Identification of Phosphodiesterease 3A Polymorphism With Potential to Increase Effectiveness of PDE3 Inhibitors Published in...
March 18 2019 - 8:30AM
ARCA biopharma, Inc. (Nasdaq: ABIO), a biopharmaceutical company
applying a precision medicine approach to developing
genetically-targeted therapies for cardiovascular diseases, today
announced that the paper “PDE3A Promoter Polymorphism Regulates
cAMP-Induced Transcriptional Activity in Failing Human Left
Ventricles” was recently published in the Journal of the American
College of Cardiology (JACC)
(http://www.onlinejacc.org/content/73/10/1173).
The lead author on the paper is University of
Colorado molecular biologist Carmen Sucharov, PhD and the senior
author is Michael R. Bristow MD, PhD, ARCA’s Chief Executive
Officer, who is also the Director of the University of Colorado
Cardiovascular Institute (CU CVI) Section of Pharmacogenomics. The
work was sponsored by a Leducq Foundation Transatlantic Networks of
Excellence grant awarded to Dr. Bristow and to Matthew Movsesian,
MD of the University of Utah, who is also an author on the
paper.
The paper describes the discovery and
characterization of a polymorphism in the promoter region of the
phosphodiesterase 3A (PDE3A) gene, which encodes the target of Type
3 phosphodiesterase inhibitors (PDE3Is). Members of this drug class
(milrinone, enoximone) are used intravenously to treat acutely
decompensated heart failure, to provide short-term circulatory
support in other settings, and in selected patients as a bridge to
cardiac transplantation. These agents uniformly have favorable
short-term hemodynamic effects, but when oral forms were used long
term to treat advanced chronic heart failure there was either a
safety concern or a lack of effectiveness. The JACC paper
investigators identified a high frequency polymorphism in the PDE3A
gene that may explain the heterogeneity of patient response to
PDE3Is.
The 29 nucleotide (nt) insertion/deletion
(indel) polymorphism is 2214 nts upstream from the PDE3A1
translation start site that regulates transcriptional activity in
response to cyclic adenosine monophosphate (cAMP) levels, with the
insertion (INS) allele having a frequency of 0.41. When a cAMP
analogue or a PDE3I was administered to cultured cardiac myocytes
transfected with promoter-reporter constructs containing one of the
alleles, PDE3A transcription increased with the deletion (DEL)
variant. In contrast, the INS form of the polymorphism acted as a
repressor, and a pharmacologic increase in cAMP did not result in
increased gene transcription. The investigators then measured PDE3
activity and PDE3A1 mRNA abundance in failing explanted left
ventricle tissue samples from patients who had or hadn’t been
treated with milrinone or enoximone prior to cardiac
transplantation, and found that enzyme activity and mRNA abundance
were higher in DEL compared to INS homozygotes who had been treated
with PDE3Is. This indicated that the favorable hemodynamic effects
of restoring cAMP levels towards normal were blunted in DEL
genotype patients by up-regulation in PDE3A enzyme activity and
subsequent increased hydrolysis of cAMP, through a functionally
negative feedback loop.
In an accompanying editorial, Dr. Arthur M.
Feldman of Lewis Katz School of Medicine at Temple University
remarked, "The approach that Sucharov et al. used to interrogate
the biology of the PDE3A genetic variant, including expression
screening, DNA sequencing, and microsomal fractions from failing
human heart, is novel. This in vitro approach may prove useful for
evaluating what will undoubtedly be an increasing number of genetic
variants as studies such as the National Institutes of
Health–sponsored “All of Us,” which plans to genotype 1 million
Americans, gain traction."
Dr. Bristow commented: “One of the first
molecular defects identified in failing human hearts was a decrease
in myocardial cAMP levels, which should be restorable towards
normal with PDE3Is. However, when PDE3Is were administered in
higher doses there was either loss of initial effectiveness and
subsequent progression of heart failure, or an increase in
mortality. Subsequent lower dose long term treatment approaches
were safe but lacked effectiveness. The data in the JACC
publication suggest that loss of effectiveness with PDE3Is may have
a pharmacogenetic basis and could be avoided in INS genotypes. This
hypothesis can be readily tested in a small hemodynamic and
exercise tolerance trial with genotyping for this
polymorphism.”
ARCA biopharma has licensed from the University
of Colorado the intellectual property around the use of the PDE3A
indel for guiding PDE3I therapy and a U.S. patent has been
issued.
About ARCA biopharma
ARCA biopharma is dedicated to developing
genetically-targeted therapies for cardiovascular diseases through
a precision medicine approach to drug development. ARCA’s platform
approach is to identify functionally important genetic variation in
drug targets using human cardiovascular tissues or cells, and then
screen for and identify compounds whose action is uniquely enhanced
in a particular variant. ARCA’s lead product candidate,
Gencaro™ (bucindolol hydrochloride), is an investigational,
pharmacologically unique beta-blocker and mild vasodilator being
developed for the potential treatment of atrial fibrillation in
heart failure patients with mid-range ejection fraction. ARCA has
identified common genetic variations that it believes predict
individual patient response to Gencaro, giving it the potential to
be the first genetically-targeted AF prevention treatment.
The Gencaro development program has been granted Fast Track
designation by FDA. ARCA is also developing AB171, a
thiol-substituted isosorbide mononitrate, as a potential
genetically-targeted treatment for heart failure and peripheral
arterial disease (PAD). For more information, please visit
www.arcabio.com.
Safe Harbor Statement
This press release contains "forward-looking
statements" for purposes of the safe harbor provided by the Private
Securities Litigation Reform Act of 1995. These statements include,
but are not limited to, statements regarding the ability of ARCA’s
financial resources to support its operations through the end of
the second quarter of 2019, potential future development plans for
Gencaro, the expected features and characteristics of Gencaro or
AB171, including the potential for genetic variations to predict
individual patient response to Gencaro, Gencaro’s potential to
treat AF, AB171’s potential to treat HF, future treatment options
for patients with AF, and the potential for Gencaro to be the first
genetically-targeted AF prevention treatment. Such statements are
based on management's current expectations and involve risks and
uncertainties. Actual results and performance could differ
materially from those projected in the forward-looking statements
as a result of many factors, including, without limitation, the
risks and uncertainties associated with: ARCA’s financial resources
and whether they will be sufficient to meet its business objectives
and operational requirements; ARCA may not be able to raise
sufficient capital on acceptable terms, or at all, to continue
development of Gencaro or to otherwise continue operations in the
future; results of earlier clinical trials may not be confirmed in
future trials; the protection and market exclusivity provided by
ARCA’s intellectual property; risks related to the drug discovery
and the regulatory approval process; and, the impact of competitive
products and technological changes. These and other factors
are identified and described in more detail in ARCA’s filings with
the Securities and Exchange Commission, including without
limitation ARCA’s annual report on Form 10-K for the year ended
December 31, 2018, and subsequent filings. ARCA disclaims any
intent or obligation to update these forward-looking
statements.
Investor & Media
Contact:Derek Cole720.940.2163derek.cole@arcabio.com
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