IPN60210

Although inhibitors targeting SETD2 (e.g., EZM0414) and EZH2 (e.g., tazemetostat) demonstrate antitumor activity in preclinical models, their clinical efficacy remains constrained by drug resistance and tumor microenvironment heterogeneity. Emerging evidence suggests that combining epigenetic therapies with immunotherapy may enhance therapeutic outcomes. This review comprehensively systematically examines the molecular mechanisms underlying the SETD2/EZH2 axis in prostate cancer, providing a theoretical foundation for developing precision therapies based on SETD2- or EZH2-mediated epigenetic modifications.

P1, N=13, Terminated, Epizyme, Inc. | N=96 --> 13 | Trial completion date: Jun 2025 --> Apr 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2024 --> Apr 2024; Strategic business decision

P1, N=96, Active, not recruiting, Epizyme, Inc. | Recruiting --> Active, not recruiting

Our study uncovers a new biomarker, Tri-Methyl-Histone H3 (Lys27), that could be used to predict response to neoadjuvant chemoradiation in rectal cancer patients. Our preclinical data indicates that targeting SETD2 to reduce Tri-Methyl-Histone H3 (Lys27) mediated DNA repair could improve the efficacy of radiation therapy for rectal cancer patients.

In vitro treatment with a novel SETD2 inhibitor, EZM0414, led to a 2-fold increase in DNA damage following IR (5 Gy) as measured by ?H2aX foci staining... Our study uncovers a new biomarker, Tri-Methyl-Histone H3 (Lys27), that could be used to predict response to neoadjuvant chemoradiation in rectal cancer patients. Our preclinical data indicates that targeting SETD2 to reduce Tri-Methyl-Histone H3 (Lys27) mediated DNA repair could improve the efficacy of radiation therapy for rectal cancer patients.

Herein we describe the conformational-design-driven evolution of the advanced chemistry lead, which resulted in compounds appropriate for clinical evaluation. Further optimization of this chemical series led to the discovery of EZM0414, which is a potent, selective, and orally bioavailable inhibitor of SETD2 with good pharmacokinetic properties and robust pharmacodynamic activity in a mouse xenograft model.

Because H3K36me2 is the substrate of SETD2, we hypothesized that inhibiting SETD2 could target the underlying oncogenic mechanism driven by the dysregulated H3K36 methylation from MMSET overexpression in t(4;14) MM patients, and would establish proof of concept in this and other B cell malignancies (e.g. DLBCL) that may demonstrate dysregulated H3K36me3 or a dependency on SETD2. In this presentation, we will describe the discovery and structure of our clinical candidate EZM0414, a first-in-class, potent, selective, orally bioavailable small molecule inhibitor of the enzymatic activity of SETD2; robust anti-tumor effects of SETD2 inhibition with EZM0414 in MM (including t(4;14) MM) and DLBCL preclinical studies; and the outline of the ongoing first-in-human Ph1/1b open-label, multicenter study of EZM0414 in patients with relapsed/refractory MM or DLBCL.

Study Design and Methods : This first-in-human, 2-part, multicenter, open-label study will enroll patients aged ≥18 years with R/R MM who have received prior treatment with immune modulators, proteasome inhibitors, and anti-CD38 therapy, or who are intolerant to established therapies known to provide clinical benefit in MM, or with R/R DLBCL who have received at least 2 prior lines of therapy, including treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH); rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-hyper CVAD); or other standard of care therapies. Exploratory endpoints include a pharmacokinetic/pharmacodynamic profile analysis and the determination of mechanism of action biomarkers, such as histones and histone methylation. The study design will include a futility assessment in the phase 1b part of the study, which will be initiated when clinical data from the first 10, 15, and 20 enrolled patients in the expansion cohort are available.

Targeting SETD2 with a small molecule inhibitor results in significantly reduced growth of t(4;14) MM, as well as non-t(4;14) MM and DLBCL cell lines, in both in vitro and in vivo preclinical studies. In addition, in vitro synergy was observed with EZM0414 and certain SOC agents commonly used in MM and DLBCL, supporting the combination of SETD2 inhibition with current MM and DLBCL therapies. This work provides the rationale for targeting SETD2 in B cell malignancies such as MM, especially t(4;14) MM, as well as DLBCL, and forms the basis for conducting Phase 1/1b clinical studies to evaluate the safety and activity of EZM0414 in patients with R/R MM and DLBCL.