IPN60210 News - LARVOL Sigma

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Targeting Tri-Methyl-Histone H3 (Lys27) in Rectal Cancer: A Novel Strategy to Enhance Radiosensitivity and Predict Response to Neoadjuvant Therapy (Room 30 D/E) - Aug 22, 2023 - Abstract #ASTRO2023ASTRO_815;
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.

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Journal: Conformational-Design-Driven Discovery of EZM0414: A Selective, Potent SETD2 Inhibitor for Clinical Studies. (Pubmed Central) - Jul 23, 2022
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.

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Enrollment open:  SET-101: A Study of the Safety, Tolerability and Effectiveness of EZM0414 Investigative Product in Participants With Relapsed/Refractory Multiple Myeloma and Relapsed/Refractory Diffuse Large B Cell Lymphoma (clinicaltrials.gov) -  Apr 25, 2022
P1, N=96, Recruiting,  Sponsor: Epizyme, Inc.
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. Not yet recruiting --> Recruiting

|||||||||| EZM0414 / Epizyme
Discovery and First Structural Disclosure of EZM0414: A potent and selective small molecule inhibitor of the histone methyltransferase SETD2 (La Nouvelle Orleans A-B, Convention Center) - Mar 23, 2022 - Abstract #AACR2022AACR_8007;
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.

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A Phase 1/1b Open-Label, Multicenter, Two-Part Study of SETD2 Inhibitor EZM0414 in Patients with Relapsed/Refractory Multiple Myeloma or Diffuse Large B-Cell Lymphoma (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_3260;
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.

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Pharmacologic Inhibition of the Histone Methyltransferase SETD2 with EZM0414 As a Novel Therapeutic Strategy in Relapsed or Refractory Multiple Myeloma and Diffuse Large B-Cell Lymphoma (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_2698;
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.



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