Epizyme In Vivo Data Shows Promise in Personalized Therapeutics Programs for Acute Leukemia and Lymphoma

 Epizyme In Vivo Data Shows Promise in Personalized Therapeutics Programs for
                         Acute Leukemia and Lymphoma

Preclinical Study Results to be Presented at ASH 2012 Show Selectivity,
Efficacy of DOT1L and EZH2 Inhibitors

PR Newswire

CAMBRIDGE, Mass., Nov. 29, 2012

CAMBRIDGE, Mass., Nov. 29, 2012 /PRNewswire/ --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 54^th 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.

  oAbrogation 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)
  oMLL-AF6 Mediated Transformation Is Dependent On the H3K79
    MethyltransferaseDOT1L (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.

Preclinical Characterization of E7438, a Potent, Selective Inhibitor of
Protein Methyltransferase EZH2 with Robust Antitumor Activity Against EZH2
Mutated Non-Hodgkin Lymphoma Xenografts in Mice (Abstract #3712)

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

Building on previous research demonstrating that a small molecule inhibitor of
EZH2 selectively kills lymphoma cells bearing EZH2 mutations with minimal
effect on non-mutant lymphoma cells, Epizyme researchers developed E7438, a
selective inhibitor of EZH2 with properties consistent with a viable drug
candidate. The compound potently and selectively inhibits all mutants of EZH2
that have been identified in non-Hodgkin lymphoma (NHL) patient samples with
35-fold selectivity against the closely related enzyme EZH1 and greater than
4,500-fold selectivity compared to all other histone methyltransferases
tested.

In the abstract, oral administration of E7438 resulted in significant
antitumor activity in nude, SCID or NSG mice implanted subcutaneously with
various EZH2 mutant-bearing human lymphomas. Importantly, tumor regression was
shown to be sustained following discontinuation of E7438. E7438 administration
was well-tolerated at doses representing high multiples of doses in which
antitumor activity was demonstrated. Activity against the EZH2 target histone
H3K27, demonstrated by reduction in trimethylation status of H3K27 by ELISA in
samples of tumor, bone marrow, skin and peripheral blood mononuclear cells
(PBMCs), indicated the potential for a non-invasive biomarker for use in human
clinical trials.

Epizyme has partnered the EZH2 program with Eisai Co., Ltd., Tokyo, Japan with
Epizyme retaining US profit share and co-commercialization rights, and expects
to initiate the Phase I trial for E7438 in the near future.

About Epizyme, Inc.

Epizyme is leading the creation of small molecule histone methyltransferase
inhibitors (HMTi), a new class of personalized therapeutics for patients with
genetically defined cancers. Genetic alterations in HMTs, a class of
epigenetic enzymes, drive multiple human diseases. Our approach represents the
future of healthcare by matching better medicines with the right patients.

Epizyme has benchmark alliances with Celgene, GSK and Eisai and receives
funding and strategic support from the Multiple Myeloma Research Foundation
(MMRF) and the Leukemia & Lymphoma Society (LLS). For more information, visit
www.epizyme.com.

SOURCE Epizyme, Inc.

Website: http://www.epizyme.com
Contact: Amanda Sellers, +1-301-332-5574 (Onsite phone),
asellers@spectrumscience.com
 
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