Epizyme debuts preclinical EZH2 inhibitor data at ASH meeting

EPZ-6438 has engendered partial response in two non- Hodgkin lymphoma patients; maximum tolerated dose not yet reached

Kelsey Kaustinen
COLORADO SPRINGS, Colo.—This year’s ASH Meeting on Lymphoma Biology, held by the American Society of Hematology Aug. 10-13, saw Epizyme Inc. presenting preclinical data and early clinical observations from an ongoing Phase 1 trial of EPZ-6438 in patients with advanced solid tumors and B-cell lymphomas. Epizyme is conducting the trial in collaboration with Eisai, the Institut Gustave Roussy and the Institut Bergonie.
 
EPZ-6438 is a small-molecule inhibitor of EZH2 created with Epizyme’s proprietary product platform. EZH2 is a histone methyltransferase, and there is increasing evidence that it plays an oncogenic role in several cancers, such as INI1-deficient cancers, which includes synovial sarcoma and malignant rhabdoid tumors, germinal center non-Hodgkin lymphomas and other solid tumors. In several cancers, misregulated EZH2 enzyme activity causes misregulation of genes that control cell proliferation, which in turn allows cancer cells to grow rapidly and unchecked.
 
Epizyme and Eisai are developing the compound as a treatment for non-Hodgkin lymphoma (NHL). Eisai was granted a worldwide license to EPZ-6438, though Epizyme retains a right to opt in for co-development, co-commercialization and profit-share arrangements in the United States. In addition, Epizyme is also working with Eisai and Roche on a companion diagnostic to identify patients with non-wild type EZH2, where EZH2 contains point mutations. Last June, Epizyme and Eisai launched a Phase 1/2 clinical trial of EPZ-6438 in patients with advanced solid tumors or B-cell lymphomas.
 
“EPZ-6438 is the first EZH2 inhibitor to enter the clinic. We are very pleased to see that the maximum tolerated dose has not been reached and that there was a clear PK and PD dose relationship through the first three cohorts that have been evaluated,” Dr. Robert Gould, CEO of Epizyme, said in a news release. “Additionally, we saw two objective responses among NHL patients enrolled in the first three cohorts of the Phase 1 dose escalation study. We plan to present more complete Phase 1 results at a scientific conference later in 2014. Pending review of those results, we expect to initiate two Phase 2 studies in 2014: one in NHL and one in INI1-deficient tumors, such as malignant rhabdoid tumors.”
 
In preclinical studies of EZH2 wild-type germinal center NHL cell lines, Epizyme combined EPZ-6438 with CHOP, a chemotherapy cocktail regimen considered a standard of care in NHL. This combination engendered “strong synergy of lymphoma cell killing,” Epizyme noted in a news release, and when the compound was combined with each individual component of the CHOP regimen, the synergy was greatest with prednisone. The corticosteroid “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,” according to Epizyme, with similar results seen in combining EPZ-6438 with dexamethasone, another corticosteroid.
 
In the ongoing Phase 1 dose escalation study, Epizyme and its partners are seeking to evaluate the safety and tolerability of EPZ-6438, as well as to determine the maximum tolerated dose or recommended Phase 2 dose. The study is composed of five dosing cohorts, and of those, three have been completed—100, 200 and 400 mg—with 12 patients dosed, four of whom had NHL. Early clinical observations include that the maximum tolerated dose has not yet been reached, pharmacodynamic evidence of target inhibition was seen in skin and two NHL patients saw objective responses: a partial response in a patient with relapsed transformed diffuse large B-cell lymphoma, and an ongoing partial response in a patient with primary refractory mediastinal B-cell lymphoma.
 
Leerink Partners LLC noted in a recent document covering these results that they are “encouraged by the activity seen at the two lowest doses and in patients with wild-type EZH2, as preclinical biology would appear to suggest that patients with EZH2 mutation could potentially be more responsive. We see the initial proof of principle for this first-in-class agent as an exciting development for [Epizyme] due to the large addressable market: 22-27 percent of patients with germinal-center diffuse large B-cell lymphoma and follicular lymphoma with EZH2 mutation, with upside to broader population of lymphoma patients with wild-type EZH2.” Leerink added that they were increasing their price target range of Epizyme’s stock “from $38 to $48 to reflect the progress of the EZH2 program.”

Kelsey Kaustinen

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