[July 21, 2017] |
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Syros Publishes Foundational Data Supporting Ongoing Phase 2 Clinical Trial of SY-1425 for Genomically Defined AML and MDS Patients
Syros Pharmaceuticals (NASDAQ: SYRS) today announced that data providing
the foundation of its clinical development strategy for SY-1425, its
first-in-class selective retinoic acid receptor alpha (RARa) agonist
currently in a Phase 2 clinical trial in genomically defined subsets of
patients with acute myeloid leukemia (AML) and myelodysplastic syndrome
(MDS), were published online in Cancer Discovery, a peer-reviewed
journal of the American Association of Cancer Research. Syros is on
track to present initial data from the Phase 2 clinical trial this fall.
The publication highlights Syros' discovery of a subset of AML patients
with a super-enhancer associated with the RARA gene, which was
shown in preclinical studies to be predictive of response to SY-1425.
Syros also found a subset of MDS patients with high expression of the RARA
gene and demonstrated in ex vivo studies that RARA-high
MDS had a similar response to SY-1425 as that seen in AML driven by the RARA
super-enhancer.
"The publication of our work in Cancer Discovery is a
demonstration of our pioneering approach for analyzing non-coding
regulatory regions of the genome to identify disease-driving genes with
the goal of developing new medicines that make a meaningful difference
for patients," said Eric Olson (News - Alert), Ph.D., Chief Scientific Officer of
Syros. "Although genetic mutations associated with AML and MDS in
protein-coding regions of the genome are well known, there are limited
targeted therapy options in these diseases and there remains a high
unmet need. Our investigation of the regulatory genome adds a new
dimension to the understanding of AML and MDS disease biology that
offers the potential to address these underserved patient populations
and improve their prognosis and treatment."
In collaboration with the Majeti lab at Stanford University School of
Medicine, Syros used its gene control platform to analyze 66 AML
patients' tumor samples and identified six distinct patient subsets
based on super-enhancer profiles, including one enriched for a
super-enhancer associated with the RARA gene. The data show that:
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Super-enhancer profiles were strongly associated with survival
outcomes, often independent of known genetic mutations in AML.
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The RARA super-enhancer was associated with high expression of
the RARA gene, which codes for a transcription factor targeted
by SY-1425.
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The RARA super-enhancer was predictive of response to SY-1425.
In AML cells with high RARA expression, SY-1425 reduced
proliferation and promoted differentiation. Moreover, SY-1425
decreased tumor burden and prolonged survival in patient-derived
xenograft (PDX) models of AML with high RARA expression, while
no effect was found on AML cells or PDX models with low RARA
expression. Notably, ATRA, a less potent and non-selective retinoid,
produced no survival benefit in PDX models with high RARA
expression.
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SY-1425 induced profoud transcriptional changes promoting cell
differentiation in AML cells with high RARA expression but
little to no transcriptional changes in AML cells with low RARA
expression.
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DHRS3 was the most strongly and rapidly induced gene in
response to treatment with SY-1425, leading to the identification of DHRS3
induction as a pharmacodynamic marker for use in the ongoing Phase 2
clinical trial as an early indicator of whether SY-1425 is affecting
the targeted biology in defined subsets of AML and MDS patients.
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SY-1425 induced transcriptional and epigenomic changes in AML cells
with high RARA expression similar to those seen in acute
promyelocytic leukemia (APL) cells treated with SY-1425. SY-1425 is
approved in Japan as Amnolake® (tamibarotene) to treat
relapsed or refractory APL, a form of AML that is driven by fusions of
the RARA gene, and has a well-established safety and efficacy
profile in those patients.
The Phase 2 clinical trial of SY-1425 is assessing the safety and
efficacy of SY-1425 as a single agent in four AML and MDS patient
populations, as well as in combination with azacitidine, a
standard-of-care therapy, in newly diagnosed AML patients who are not
suitable candidates for standard chemotherapy. All patients in the trial
are prospectively selected using biomarkers for high expression of RARA
or IRF8, which are genes associated with the RARA pathway.
Additional details about the trial can be found using the identifier
NCT02807558 at www.clinicaltrials.gov.
About Syros Pharmaceuticals Syros Pharmaceuticals is
pioneering the understanding of the non-coding region of the genome to
advance a new wave of medicines that control expression of
disease-driving genes. Syros has built a proprietary platform that is
designed to systematically and efficiently analyze this unexploited
region of DNA in human disease tissue to identify and drug novel targets
linked to genomically defined patient populations. Because gene
expression is fundamental to the function of all cells, Syros' gene
control platform has broad potential to create medicines that achieve
profound and durable benefit across a range of diseases. Syros is
currently focused on cancer and immune-mediated diseases and is
advancing a growing pipeline of gene control medicines. Syros' lead drug
candidates are SY-1425, a selective RARa agonist in a Phase 2 clinical
trial for genomically defined subsets of patients with acute myeloid
leukemia and myelodysplastic syndrome, and SY-1365, a selective CDK7
inhibitor in a Phase 1 clinical trial for patients with advanced solid
tumors, including transcriptionally dependent cancers such as triple
negative breast, small cell lung and ovarian cancers. Led by a team with
deep experience in drug discovery, development and commercialization,
Syros is located in Cambridge, Mass.
Cautionary Note Regarding Forward-Looking Statements This
press release contains forward-looking statements within the meaning of
The Private Securities Litigation Reform Act of 1995, including without
limitation statements regarding the therapeutic benefit of SY-1425 as a
single agent and in combination with azacitidine; the reporting of
initial clinical data from the ongoing Phase 2 clinical trial of SY-1425
in the fall of 2017; and the benefits of Syros' gene control platform.
The words ''anticipate,'' ''believe,'' ''continue,'' ''could,''
''estimate,'' ''expect,'' ''intend,'' ''may,'' ''plan,'' ''potential,''
''predict,'' ''project,'' ''target,'' ''should,'' ''would,'' and similar
expressions are intended to identify forward-looking statements,
although not all forward-looking statements contain these identifying
words. Actual results or events could differ materially from the plans,
intentions and expectations disclosed in these forward-looking
statements as a result of various important factors, including Syros'
ability to: advance the development of its programs, including SY-1425,
under the timelines it projects in current and future clinical trials;
demonstrate in any current and future clinical trials the requisite
safety, efficacy and combinability of its drug candidates; replicate
scientific and non-clinical data in clinical trials; successfully
develop a companion diagnostic test to identify patients with the RARA
and IRF8 biomarkers; obtain and maintain patent protection for
its drug candidates and the freedom to operate under third party
intellectual property; obtain and maintain necessary regulatory
approvals; identify, enter into and maintain collaboration agreements
with third parties; manage competition; manage expenses; raise the
substantial additional capital needed to achieve its business
objectives; attract and retain qualified personnel; and successfully
execute on its business strategies; risks described under the caption
"Risk Factors" in Syros' Quarterly Report on Form 10-Q for the quarter
ended March 31, 2017, which is on file with the Securities and Exchange
Commission; and risks described in other filings that Syros makes with
the Securities and Exchange Commission in the future. Any
forward-looking statements contained in this press release speak only as
of the date hereof, and Syros expressly disclaims any obligation to
update any forward-looking statements, whether because of new
information, future events or otherwise.
View source version on businesswire.com: http://www.businesswire.com/news/home/20170721005115/en/
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