Epizyme, Inc., a biopharmaceutical company leading the creation of personalized therapeutics to treat patients with genetically defined cancers, today announced the presentation of data evaluating the preclinical safety and efficacy of two of the Company's novel, potent and selective small molecule inhibitors. These inhibitors individually target DOT1L and EZH2, members of a class of epigenic enzymes called histone methyltransferases (HMTs). Genetically altered or misregulated HMTs are oncogenic and therefore important targets for drug development. Data will be presented in poster sessions at the 54th Annual Meeting of the American Society of Hematology (ASH) in Atlanta, GA from December 8 – 11, 2012.
"The data Epizyme is presenting at ASH demonstrate substantial progress in our DOT1L and EZH2 inhibitor programs," said Robert J. Gould, Ph.D., President and CEO, Epizyme. "Building on our proprietary product platform, these findings show the efficacy and selectivity of our compounds in animal models of leukemia and lymphoma, in each case demonstrating robust antitumor activity in genetically defined preclinical models. We expect to report Phase I clinical data, including a preliminary assessment of efficacy in an expansion cohort, for our DOT1L program within 12 to 18 months. We also expect to initiate clinical development for the EZH2 program shortly, and to report clinical data for that program in a similar time period."
Preclinical Characterization of a Potent, Selective Inhibitor of the Protein Methyltransferase DOT1L for Use in the Treatment of MLL-Rearranged Leukemia (Abstract #2379)
Poster Session: Sunday, December 9, 2012, 6:00 p.m.-8:00 p.m. ET, Hall B1-B2, Level 1, Building B, Georgia World Congress Center
Aberrant activity of the histone methyltransferase DOT1L has been shown to be the driving genetic lesion in MLL-rearranged (MLL-r) leukemia. In this abstract, preclinical results of treatment with EPZ-5676, a S-adenosyl methionine competitive DOT1L inhibitor, in a genetically defined rat model of MLL-rearranged leukemia are reported. Continuous intravenous infusion of EPZ-5676 for 21 days in this model led to dose-dependent antitumor activity, resulting in complete tumor regression with the highest dose tested. This complete tumor regression was sustained after cessation of treatment.
EPZ-5676 is highly selective for DOT1L, demonstrating greater than 37,000-fold selectivity against all other HMTs tested. Treatment of leukemia cells with EPZ-5676 resulted in concentration- and time-dependent reduction of H3K79 methylation, the target histone for aberrant DOT1L activity in MLL-r leukemia, without impacting other histone sites. The reduction of H3K79 methylation led to inhibition of key MLL target genes, and selective cell killing of MLL-r leukemia cells with no activity against non-MLL-r leukemia cells.
Epizyme initiated a Phase I study in September 2012 to evaluate the safety, pharmacokinetics and pharmacodynamics of escalating doses of EPZ-5676 and will provide a preliminary assessment of efficacy in an expansion cohort of patients with MLL-r leukemia. Clinical data for this trial is anticipated within 12 to 18 months. Epizyme has 100% of the US development and commercialization rights to this program, which is partnered with Celgene ex-US.
Supplementary DOT1L Data
Two additional posters presented at ASH 2012 expand the spectrum of genetic alterations potentially treatable by DOT1L inhibitors.
Abrogation of MLL-AF10 and CALM-AF10 Mediated Transformation Through Genetic Inactivation or Pharmacological Inhibition of the H3K79 Methyltransferase DOT1L (Abstract #2384; Poster Session: Sunday, December 9, 2012, 6:00 p.m.-8:00 p.m. ET, Hall B1-B2, Level 1, Building B, Georgia World Congress Center)
MLL-AF6 Mediated Transformation Is Dependent On the H3K79 Methyltransferase DOT1L (Abstract #3502; Poster session: Monday, December 10, 2012, 6:00 p.m.-8:00 p.m. ET, Hall B1-B2, Level 1, Building B, Georgia World Congress Center)
Patients with MLL-AF10, CALM-AF10 or MLL-AF6 chromosomal rearrangements have a particularly poor outcome compared to patients whose leukemia cells do not contain these translocations. Findings in abstract #2384 showed that DOT1L inhibition impairs the in vitro and in vivo oncogenic activity of the MLL-AF10 and CALM-AF10 fusion oncogenes. Results in abstract #3502 demonstrated that the MLL-AF6 oncoprotein requires the activity of DOT1L for abnormal transcription of downstream target oncogenes.