Constellation Pharmaceuticals, Inc., (Nasdaq: CNST) a
clinical-stage biopharmaceutical company using its expertise in
epigenetics to discover and develop novel therapeutics, will make a
presentation on its EZH2 inhibition program in prostate cancer at
an upcoming biomedical conference.
Bill Bradley, Ph.D., Associate Director, Translational Sciences,
at Constellation, will give a poster presentation at the EORTC /
NCI / AACR Molecular Targets and Cancer Therapeutics Symposium in
Dublin, Ireland, on November 16. The presentation is titled
“EZH2 Inhibition as an Effective Treatment for Metastatic
Castration-Resistant Prostate Cancer.” The presentation
discusses preclinical evidence showing the effectiveness of the
EZH2 inhibitor CPI-1205 in treating metastatic castration-resistant
prostate cancer (mCRPC) dependent on androgen receptor signaling
(ARS). CPI-1205 was shown to combine synergistically with ARS
inhibitors, such as enzalutamide or abiraterone acetate, to inhibit
the growth of prostate cancer cell models and also was effective in
overcoming mechanisms of resistance to ARS inhibitors. The
poster also includes transcriptomic analysis, including single-cell
RNA sequencing, highlighting the mechanisms by which CPI-1205 and
its combination with ARS inhibitors restrict prostate cancer
growth. The data shown in the poster supports the potential
of EZH2 inhibition as a therapeutic approach for the mCRPC patient
population and contributes to the rationale for Constellation’s
ProSTAR trial of the EZH2 inhibitor CPI-1205 used in combination
with ARS inhibitors.
About EZH2 Inhibition in Prostate Cancer
EZH2 is an enzyme that acts as an epigenetic writer and normally
regulates gene expression by placing one or more methyl groups on a
histone protein, leading to the suppression of gene expression
programs. While this effect of EZH2 on gene expression is a
normal part of cellular development, some cancers depend on an
abnormal pattern of gene expression and re-direct EZH2 to genes
that become abnormally repressed. Cancer cells with these
abnormal gene expression programs may be more resistant to
anti-cancer therapies.
There is a strong association between EZH2 expression and
disease progression in metastatic castration-resistant prostate
cancer (mCRPC), and a therapeutic approach that targets EZH2 may
result in better outcomes than those achieved with approved
therapeutic agents that treat mCRPC. In prostate cancer, the
androgen receptor is a key regulator of gene expression and acts as
the mediator of androgen signaling in prostate cells. The AR
signaling pathway is the primary pathway used by prostate cancer
cells to promote tumor growth. We believe that EZH2, by
suppressing certain gene sets, enhances AR signaling, which can
lead to increased tumor growth. In preclinical studies, we
observed enhanced gene expression changes in prostate cancer cells
treated with a combination of enzalutamide and CPI-1205 as compared
to enzalutamide treatment alone. This corroborates our
hypothesis that EZH2 functionally cooperates with androgen receptor
signaling to promote prostate cancer growth.
We also believe that EZH2 is utilized by prostate cancer cells
to establish resistance to ARS inhibitors. We have observed
in preclinical studies that EZH2 inhibitors, such as CPI-1205, in
combination with ARS inhibitors synergistically killed tumor cells
and demonstrated activity in models that are resistant to ARS
inhibitors.
About CPI-1205
CPI-1205 is a small molecule designed to promote anti-tumor
activity by specifically inhibiting EZH2, an enzyme that suppresses
target gene expression. In preclinical studies, we observed
that CPI-1205 inhibited tumor growth as a single agent and
synergistically enhanced the efficacy of cancer therapies,
including ARS inhibitors in a prostate cancer model and immune
checkpoint inhibitors in other solid tumor models. Based on
these observations and the limited options for patients who
progress on ARS inhibitors or immune checkpoint inhibitors, we have
prioritized clinical development of CPI-1205 as a combination
therapy with ARS inhibitors in prostate cancer and immune
checkpoint inhibitors in solid tumors. We are currently
conducting the ProSTAR trial. We previously completed a Phase
1 clinical trial of CPI-1205 as a monotherapy in patients with
relapsed B-cell lymphoma in which CPI-1205 demonstrated clinical
activity and was well tolerated.
About the ProSTAR Clinical Trial
ProSTAR is an open-label Phase 1b/2 clinical trial of CPI-1205
for the treatment of metastatic castration-resistant prostate
cancer (mCRPC) in combination with enzalutamide or abiraterone
acetate, which are second-generation ARS inhibitors, in patients
with mCRPC who previously progressed on treatment with either
abiraterone acetate or enzalutamide. Patients who have previously
progressed on treatment with abiraterone acetate are treated with a
combination of enzalutamide and CPI-1205, and patients
who previously progressed on treatment with enzalutamide are
treated with a combination of abiraterone acetate
and CPI-1205. In the Phase 1b portion of this trial, we
aim to establish safety, pharmacokinetics, pharmacodynamics,
maximum tolerated dose, and a recommended Phase 2 dose
of CPI-1205 with these agents. Based on results
from the Phase 1b trial, we expect to select either abiraterone
acetate or enzalutamide to be combined with the optimal dose
regimen of CPI-1205 for the Phase 2 portion of the trial.
In the Phase 2 trial, we will assess response rate as the
primary endpoint, defined as the proportion of patients who have
any of (i) a prostate-specific-antigen reduction of 50% or more
from baseline, (ii) a decline of 30% or more in
circulating-tumor-cell count from baseline or (iii) for patients
with measurable soft tissue disease, an objective response, defined
as a complete response or partial response per RECIST 1.1
criteria.
About Constellation Pharmaceuticals
Constellation Pharmaceuticals is a clinical-stage
biopharmaceutical company developing novel therapeutics that
selectively modulate gene expression to address serious unmet
medical needs in patients with cancer. The Company has a deep
understanding of how epigenetic and chromatin modifications in
cancer cells and in the tumor and immune microenvironment play a
fundamental role in driving disease progression and drug
resistance. Constellation is driving development of the EZH2
inhibitors CPI-1205 and CPI-0209 for the treatment of metastatic
castration-resistant prostate cancer and other cancers as well as
the BET inhibitor CPI-0610 for the treatment of
myelofibrosis. The Company is also applying its broad
research and development capabilities to explore other novel
targets that directly and indirectly impact gene expression to fuel
a sustainable pipeline of innovative small-molecule product
candidates.
Forward-Looking Statements
This press release contains “forward-looking statements” within
the meaning of the Private Securities Litigation Reform Act of 1995
that involve substantial risks and uncertainties, including
statements regarding the anticipated presentation of preclinical
data, and its potential implications in the treatment of
diseases. All statements, other than statements of historical
facts, contained in this press release, including statements
regarding the Company’s strategy, future operations, future
financial position, prospects, plans and objectives of management,
are forward-looking statements. The words “anticipate,” “believe,”
“continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,”
“potential,” “predict,” “project,” “should,” “target,” “will,”
“would” and similar expressions are intended to identify
forward-looking statements, although not all forward-looking
statements contain these identifying words. Any forward-looking
statements are based on management’s current expectations of future
events and are subject to a number of risks and uncertainties that
could cause actual results to differ materially and adversely from
those set forth in, or implied by, such forward-looking statements.
These risks and uncertainties include, but are not limited to,
risks associated with Constellation’s ability to: obtain and
maintain necessary approvals from the FDA and other regulatory
authorities; continue to advance its product candidates in clinical
trials; replicate in later clinical trials positive results found
in preclinical studies and early-stage clinical trials of CPI-1205,
CPI-0610 and its other product candidates; advance the development
of its product candidates under the timelines it anticipates, or at
all, in current and future clinical trials; obtain, maintain or
protect intellectual property rights related to its product
candidates; manage expenses; and raise the substantial additional
capital needed to achieve its business objectives. For a discussion
of other risks and uncertainties, any of which could cause the
Company’s actual results to differ from those contained in the
forward-looking statements, see the “Risk Factors” section, as well
as discussions of potential risks, uncertainties, and other
important factors, in the Company’s most recent filings with the
Securities and Exchange Commission. In addition, the forward-
looking statements included in this press release represent the
Company’s views as of the date hereof and should not be relied upon
as representing the Company’s views as of any date subsequent to
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. CPI-1205, CPI-0610, CPI-0209,
and other product candidates are investigational in nature and have
not yet been approved by the FDA or other regulatory
authorities.
Contact Ronald Aldridge Investor
RelationsConstellation Pharmaceuticals+1
617-714-0539ron.aldridge@constellationpharma.com
Lauren ArnoldMedia RelationsMacDougall Biomedical
Communications+1 781-235-3060larnold@macbiocom.com
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