[September 26, 2015] |
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Epizyme Announces Updated Tazemetostat Phase 1 Data Showing Clinical Activity in a Broader Range of Adults With INI1-Negative and SMARCA4-Negative Solid Tumors
Epizyme,
Inc. (NASDAQ: EPZM) reported results today from the ongoing phase 1
trial of tazemetostat, its first-in-class EZH2 inhibitor. The data
showed that tazemetostat demonstrated clinical activity in a broader
group of patients with INI1-negative and SMARCA4-negative tumors than
previously reported, achieved inhibition of EZH2 in tumor tissue, and
had an acceptable safety profile when administered as oral monotherapy
in adult patients with relapsed or refractory INI1-negative and
SMARCA4-negative tumors. The data were presented at the European Cancer
Congress 2015 (ECC) in Vienna, Austria by Antoine Italiano, M.D., Ph.D.,
of the Institut Bergonié in Bordeaux, France. Based on tazemetostat's
clinical activity observed to date and other supportive research,
Epizyme will initiate a global phase 2 study in adults and a global
phase 1 study in children with INI1-negative tumors and synovial sarcoma
in the fourth quarter of 2015.
INI1-negative and SMARCA4-negative tumors, such as rhabdoid tumors and
epithelioid sarcoma are serious and debilitating cancers. Approximately
1,400 patients each year in the major global markets develop these tumors1,
which have no established standard of care. INI1 and SMARCA4 are
critical proteins of the SWI/SNF complex, which oppose the activity of
EZH2. Genetic alterations or loss of function of either can result in
EZH2-dependent oncogenesis in certain cancer backgrounds, thus rendering
these tumors sensitive to EZH2 inhibition.
"INI1-negative tumors represent a group of devastating diseases with a
very poor prognosis even for patients who can undergo a complete
surgical resection. Tazemetostat has induced objective responses that
are durable for some patients and has an excellent safety profile," said
Dr. Italiano. "Our data provide evidence that potentially changes the
landscape of clinical research in this group of tumors and could improve
the treatment paradigm for these traditionally refractory diseases."
"We are excited by these data, which show clinical activity in patients
with INI1-negative and SMARCA4-negative tumors. These results are
consistent with preclinical data that demonstrate the important role of
EZH2 in INI1- and SMARCA4-negative tumors such as malignant rhabdoid
tumors where median survival after relapse is approximately nine
months," said Peter Ho, M.D., Ph.D., Chief Medical Officer, Epizyme. "We
are now turning our attention to initiating global
registration-supporting clinical trials in adults and children with
these aggressive tumors, for which new treatments are needed."
In total, 30 patients with solid tumors were enrolled into this ongoing
phase 1 study, including eight patients in a food effect sub-study. Of
these 30 patients, eight had INI1-negative tumors, comprised of five
with malignant rhabdoid tumors and three with epithelioid sarcomas (ES).
Additionally, three patients had SMARCA4-negative tumors including two
patients with malignant rhabdoid tumor of the ovary, also referred to as
small cell carcinoma of the ovary hypercalcemic type (SCCOHT), and one
patient with thoracic sarcoma. Nineteen patients had other solid tumors
that were not characterized by INI1 or SMARCA4 loss, including three
patients with synovial sarcomas.
Synovial sarcomas occur in approximately 1,800 patients each year in the
major markets. Synovial sarcomas are INI1-deficient rather than
INI1-negative. A fusion protein that is characteristic for synovial
sarcoma displaces INI1 from the SWI/SNF complex. Displacement of INI1
confers dependence of these tumors on EZH2, and hence sensitivity to an
EZH2 inhibitor in preclinical models.
In addition to the 30 patients with solid tumors, 21 patients with
advanced Non-Hodgkin Lymphoma (NHL) were also enrolled into this ongoing
phase 1 study, and the safety data from the ECC update presentation
includes these patients. The data cutoff for this presentation was
August 31, 2015.
Summary of Results
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A total of 11 patients with INI1-negative or SMARCA4-negative tumors
have been treated. The tumor histology of these patients includes MRT,
MRTO, ES and thoracic sarcoma. Nine of these 11 patients have been
treated at or above the recommended phase 2 dose of 800 mg twice daily.
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Six of the 11 patients experienced a reduction in tumor size as best
response, with four patients experiencing tumor reduction of over 30%.
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Of five patients with an INI1-negative malignant rhabdoid tumor, one
patient chieved a complete response (CR) at week eight and remains on
study and in CR through week 65.
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Of three patients with SMARCA4-negative tumors, two patients have
malignant rhabdoid tumor of the ovary. One MRTO patient achieved a PR
at week 8 and remains on study through week 25. A second MRTO patient
remains on study with stable disease (SD) through week 26.
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Of three patients with an INI1-negative epithelioid sarcoma, one
patient achieved a PR of short duration and remains on study with SD
through week 25. The second patient remains on study with SD through
week 24.
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Clinical activity was not observed in the 19 patients with other
tumors, including the three patients with synovial sarcomas.
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Inhibition of EZH2, as measured by post-treatment H3K27 trimethylation
compared to baseline, was observed in tumor tissue of INI1-negative
patients as assessed by immunohistochemistry.
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The majority of adverse events observed in the study were grade 1 or
grade 2 within the entire population of 51 patients with NHL and solid
tumors. The most frequent adverse events regardless of attribution
were asthenia, decreased appetite, thrombocytopenia, nausea, dyspnea,
anemia and constipation. Five grade 3 or greater treatment-related
adverse events have been observed including one each of:
thrombocytopenia, neutropenia, hypertension, liver function test
elevation and decreased appetite.
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Solid tumor patients enrolled in this study had been heavily
pre-treated, with over half of patients having received three or more
prior anti-cancer therapies.
Study Design The data presented at ECC are from the ongoing
first-in-human phase 1 trial of tazemetostat in adults with relapsed or
refractory B-cell lymphomas or advanced solid tumors. The primary
objective of the study was to determine the recommended phase 2 dose.
Secondary endpoints included safety, pharmacokinetics, pharmacodynamics
and tumor response evaluated every eight weeks. Tazemetostat is
administered orally twice daily. Five cohorts were studied in the dose
escalation phase: 100 mg, 200 mg, 400 mg, 800 mg and 1600 mg; and two
cohorts, 800 mg and 1600 mg, were evaluated in the dose expansion phase.
Patients enrolled into the food effects sub-study received tazemetostat
at 400 mg.
Expanded Tazemetostat Phase 1 and Phase 2 Plans A planned
phase 2 trial studying tazemetostat in adult patients with INI1-negative
solid tumors or synovial sarcoma is expected to begin in the fourth
quarter of 2015. A phase 1 dose escalation study in pediatric patients
with INI1-deficient solid tumors is also expected to start in the fourth
quarter of 2015. The INI1-deficient tumor studies will enroll subjects
in the U.S., EU and Australia.
Epizyme is already enrolling patients into an international five-arm,
multi-center, phase 2 study that will assess the safety and efficacy of
tazemetostat in patients with relapsed or refractory NHL, stratified by
cell of origin and EZH2 mutation status.
The company plans to initiate additional trials of tazemetostat,
including:
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A combination study of tazemetostat with R-CHOP in patients with
diffuse large B-cell lymphoma (DLBCL), including higher risk
front-line patients. R-CHOP, which represents the current first-line
regimen for patients with DLBCL, is comprised of rituximab,
cyclophosphamide, doxorubicin, vincristine and prednisone.
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A combination study of tazemetostat with a B-cell signaling agent or
other emerging targeted therapy for B-cell lymphomas.
About EZH2 in Cancer EZH2 is a histone methyltransferase
(HMT) that is increasingly understood to play a potentially oncogenic
role in a number of cancers. These include non-Hodgkin lymphomas,
rhabdoid tumors and other INI1-deficient cancers such as epithelioid
sarcomas and synovial sarcoma as well as a range of other solid tumors.
About Tazemetostat Epizyme is developing tazemetostat for
the treatment of non-Hodgkin lymphoma patients and patients with
INI1-deficient solid tumors. Tazemetostat is a first-in-class small
molecule inhibitor of EZH2 created by Epizyme using its proprietary
product platform. In many human cancers, aberrant EZH2 enzyme activity
results in misregulation of genes that control cell proliferation
resulting in the rapid and unconstrained growth of tumor cells.
Tazemetostat is the WHO International Non-Proprietary Name (INN) for
EPZ-6438.
Additional information about this program, including clinical trial
information, may be found here: https://clinicaltrials.gov/ct2/show/NCT01897571
Conference Call Information
Epizyme will host a conference call and live audio webcast with slides
on Monday, September 28, 2015, at 8:00 a.m. ET to discuss these results
and development plans for tazemetostat.
To participate in the conference call, please dial (877) 844-6886
(domestic) or (970) 315-0315 (international) and refer to conference ID
23660411. The live webcast can be accessed under "Events and
Presentations" in the Investor Relations section of the Company's
website at www.epizyme.com.
Slides will be available on the Company's website prior to the
conference call.
About Epizyme, Inc. Epizyme, Inc. is a clinical-stage
biopharmaceutical company creating novel epigenetic therapeutics for
cancer patients. Epizyme has built a proprietary product platform that
the Company uses to create small molecule inhibitors of a 96-member
class of enzymes known as histone methyltransferases, or HMTs. HMTs are
part of the system of gene regulation, referred to as epigenetics, that
controls gene expression. Genetic alterations can result in changes to
the activity of HMTs, making them oncogenic (cancer-causing). By
focusing on the genetic drivers of cancers, Epizyme's targeted science
seeks to match the right medicines with the right patients.
For more information, visit www.epizyme.com
and connect with us on Twitter (News - Alert) at @EpizymeRx.
Cautionary Note on Forward-Looking Statements Any statements
in this press release about future expectations, plans and prospects
for Epizyme, Inc. and other statements containing the words
"anticipate," "believe," "estimate," "expect," "intend," "may," "plan,"
"predict," "project," "target," "potential," "will," "would," "could,"
"should," "continue," and similar expressions, constitute
forward-looking statements within the meaning of The Private
Securities Litigation Reform Act of 1995. Actual results may differ
materially from those indicated by such forward-looking statements as a
result of various important factors, including: uncertainties inherent
in the initiation of future clinical studies or expansion of ongoing
clinical studies, availability and timing of data from ongoing clinical
studies, whether interim results from a clinical trial such as the
results described in this release will be predictive of the final
results of the trial or the results of future trials, expectations for
regulatory approvals to conduct trials or to market products,
development progress of the Company's companion diagnostics,
availability of funding sufficient for the Company's foreseeable and
unforeseeable operating expenses and capital expenditure requirements,
other matters that could affect the availability or commercial potential
of the Company's therapeutic candidates or companion diagnostics and
other factors discussed in the "Risk Factors" section of our Form 10-Q
most recently filed with the SEC (News - Alert), and in our other filings from time to
time with the SEC. In addition, the forward-looking statements included
in this press release represent the Company's views as of the date
hereof. The Company anticipates that subsequent events and developments
will cause the Company's views to change. However, while the Company may
elect to update these forward-looking statements at some point in the
future, the Company specifically disclaims any obligation to do so.
These forward-looking statements should not be relied upon as
representing the Company's views as of any date subsequent to the date
hereof.
1 According to a market research study commissioned by
Epizyme.
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