 2025 | Trial primary completion date: Aug 2024 ➔ Aug 2025

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • FLT3 • IDH1 • SF3B1 • SRSF2 • U2AF1 • ZRSR2

A molecular glue RBM39-degrader induces synthetic lethality in cancer cells with homologous recombination repair deficiency. (PubMed, NPJ Precis Oncol) - "E7820 and Indisulam (E7070) are sulfonamide molecular glues that modulate RNA splicing by degrading the splicing factor RBM39 via ternary complex formation with the E3 ligase adaptor DCAF15. Furthermore, E7820, in combination with olaparib, exerted a synergistic effect, and E7820 was even effective in an olaparib-resistant cell line. In conclusion, HRD is a promising predictive biomarker of E7820 efficacy and has a high potential to improve the prognosis of patients with HRD-positive cancers."

Journal • Synthetic lethality • Oncology • Solid Tumor • Targeted Protein Degradation • BAP1 • BRCA1 • BRCA2 • HRD • RBM39

Native mass spectrometry of complexes formed by molecular glues reveals stoichiometric rearrangement of E3 ligases. (PubMed, Analyst) - "We have shown that nMS can unambiguously identify complexes formed between the CRBN : DDB1 E3 ligase and the POI GSPT1 upon the addition of lenalidomide, pomalidomide or thalidomide. Ternary complex formation was also identified involving the DCAF15 : DDA1 : DDB1 E3 ligase in the presence of MG (E7820 or indisulam) and POI RBM39. Moreover, we uncovered that the DCAF15 : DDA1 : DDB1 E3 ligase self-associates into dimers and trimers when analysed alone at low salt concentrations (100 mM ammonium acetate) which dissociate into single copies of the complex at higher salt concentrations (500 mM ammonium acetate), or upon the addition of MG and POI, forming a 1 : 1 : 1 ternary complex. This work demonstrates the strength of nMS in TPD research, reveals novel binding mechanisms of the DCAF15 E3 ligase, and its self-association into dimers and trimers at reduced salt concentration during structural analysis."

Journal • Targeted Protein Degradation • CRBN • DDB1 • GSPT1 • RBM39

E7820, an anti-cancer sulfonamide, degrades RBM39 in patients with splicing factor mutant myeloid malignancies: a phase II clinical trial. (PubMed, Leukemia) - No abstract available

Journal • P2 data • Hematological Malignancies • Oncology • RBM39

FOLFIRI Alone Versus FOLFIRI Plus Bevacizumab Versus FOLFIRI Plus E7820 as Second-Line Therapy in Patients With Locally Advanced or Metastatic Colorectal Cancer (clinicaltrials.gov) - P1/2 | N=5 | Terminated | Sponsor: Eisai Inc. | Completed ➔ Terminated; The study was terminated early as the combination of E7820 and FOLFIRI was deemed to be not tolerable, hence no efficacy analysis was conducted.

Metastases • Trial termination • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

A Study of E7820 in People With Bone Marrow (Myeloid) Cancers (clinicaltrials.gov) - P2 | N=12 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Aug 2023 ➔ Aug 2024 | Trial primary completion date: Aug 2023 ➔ Aug 2024

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • FLT3 • IDH1 • SF3B1 • SRSF2 • U2AF1 • ZRSR2

Oxalamide containing compounds degrade cellular RBM39 and CENP-I (ACS-Fall 2023) - "A series of sulphonamides, including Indisulam and E7820, act as molecular glues between RBM39 and DCAF15, leading to selective degradation of RBM39. CENP-I is a member of centromere proteins, which is critically important for accurate chromosome segregation and mitosis. Our data suggest that molecular glue CB039-promoted degradation of CENP-I plays an important role in its cell cycle arrest function."

Acute Myelogenous Leukemia • Oncology • Targeted Protein Degradation • CENPI

A Phase II trial evaluating E7820 in patients with AML with splicing factor mutations (YouTube) - "In this video, Eytan Stein, MD...discusses a Phase II study evaluating the safety and efficacy of E7820 in patients with acute myeloid leukemia (AML) with splicing factor mutations (NCT05024994). Although the clinical efficacy of this agent was limited, Dr Stein highlights the promising biological activity observed and the possibility of exploring combination approaches to augment the activity of E7820. This interview took place at the 64th ASH Annual Meeting and Exposition congress held in New Orleans, LA."

Interview • Video

Attenuation of Graft-Versus-Host-Disease Via Genetic or Pharmacologic Inhibition of the RNA Splicing Factor RBM39 (ASH 2022) - P2 | "Our results identify cell-type specific roles for RBM39 in hematopoiesis and immune cells and suggest a therapeutic approach for GVHD via direct modulation of RNA splicing. Of note, as the RBM39 degrader E7820 is currently in phase II clinical trials for relapsed myeloid neoplasms, our previous studies and this data identify a treatment for myeloid neoplasms in the post-transplant setting, where RBM39 degraders mediate both direct and immune-mediated anti-tumor effects while also attenuating GVHD via modulation of RNA splicing in T cells."

Bone Marrow Transplantation • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immune Modulation • Immunology • Inflammation • Lymphoma • Oncology • Transplantation • CD8 • ITGB1

A Phase II Clinical Trial of E7820 for Patients with Relapsed/Refractory Myeloid Malignancies with Mutations in Splicing Factor Genes (ASH 2022) - P2 | "In this phase II trial of E7820 in AML and MDS patients with splicing factor mutations, we found acceptable safety of E7820 monotherapy at the previously established maximum tolerated dose. Although the efficacy of E7820 was limited, evidence of target engagement combined with the tolerability of RBM39 degradation serves as a proof of concept that splicing factor mutant disease can be targeted in humans. Combination therapies of E7820 with standard of care agents and the use of newer generation RBM39 degraders are in development."

Clinical • P2 data • Acute Myelogenous Leukemia • Anemia • Bone Marrow Transplantation • Cardiovascular • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • Pain • Respiratory Diseases • Targeted Protein Degradation • Thrombocytopenia • Transplantation • SF3B1 • SRSF2 • U2AF1 • ZRSR2

A Study of E7820 in People With Bone Marrow (Myeloid) Cancers (clinicaltrials.gov) - P2 | N=12 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Recruiting ➔ Active, not recruiting | N=38 ➔ 12

Enrollment change • Enrollment closed • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • FLT3 • IDH1 • SF3B1 • SRSF2 • U2AF1 • ZRSR2

Irinotecan Plus E7820 Versus FOLFIRI in Second-Line Therapy in Patients With Locally Advanced or Metastatic Colon or Rectal Cancer (clinicaltrials.gov) - P1/2 | N=82 | Terminated | Sponsor: Eisai Inc. | Completed ➔ Terminated; The study was terminated by the Sponsor due to E7820 plus irinotecan being potentially inferior to FOLFIRI

Trial termination • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Rectal Cancer • Solid Tumor

Role of integrin α2 in methotrexate-induced epithelial-mesenchymal transition in alveolar epithelial A549 cells. (PubMed, Toxicol Res) - "Methotrexate (MTX) is widely used to treat various diseases. Finally, E7820, an ITGA2 inhibitor, suppressed MTX-induced EMT-related phenotypic changes, such as morphology and mRNA and protein expression of α-smooth muscle actin, a representative EMT marker. These findings suggest that ITGA2 may play a key role in MTX-induced EMT in alveolar epithelial cells."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

A Study of E7820 in People With Bone Marrow (Myeloid) Cancers (clinicaltrials.gov) - P2; N=38; Recruiting; Sponsor: Memorial Sloan Kettering Cancer Center

Clinical • New P2 trial • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • FLT3 • IDH1 • SF3B1 • SRSF2 • U2AF1

Integrin alpha 2 is associated with tumor progression and postoperative recurrence in non-small cell lung cancer. (PubMed, Jpn J Clin Oncol) - "Integrin alpha 2 may play a significant role in lung cancer adhesion and migration, and may lead to a higher risk of recurrence."

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