Date: 2014-08-12
Type of information: Presentation of results at a congress
phase: preclinical
Announcement: presentation of results at the American Society of Hematology (ASH) meeting on Lymphoma Biology, held August 10-13 in Colorado Springs, Colorado
Company: Epizyme (USA - MA) Eisai (Japan)
Product: EPZ-6438 (E7438)
Action
mechanism: EZH2 is a histone methyltransferase (HMT) that is increasingly understood to play a potentially oncogenic role in a number of cancers. These include germinal center (GC) non-Hodgkin lymphomas, INI1-deficient cancers such as synovial sarcoma and malignant rhabdoid tumors, and a range of other solid tumors. EPZ-6438 is a small molecule inhibitor of EZH2 created with Epizyme’s proprietary product platform, for the treatment of non-Hodgkin lymphoma patients. In many human cancers, misregulated EZH2 enzyme activity results in misregulation of genes that control cell proliferation — without these control mechanisms, cancer cells are free to grow rapidly. Epizyme granted Eisai a worldwide license to EPZ-6438 (Eisai refers to this therapeutic candidate as E7438), subject to Epizyme\'s right to opt in for co-development, co-commercialization and profit share arrangement with Eisai in the United States. Epizyme is working with Roche and Eisai to develop a companion diagnostic to identify patients with non-wild type EZH2, where EZH2 contains point mutations.
Disease: advanced solid tumors B-cell lymphomas
Therapeutic area: Cancer - Oncology
Country:
Trial details:
Latest
news: * On August 12, 2014, Epizyme, a clinical stage biopharmaceutical company creating innovative personalized therapeutics for patients with genetically defined cancers, reported pre-clinical data and early clinical observations from an ongoing Phase 1 trial, being conducted in collaboration with Eisai, the Institut Gustave Roussy, and the Institut Bergonie, of EZH2 inhibitor EPZ-6438 (E7438) in patients with advanced solid tumors and B-cell lymphomas. These data were presented by Robert Copeland, Ph.D., Chief Scientific Officer, Epizyme, during an oral session on novel therapeutics in lymphoma at the American Society of Hematology (ASH) meeting on Lymphoma Biology, held August 10-13 in Colorado Springs, Colorado. The presentation is available on the Epizyme website.
Pre-Clinical Findings: Pre-clinical data have shown the utility of single-agent EZH2 inhibitors in both EZH2 mutant and EZH2 wild type germinal center (GC) NHL models. Data presented showed that in pre-clinical studies in GC NHL cell lines, combining EPZ-6438 with CHOP, a chemotherapy cocktail regimen that is a standard of care in NHL, resulted in strong synergy of lymphoma cell killing. When EPZ-6438 was combined with each individual component of the CHOP regimen, the synergy was greatest with prednisone, the corticosteroid component of CHOP. Prednisone greatly enhanced the potency of EPZ-6438 for killing EZH2 mutant-bearing lymphoma cell lines, and broadened the activity of EPZ-6438 to all GC NHL cell lines, regardless of EZH2 mutational status. Combining EPZ-6438 with dexamethasone, another corticosteroid, yielded similar synergistic results. Synergy was also observed in both EZH2 mutant and wild type cell lines when EPZ-6438 was combined with B-cell signaling pathway agents and BCL2 antagonists.
Early Clinical Observations: The primary objective of the ongoing Phase 1 dose escalation study is to evaluate the safety and tolerability of EPZ-6438 and determine the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D); the secondary objectives are to determine pharmacokinetics (PK) and pharmacodynamics (PD) of EPZ-6438. The study to date consists of five dosing cohorts, with evaluation of doses of 100 mg to 1600 mg BID, orally administered in 28-day cycles without a drug holiday in patients with advanced solid tumors or with relapsed or refractory B-cell lymphoma. Three of five dosing cohorts (100, 200 and 400 mg) have been completed with 12 evaluable patients dosed, four of whom were NHL patients. Dose cohorts evaluating 800 mg and 1600 mg are ongoing.
Early clinical observations from the three completed cohorts include: MTD has not been reached; there were no DLTs or AE-related treatment discontinuations; PK was dose-proportional across these three cohorts; PD evidence of target inhibition was observed in skin
Two NHL patients achieved objective responses: a partial response in a patient with relapsed transformed diffuse large B-cell lymphoma (DLBCL), and an ongoing partial response in a patient with primary refractory mediastinal B-cell lymphoma (PMBCL)
Additionally, a patient with follicular lymphoma with EZH2 mutation had stable disease
In June 2013, Epizyme and Eisai initiated a Phase 1/2 clinical trial of EPZ-6438 (E7438) in patients with advanced solid tumors or B-cell lymphomas. This program is currently in the dose escalation phase. EPZ-6438 is the second HMTi to enter human clinical development (following Epizyme\'s DOT1L inhibitor, EPZ-5676). More complete Phase 1 data will be presented in late 2014 and initiation of Phase 2 studies in non-Hodgkin lymphoma (NHL) and INI1-deficient tumors are planned in late 2014, pending review of Phase 1 results.
