– PDE9 inhibitor, CRD-740, demonstrated favorable safety profile
and achieved statistical significance for the trial’s primary
endpoint, median increase in plasma cyclic guanosine monophosphate
(cGMP) –
– This clinical trial confirms that high levels of PDE9
inhibition lead to increases in cGMP, reflecting increased
activation of the myocardial natriuretic peptide (NP) signaling
pathway –
– Targeting PDE9 represents a novel approach to activating the
NP signaling pathway, a highly validated pathway with established
clinical benefits in heart failure –
– Clinical results presented today at the Annual Congress of the
Heart Failure Association of the European Society of Cardiology
–
Cardurion Pharmaceuticals, Inc. (“Cardurion”), a clinical-stage
biotechnology company developing next-generation therapeutics for
the treatment of cardiovascular diseases, today announced the
presentation of positive clinical data from CARDINAL‑HF, the first
Phase 2 proof-of-concept clinical trial of a phosphodiesterase-9
(PDE9) inhibitor in patients with heart failure. These data were
presented today at the Annual Congress of the Heart Failure
Association of the European Society of Cardiology taking place on
May 11-14 in Lisbon, Portugal.
In the CARDINAL-HF Phase 2a trial, CRD-740 met the primary
endpoint in patients with heart failure with reduced ejection
fraction (HFrEF), demonstrating a statistically significant median
increase in plasma cyclic guanosine monophosphate (cGMP) after four
weeks of treatment. Plasma cGMP is a biomarker for intracellular
cGMP whose levels reflect the activity of the protective myocardial
natriuretic peptide (NP) signaling pathway, which has proven
clinical benefits in heart failure. CRD-740 was generally well
tolerated in the trial.
“These very promising data from the first Phase 2
proof-of-concept clinical trial of a PDE9 inhibitor in patients
with heart failure represent an important next step in the
development of this novel mechanism,” said James Udelson, MD, Chief
of Cardiology at Tufts Medical Center and Principal Investigator
for the CARDINAL-HF trial. “The results of this trial are
impressive, showing robust PDE9 inhibition with significant
increases in plasma and urinary cGMP, along with a favorable safety
profile, both of which support moving into further clinical testing
in heart failure.”
“Therapeutic targeting of the NP signaling pathway is
precedented by today’s standard of care treatment for patients with
heart failure, and PDE9 inhibition represents a new mechanism for
activating this pathway to seek improved patient outcomes.
Significant unmet needs remain, as heart failure is a prevalent and
growing chronic condition that causes significant morbidity and
mortality for millions of people,” said Scott D. Solomon, MD,
Professor of Medicine at Harvard Medical School.
The oral presentation of these results, entitled, “A Phase 2,
Randomized, Double-Blind, Placebo-Controlled Study to Assess the
Tolerability and Pharmacodynamic Effects of CRD-740, a PDE9
Inhibitor, in Participants with Chronic Heart Failure,” were
presented today by James Udelson, M.D., Principal Investigator of
CARDINAL-HF and Chief of Cardiology at Tufts Medical Center, in the
“Late-Breaking Clinical Trials: Medical Therapy” session at the
Annual Congress of the Heart Failure Association of the European
Society of Cardiology. Key findings presented include:
- CRD-740 was generally well-tolerated in patients with HFrEF, a
disease representing approximately one-half of patients with
chronic heart failure.
- PDE9 inhibition with CRD-740 achieved statistically significant
median increases in plasma cGMP at four weeks, compared to placebo,
which was the primary endpoint in the trial. Statistically
significant median increases in urinary cGMP were also observed in
the patients who received CRD-740, compared to placebo.
- Increases in cGMP of the magnitude seen in the trial
demonstrate that CRD-740 achieves high levels of PDE9 inhibition,
which prevents cGMP metabolism by the PDE9 enzyme and leads to
increased activation of the NP signaling pathway. Activation of the
clinically validated NP signaling pathway has been shown to benefit
patients with chronic heart failure in outcome studies with
sacubitril/valsartan.
- These increases in plasma and urinary cGMP were observed in
patients who received CRD‑740 with and without background treatment
with sacubitril/valsartan, supporting the potential for CRD-740 as
a monotherapy, and as a new approach to augment efficacy in the
setting of sacubitril/valsartan therapy and to further activate the
NP signaling pathway.
Based on the results of the CARDINAL-HF Phase 2a trial,
Cardurion has launched two Phase 2 clinical trials in 640 patients,
including a dose-ranging trial in patients with HFrEF and a
proof-of-concept trial in patients with heart failure with
preserved ejection fraction (HFpEF).
“These findings from Cardurion’s pioneering program in PDE9
support our conviction that PDE9 inhibition presents an important
new mechanism for independently targeting and further activating
the well-validated NP signaling pathway. The data from this trial
suggest that PDE9 inhibition has the potential to provide benefit
to patients when administered alone or in combination with
guideline directed medical therapy, and ultimately become standard
of care for patients with both types of heart failure,” said Peter
Lawrence, Chief Executive Officer of Cardurion Pharmaceuticals.
“We are delighted to share these clinical results for CRD-740 as
our team advances PDE9 inhibition as a novel approach to addressing
the unmet needs of patients with chronic heart failure,” said
Howard Surks, MD, Chief Medical and Scientific Officer of Cardurion
Pharmaceuticals. “We thank our patients and investigators for their
partnership and look forward to continuing the development of our
PDE9 inhibitors to improve outcomes for patients.”
About the CARDINAL-HF clinical trial
CARDINAL-HF is the first Phase 2 proof-of-concept trial of a
PDE9 inhibitor for the treatment of patients with heart failure.
The Phase 2a clinical trial is a randomized, placebo-controlled
trial of 60 chronic, stable patients with heart failure with
reduced ejection fraction (HFrEF) who were receiving
guideline-directed medical therapy (GDMT). The primary endpoints of
the trial are safety and tolerability of CRD-740 and changes in
plasma cGMP at four weeks, a precedented biomarker for activation
of the NP signaling pathway. Other endpoints include changes in
urinary cGMP and N-terminal pro b-type natriuretic peptide
(NTpro-BNP) and effect of CRD-740 administration on the Kansas City
Cardiomyopathy questionnaire (KCCQ), which measures symptoms,
physical and social limitations, and quality of life in patients
with heart failure.
The Executive Committee for the CARDINAL-HF trial includes Dr.
James Udelson, Principal Investigator and Chief of Cardiology at
Tufts Medical Center; Dr. Scott Solomon, Professor of Medicine at
Harvard Medical School; and Dr. John McMurray, Professor of Medical
Cardiology and Deputy Director of the Institute of Cardiovascular
and Medical Sciences at the University of Glasgow. Drs. Udelson,
Solomon and McMurray, along with Dr. Eugene Braunwald, the
Distinguished Hersey Professor of Medicine at Harvard Medical
School, also lead Cardurion’s Clinical Advisory Board. The
CARDINAL-HF Steering Committee is further comprised of leading
international heart failure clinical investigators.
About PDE9 inhibition
PDE9 inhibitors target phosphodiesterase (PDE) 9, an enzyme
whose elevated activity in patients with heart failure reduces the
beneficial effects of the natriuretic peptide (NP) pathway,
fundamental to cardiovascular homeostasis. The beneficial effects
of the NP signaling pathway in the heart muscle cell are mediated
by cyclic guanosine monophosphate (cGMP) and activation of its
downstream signaling molecule protein kinase G1. PDE9 is an enzyme
that selectively degrades cGMP; therefore, by inhibiting PDE9, our
goal is to preserve cGMP generation and enhance the beneficial
natriuretic peptide signaling within heart muscle cells.
About Chronic Heart Failure
Heart failure is a prevalent and growing condition that is
responsible for substantial morbidity and mortality. Approximately
6.5 million people in the United States suffer from heart failure,
and 50 percent of these patients die from the condition within five
years of diagnosis. One in five patients with heart failure are
hospitalized annually, and 25% of these patients will be admitted
again within a month of discharge. Approximately half of all
patients with heart failure have reduced ejection fraction (HFrEF)
and half have preserved ejection fraction (HFpEF). Despite the
availability of drugs indicated to reduce morbidity and mortality
in patients with both types of heart failure, substantial unmet
medical need remains.
About Cardurion Pharmaceuticals
Cardurion Pharmaceuticals is a clinical-stage biotechnology
company focused on the discovery and development of novel,
next-generation therapeutics for the treatment of cardiovascular
diseases. Cardurion was founded by physician-scientists with
world-class expertise in cardiovascular signaling pathways, and a
shared passion to find and develop a pipeline of novel treatment
options to improve the lives of patients. Cardurion has two
groundbreaking clinical programs in development, a PDE9 inhibitor
targeting heart failure and the first ever CaMKII inhibitor in
clinical development targeting multiple cardiovascular
indications.
Cardurion Pharmaceuticals has facilities in Burlington,
Massachusetts and Shonan, Japan. For more information, please visit
the company’s website at https://cardurion.com.
View source
version on businesswire.com: https://www.businesswire.com/news/home/20240511287537/en/
Kathryn Morris The Yates Network kathryn@theyatesnetwork.com