CAMBRIDGE, MA, USA I December 11, 2021 I Epizyme, Inc. (Nasdaq: EPZM), a fully integrated, commercial-stage biopharmaceutical company developing and delivering transformative therapies against novel epigenetic targets, today shared preclinical data and the Phase 1/1b trial design for EZM0414, the Company’s novel, first-in-class, oral SETD2 inhibitor, an investigational agent being developed for the treatment of adult patients with relapsed or refractory multiple myeloma (MM) or with diffuse large B-cell lymphoma (DLBCL). The data and the design were presented today at the 2021 American Society of Hematology (ASH) Annual Meeting.

The data presented from both in vitro and in vivo preclinical studies (Abstract #1142), demonstrated that targeting SETD2 with EZM0414 resulted in significantly reduced growth of t(4;14) MM cell lines, as well as non-t(4;14) MM and DLBCL cell lines. Additionally, in in vitro studies, EZM0414 showed synergy with MM and DLBCL standard of care and emerging therapies, which supports the potential for the study of EZM0414 in combination with current MM and DLBCL treatments.

“We are excited to share our preclinical data on EZM0414 with the research community at ASH, which highlights its anti-tumor activity in multiple myeloma and DLBCL xenograft models, as well as its in vitro combination activity,” said Dr. Jeffery Kutok, MD, PhD, Chief Scientific Officer at Epizyme. “This work has increased our understanding of the potential for EZM0414 in B cell malignancies and formed the basis for our first-in-human studies, beginning with our SET-101 Phase 1/1b trial.”

Epigenetic mutations and dependencies have been identified in B cell malignancies, including MM and DLBCL, providing therapeutic rationale for epigenetic inhibitors in these tumor types. Previous data demonstrated that there is broad sensitivity of MM cell lines to SETD2 inhibition, and in particular, t(4;14) MM cell lines, which are dependent on SETD2 due to overexpression of MMSET by the high-risk t(4;14) translocation.

These preclinical data form the basis for SET-101, the Company’s Phase 1/1b clinical study (Abstract #1679), which is designed to evaluate the safety and determine the optimal dose of EZM0414. Under the trial protocol, following the Phase 1 dose ranging portion of the trial, the study will be expanded to evaluate EZM0414 in three patient cohorts: t(4;14) MM, non-t(4;14) MM, and DLBCL.

In the Phase 1 portion of the study, adult patients with relapsed or refractory MM and DLBCL will be enrolled and treated in a Bayesian optimal interval design to evaluate the safety, tolerability, and pharmacokinetics of EZM0414 at six dose levels. Up to 36 patients will be enrolled, and at least nine patients will be evaluated for maximum tolerated dose. At least eight patients, each with t(4;14) MM, non-t(4;14) MM, or DLBCL will be included. The primary endpoints include the safety and tolerability of EZM0414 and the maximum tolerated dose.

The Phase 1b dose expansion portion of the study will include three cohorts, t(4;14) MM, non-t(4;14) MM, and DLBCL, of up to 20 patients each. There will be two interim assessments when clinical data from the first 10 and 15 patients enrolled in each expansion cohort are available. Futility assessments will also be conducted at that time. The final analysis will be performed when all data from the 20 patients in each expansion cohort are available. Primary endpoints include the recommended Phase 2 dose, and secondary endpoints include efficacy and response rates. The trial is currently enrolling patients in the United States and has been screening patients for enrollment.

“There is a significant unmet need for new therapeutic options for patients living with multiple myeloma and DLBCL, which are both very aggressive and difficult-to-treat malignancies,” said Dr. Shefali Agarwal, Executive Vice President and Chief Medical and Development Officer at Epizyme. “We are thrilled to bring the first SETD2 inhibitor into the clinic to learn more about its potential in the treatment of these diseases, which is an important milestone for our oncology portfolio. The SET-101 study is open, we’re actively screening patients and we look forward to dosing our first patient and sharing more about EZM0414 as trial data become available.”

About EZM0414

EZM0414 is a potent, selective, oral, small molecule, investigational drug agent that inhibits the histone methyltransferase, SETD2, which plays a role in oncogenesis. SETD2 methylates histone as well as non-histone proteins, and this activity is involved in several key biological processes including transcriptional regulation, RNA splicing, and DNA damage repair. Based on the preclinical data on SETD2 inhibition by EZM0414 in multiple settings, including high risk t(4;14) multiple myeloma (MM) and in other B-cell malignancies such as diffuse large B-cell lymphoma (DLBCL), the Company is conducting SET-101, a Phase 1/1b study of EZM0414, for the treatment of adult patients with relapsed or refractory MM and DLBCL.

About Epizyme, Inc.

Epizyme, Inc. is a fully integrated, commercial-stage biopharmaceutical company committed to its mission of rewriting treatment for cancer through novel epigenetic medicines. The Company is focused on creating medicines that are targeted at specific causes of diseases, that are orally administered, tolerable, easy to take and based on a deep understanding of the patients that may benefit from them. The Company aspires to change the standard-of-care for patients and physicians by developing medicines with fundamentally new mechanisms of action. For more information, visit

SOURCE: Epizyme