Valemetostat Tosilate

Researchers have revealed the mechanism of the drug valemetostat shown to be effective in treating certain types of cancer by targeting a protein modification (histone methylation) silencing the expression of tumor suppressor genes and restoring their function. The researchers also demonstrated in clinical trials the efficacy of the drug in treating blood cancers by reducing tumor growth. The findings could lead to sustainable, longer-term treatments for the disease, as well as therapies for other types of cancer with similar underlying causes. Researchers have revealed the mechanism of a drug shown to be effective in treating certain types of cancer, which targets a protein modification silencing the expression of multiple tumor suppressor genes. They also demonstrated in clinical trials the efficacy of the drug in reducing tumor growth in blood cancer. The findings could lead to longer-term treatments for the disease and therapies for other types of cancer with similar underlying causes. A team of researchers from the University of Tokyo and their collaborators focused on therapies targeting H3K27me3, a modification on a DNA-packaging histone protein, which plays a large role in regulating gene expression. The modification occurs when methyl groups, each consisting of three hydrogen atoms bonded to a single carbon atom (CH3), are added to the protein in a process called methylation. The modification, also referred to as being epigenetic (a heritable change in gene function that occurs without altering the sequence of the DNA), has been tied to the repression, or reducing the expression, of tumor suppressor genes, with the accumulation of the methylated histones around the genes. Because of its effects on repressing genes, H3K27me3 is being targeted by therapies to correct some of the disordered gene expression observed in cancer cells. While this therapy is effective for some cancers, the mechanism of H3K27me3 therapies on tumor cells was not yet known. The research team conducted a study characterizing the effects of H3K27me3 on cancer cells by treating patients who have adult T-cell leukemia/lymphoma (ATL), a rare type of blood cancer, with valemetostat. The drug prevents the methylation of histone H3 by inhibiting the histone-modifying enzymes EZH1 and EZH2, which increase H3K27 and have been found to be abnormal in cancers. Treating patients with valemetostat decreased H3K27me3 and the condensation of DNA, opening up several tumor-suppressor genes for expression in cancer cells. "Before H3K27me3-inhibitor therapies were developed, no effective treatments for blood cancers with accumulated genetic abnormalities existed, and new treatments needed to be developed," said Makoto Yamagishi, first author of the paper and associate professor at the Graduate School of Frontier Sciences at the University of Tokyo. "Once we established that these therapies were effective against some types of cancer, understanding the therapeutic mechanisms of these drugs became extremely important." The team established that valemetostat treatment decreased tumor size and produced a durable clinical response to therapy in the clinical trial of patients with ATL, an aggressive cancer with many genetic mutations. The patients were able to safely remain on valemetostat treatment for more than two years. "In blood cancers with poor prognosis due to genetic abnormalities, epigenetic mechanisms mediated by methylated histones can be targeted therapeutically," said Professor Kaoru Uchimaru, also of the Graduate School of Frontier Sciences and last author of the study. "Valemetostat can restore expression of many tumor suppressor genes and sustainably inhibit tumor cell growth." Characterizing the mechanism of valemetostat therapy in patients with ATL is a huge step forward for epigenetic cancer treatments that target the expression of genes in cancer cells. The team recognizes, however, that many challenges remain. Cancers can become resistant to H3K27me3-inhibitor therapies if patients are treated for long periods of time, allowing cancer to recur. In some cases, cancer cells had acquired new mutations that interfered with valemetostat's effectiveness over time and reduced long-term patient response to the drug. "EZH1/2 inhibitors are effective treatments, but a mechanism of resistance to long-term treatment has also been identified," said Yamagishi. "Based on this mechanism of resistance, it is important to continue to improve treatment methods and develop combination therapies that provide longer-term therapeutic effects."

Annual R&D Day to provide overview of data and updated strategy across Daiichi Sankyo R&D pipeline BASKING RIDGE, N.J.--(BUSINESS WIRE)-- Daiichi Sankyo (TSE: 4568) will present new clinical research across its oncology portfolio in multiple types of solid and blood cancers at the 2023 ESMO Asia Congress (#ESMOAsia23), San Antonio Breast Cancer Symposium (#SABCS23) and American Society of Hematology (#ASH23) Annual Meeting prior to its annual R&D Day. Presentation highlights include the first presentation of results from three trials from Daiichi Sankyo’s DXd ADC and hematology portfolio, which include the DESTINY-Gastric06 phase 2 trial of ENHERTU® (trastuzumab deruxtecan) in Chinese patients with previously treated HER2 positive locally advanced/metastatic gastric cancer or gastroesophageal junction adenocarcinoma at ESMO Asia, the DESTINY-Breast08 phase 1b trial of ENHERTU in combination with anastrozole or fulvestrant in patients with HER2 low metastatic breast cancer at SABCS and the VALENTINE-PTCL01 phase 2 trial of valemetostat in patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) at ASH. “Our goal is to push the boundaries of science to change the way cancer is treated,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “These data reinforce the breadth and depth of our oncology pipeline and the important progress we are making in developing innovative medicines and exploring combination strategies for patients across a wide range of cancers, including breast, lung, gastric, acute myeloid leukemia and peripheral T-cell lymphoma.” Subgroup analyses of the TROPION-Lung05 phase 2 trial of datopotamab deruxtecan (Dato-DXd) in Asian patients with non-small cell lung cancer (NSCLC) with actionable genomic alterations and the DESTINY-Lung02 phase 2 trial of ENHERTU in Asian patients with HER2 mutant NSCLC will be presented at ESMO Asia. Additional subgroup analyses of the QuANTUM-First phase 3 trial in patients with newly diagnosed FLT3-ITD positive acute myeloid leukemia (AML), which formed the basis of recent approvals of VANFLYTA® (quizartinib) in the EU, Japan and U.S. will be presented at ASH. Daiichi Sankyo will hold its annual R&D Day for investors, analysts and media on Monday, December 11 at 5:30 - 7:00 pm EST/Tuesday, December 12 at 7:30 - 9:00 am JST. Company executives will provide highlights of Daiichi Sankyo’s research data presented at SABCS and ASH, as well as updates on the company’s R&D strategy. ESMO Asia Data Encore presentations of the TROPION-Lung01 phase 3 trial and TROPION-Lung05 phase 2 trial of datopotamab deruxtecan (Dato-DXd) as well as the DESTINY-PanTumor02 phase 2 trial of ENHERTU will be presented at ESMO Asia from December 1 - 3 in Singapore, along with other data, including: Presentation Title Presenter Abstract Presentation ENHERTU (trastuzumab deruxtecan; T-DXd) Lung Trastuzumab deruxtecan (T-DXd) in Asian patients with human epidermal growth factor receptor 2 (HER2; ERBB2) mutant (HER2m) metastatic non–small cell lung cancer: subgroup analysis of DESTINY-Lung02 Y. Goto 510MO Mini-Oral Session December 2, 2023 9:00 – 10:30 am SGT Pan Tumor Trastuzumab deruxtecan (T-DXd) for pretreated patients with HER2 expressing solid tumors: primary analysis from the DESTINY-PanTumor02 study D. Oh 74MO Mini-Oral Session December 1, 2023 10:45 am – 12 :15 pm SGT Gastric Trastuzumab deruxtecan (T-DXd) in Chinese patients with previously treated HER2 positive locally advanced/ metastatic gastric cancer or gastroesophageal junction adenocarcinoma: primary efficacy and safety from the phase 2 single-arm DESTINY-Gastric06 trial L. Shen 172P Poster Presentation December 2, 2023 Datopotamab deruxtecan (Dato-DXd) Lung Datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated advanced/metastatic non-small cell lung cancer: results of the randomized phase 3 study TROPION-Lung01 M. Ahn 509MO Mini-Oral Session December 2, 2023 9:00 – 10:30 SGT TROPION-Lung05: datopotamab deruxtecan (Dato-DXd) in previously treated non-small cell lung cancer with actionable genomic alterations S. Kitazono 518MO Mini-Oral Session Sunday, December 3 9:00 – 10:30 am SGT TROPION-Lung05: datopotamab deruxtecan (Dato-DXd) in Asian patients with previously treated non-small cell lung cancer with actionable genomic alterations Y. Goto 552P Poster Presentation December 2, 2023 SABCS Data Highlights of Daiichi Sankyo data across several subtypes of breast cancer to be presented at SABCS from December 5 - 9 in San Antonio, Texas, include: Presentation Title Author Abstract Presentation ENHERTU (trastuzumab deruxtecan; T-DXd) HER2 Low Breast Trastuzumab deruxtecan (T-DXd) in combination with anastrozole or fulvestrant in patients with HER2 low HR+ advanced/metastatic breast cancer: a phase 1b, open-label, multicenter, dose-expansion study (DESTINY-Breast08) K. Jhaveri RF02-03 Rapid-Fire Mini-Oral December 7, 2023 12:00 – 12:45 pm CST An open-label, interventional multicenter study of trastuzumab deruxtecan monotherapy in patients with unresectable and/or metastatic HER2 low or HER2 immunohistochemistry 0 breast cancer: DESTINY-Breast15 S. Modi PO2-19-06 Poster Presentation December 6, 2023 5:00 – 7:00 pm CST HER2 Positive Breast European real-world experience of patients with HER2+ advanced/metastatic breast cancer accessing trastuzumab deruxtecan through a named patient program: first interim analysis of EUROPA T-DXd M. De Laurentiis PO3-16-12 Poster Presentation December 7, 2023 12:00 – 2:00 pm CST Real-world experience with trastuzumab deruxtecan in patients with breast cancer: 6 month interim analysis of an all patient post marketing surveillance in Japan J. Tsurutani PO3-17-07 Poster Presentation December 7, 2023 12:00 – 2:00 pm CST Population pharmacokinetics of trastuzumab deruxtecan (T-DXd) in HER2 positive breast cancer subjects: analyses across 12 Phase 1-3 studies C. Li PO3-04-01 Poster Presentation December 7, 2023 12:00 – 2:00 pm CST Exposure-efficacy and exposure-safety analysis of trastuzumab deruxtecan in patients with advanced metastatic HER2+ breast cancer: analyses from phase 3 studies DESTINY-Breast02 and DESTINY-Breast03 C. Li PO3-04-02 Poster Presentation December 7, 2023 12:00 – 2:00 pm CST Datopotamab deruxtecan (Dato-DXd) HR Positive Breast Randomized phase 3 study of datopotamab deruxtecan vs chemotherapy for patients with previously treated inoperable or metastatic hormone receptor positive, HER2 negative breast cancer: results from TROPION-Breast01 A. Bardia GS02-01 Oral Presentation December 7, 2023 8:15 - 8:30 am CST TNBC Durvalumab + datopotamab deruxtecan in patients with PD-L1 positive advanced/metastatic triple negative breast cancer: arm 8 of the phase 1b/2, open label, platform BEGONIA study P. Schmid PO1-19-10 Poster Presentation December 6, 2023 12:00 - 2:00 pm CST ASH Data Highlights of Daiichi Sankyo data from its hematology portfolio to be presented at ASH from December 9 - 12 in San Diego, California, include: Presentation Title Presenter Abstract Presentation Valemetostat (EZHARMIA in Japan only) T-cell Lymphoma Efficacy and safety of valemetostat monotherapy in patients with relapsed or refractory peripheral T-cell lymphomas: primary results of the phase 2 VALENTINE-PTCL01 study S. Horwitz 302 Oral Presentation December 9, 2023 4:15 pm PST Valemetostat for relapsed or refractory peripheral T- cell lymphomas: primary results from a phase 1 trial E. Jacobsen 303 Oral Presentation December 9, 2023 4:30 pm PST B-cell Lymphoma Valemetostat for relapsed or refractory B-cell lymphomas: primary results from a phase 1 trial K. Izutsu 1731 Poster Presentation December 9, 2023 5:30 - 7:30 pm PST VANFLYTA (quizartinib) FLT3-ITD AML QuANTUM-First: FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)-specific measurable residual disease (MRD) clearance assessed through induction and consolidation is associated with improved overall survival in newly diagnosed FLT3-ITD+ AML patients A. Perl 832 Oral Presentation December 11, 2023 3:30 pm PST QuANTUM-First: safety by treatment phase and by age in newly diagnosed patients with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) positive acute myeloid leukemia (AML) H. Erba 972 Oral Presentation December 11, 2023 5:45 pm PST Patient-reported outcomes in acute myeloid leukemia patients with FLT3-ITD mutation receiving quizartinib vs. standard chemotherapy: results from the QuANTUM-First trial E. Oliva 918 Oral Presentation December 11, 2023 4:00 pm PST QuANTUM-First: clinical bridging study for FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) companion diagnostic development J. Rohrbach 4260 Poster Presentation December 11, 2023 6:00 - 8:00 pm PST Kinetics of complete remission (CR) and CR duration and its impact on overall survival (OS) and event-free survival (EFS) in QuANTUM-First P. Montesinos 4254 Poster Presentation December 11, 2023 6:00 - 8:00 pm PST About the DXd ADC Portfolio of Daiichi Sankyo The DXd ADC portfolio of Daiichi Sankyo currently consists of six ADCs in clinical development across multiple types of cancer. ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with Merck & Co., Inc., Rahway, NJ. U.S.A. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo. Designed using Daiichi Sankyo’s proprietary DXd ADC technology to target and deliver a cytotoxic payload inside cancer cells that express a specific cell surface antigen, each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan and DS-3939 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established. About Daiichi Sankyo Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical need. For more information, please visit .