Dose Response of Beta-Blockers in Adrenergic Receptor Polymorphism Genotypes Paper Published in Circulation: Genomic and Prec...
March 06 2019 - 8:00AM
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 “Dose Response of Beta-Blockers in
Adrenergic Receptor Polymorphisms” was recently published
(https://www.ahajournals.org/doi/10.1161/CIRCGEN.117.002210) in
Circulation: Genomic and Precision Medicine, a journal of the
American Heart Association.
The lead author on the paper is Duke University
cardiologist Kishan S. Parikh and the senior author is Dr. Michael
R. Bristow, ARCA’s Chief Executive Officer, formerly Chairman of
the Substudies Committee in the National Heart, Lung, and Blood
Institute (NHLBI)-sponsored BEST (Beta-Blocker Evaluation of
Survival Trial) trial.
In heart failure (HF) with reduced ejection
fraction (HFrEF), two NHLBI sponsored clinical trials, BEST and
HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes
of Exercise TraiNing), have reported an effectiveness interaction
between the beta-1 adrenergic receptor (ADRB1) Arg389Gly
polymorphism and beta-blockers. In the HF-ACTION DNA
substudy, the Arg389 homozygous genotype (ADRB1 Arg389Arg) reported
interaction was a decrease in all-cause mortality (ACM) in patients
treated with high doses (>25 mg/day in carvedilol equivalents)
versus no/low (0-25 mg/day) doses of conventional, HFrEF approved
beta-blockers, primarily carvedilol and metoprolol (Fiuzat et al.
Eur J Heart Fail 2013;15:258-6). In contrast, in BEST,
bucindolol produced a reduction in ACM versus placebo in Arg389
homozygous advanced HFrEF patients treated mostly with high, target
doses of the experimental beta-blocker (Liggett SB et al. PNAS
2006;103:11288-93). In the current Parikh et al. Circulation:
Genomic and Precision Medicine paper, the authors used uniform
methodology and the same dose range definitions for beta-blockers
to investigate high (defined for bucindolol as >25 mg/day)
versus no/low beta-blocker dose-ADRB1 Arg389Gly polymorphism
interactions with major clinical end points in BEST and HF-ACTION,
to further investigate pharmacogenetic interactions of
beta-blockers.
The results indicated that compared to 389Gly
genotypes, ADRB1 Arg389Arg subjects in each trial had less ACM with
high- versus no/low-dose beta-blocker (BEST/bucindolol: hazard
ratio [HR]=0.40 (0.24,0.65), P=0.0002; HF-ACTION
beta-blockers: HR=0.45 (0.26,0.78) P = 0.005), compared to 389Gly
genotypes (Gly carriers, high vs. no/low dose in both trials
P>0.2). However, the basis for the more favorable effect
of high vs. no/low dose groups in the Arg389Arg genotype differed
between bucindolol and conventional beta-blockers. For conventional
beta-blockers, the HR difference was due to increased mortality in
the no/low dose group (HR vs. Gly carrier counterpart genotypes =
1.83 (1.13,2.97), P = 0.015) with no evidence of a favorable effect
in the high dose group (HR 0.84 (0.84,1,49), P = 0.55). In
HF-ACTION, the ACM event rate was 21% in no/low dose Arg389Arg
patients treated with conventional beta-blockers, compared to 10%
in the high dose group, and respectively 14% and 13% in the no/low
and high dose 389Gly carrier groups. In marked contrast, in the
BEST DNA substudy no/low bucindolol was not associated with an
increase in mortality in patients with an Arg389Arg genotype
compared to 389 Gly carriers (HR 1.06 (0.73,1.53), P = 0.77).
Rather, the advantage of bucindolol in high vs. no/low dose ADRB1
Arg389Arg patients was due to a pronounced differentiation of ACM
prevention in the high dose group (HR 0.54 (0.33,0.90), P = 0.018
compared to Gly389 carrier subjects). Therefore, compared to Gly389
genotypes, no/low doses of conventional HF beta-blockers were
associated with an 83% increase in ACM while high dose bucindolol
produced a 60% decrease in ACM with no increase in ACM at no/low
dose.
In the paper the authors concluded:
“Beta-blocker dose effects on all-cause mortality risk may be
observed for patients with HFrEF with an ADRB1 Arg389Arg genotype.
The observed decreased risk compared with the alternative 389Gly
carrier genotype may be because of a true reduction in event rates
at high/target doses (bucindolol in BEST) or an increase in event
rates with lower doses (other beta-blockers in HF-ACTION). These
data support guideline recommendations that in HFrEF, beta-blockers
should be used at the higher target doses used in all positive
phase 3 trials.”
Dr. Bristow commented, “We believe these data
provide further evidence that both beta-blocker dose and the ADRB1
Arg389Gly genotype are major determinants of the functionality of
the beta-1 adrenergic receptor target of beta-blockers in the
heart, and are important modulators of beta-blocker therapeutic
responses in HFrEF patients. Moreover, the data support the idea
that, depending on the beta-blocker and dose, ADRB1 Arg389Gly
genotype can influence response in different directions. The
observation that the ADRB1 Arg389Arg genotype may increase
mortality in HFrFF patients treated with low doses of conventional,
approved HF beta-blockers is potentially important, since
substantial numbers of HF patients receive only low doses of these
agents. We believe this finding needs to be evaluated in additional
studies.”
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 lead
product candidate, GencaroTM (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, potential future development plans for
Gencaro, the expected features and characteristics of Gencaro,
including the potential for genetic variations to predict
individual patient response to Gencaro, Gencaro’s potential to
treat atrial fibrillation (AF), 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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