Cytokinetics, Incorporated (Nasdaq: CYTK) today announced that
CEDAR-HCM (
Clinical
Evaluation of
Dosing with
Aficamten to
Reduce Obstruction in a Pediatric Population in
HCM), a clinical trial of aficamten in a pediatric
population with symptomatic obstructive hypertrophic cardiomyopathy
(HCM), is open to enrollment. Aficamten is a next-in-class cardiac
myosin inhibitor in development for the potential treatment of HCM.
“We are pleased to further expand the broad
development program for aficamten with the start of CEDAR-HCM, a
trial assessing the safety and efficacy of a cardiac myosin
inhibitor in a pediatric population,” said Fady I. Malik, M.D.,
Ph.D., Cytokinetics’ Executive Vice President of Research &
Development. “As a genetic disease, HCM often casts a shadow over
entire families, including adolescents and children where it is
associated with a high risk of heart failure and serious
arrhythmias. HCM can present similarly in adolescents and children
as it does in adults and may negatively impact overall quality of
life. By evaluating the efficacy and safety of aficamten in another
very important group of people, our aim is to provide all members
of families impacted by HCM with a potential new treatment
option.”
CEDAR-HCM: Clinical Trial
Design
CEDAR-HCM is a multi-center, randomized,
double-blind, placebo-controlled and open-label extension clinical
trial to evaluate the efficacy, pharmacokinetics (PK) and safety of
aficamten in a pediatric population with symptomatic obstructive
HCM. The primary endpoint is the change in Valsalva left
ventricular outflow tract gradient (LVOT-G) from baseline to Week
12. Secondary endpoints include the change from baseline to Week 12
in resting LVOT-G, New York Heart Association (NYHA) Functional
Class, pharmacokinetics and cardiac biomarkers including NT-proBNP
and hs-cTnI.
CEDAR-HCM is expected to enroll two cohorts,
beginning with an initial cohort of approximately 40 adolescent
patients aged 12 to 17. Adolescent patients enrolled in CEDAR-HCM
must have LVEF ≥ 60%, Valsalva LVOT-G ≥ 50 mmHg and NYHA Functional
Class ≥ II. Patients will be randomized on a 2:1 basis to receive
aficamten or placebo, and those receiving aficamten will begin with
5 mg dosed once daily. At weeks 2, 4 and 6 patients will receive an
echocardiogram to determine if they will be up-titrated to
escalating doses of 10, 15 or 20 mg. Dose escalation will occur
only if a patient has a Valsalva LVOT-G ≥ 30 mmHg and an LVEF ≥
55%. Safety, efficacy and PK data obtained from at least 20
adolescent patients who have completed 12 weeks of double-blind
treatment will support the decision to open enrollment in a second
cohort of approximately 8 to 10 younger patients (aged 6 to 11).
The protocol will be amended to include eligibility criteria and
dose selection for the younger pediatric cohort. After 12 weeks of
double-blind treatment, eligible patients will rollover into the
open label extension period of CEDAR-HCM. Additional information
can be found on www.clinicaltrials.gov.
About
Aficamten
Aficamten is an investigational selective, small
molecule cardiac myosin inhibitor discovered following an extensive
chemical optimization program that was conducted with careful
attention to therapeutic index and pharmacokinetic properties and
as may translate into next-in-class potential in clinical
development. Aficamten was designed to reduce the number of active
actin-myosin cross bridges during each cardiac cycle and
consequently suppress the myocardial hypercontractility that is
associated with hypertrophic cardiomyopathy (HCM). In preclinical
models, aficamten reduced myocardial contractility by binding
directly to cardiac myosin at a distinct and selective allosteric
binding site, thereby preventing myosin from entering a force
producing state.
About the Broad Phase 3 Clinical Trials
Program for Aficamten
The development program for aficamten is
assessing its potential as a treatment that improves exercise
capacity and relieves symptoms in patients with HCM as well as its
potential long-term effects on cardiac structure and function.
SEQUOIA-HCM (Safety,
Efficacy, and Quantitative
Understanding of Obstruction
Impact of Aficamten in
HCM), was the pivotal Phase 3 clinical trial in
patients with symptomatic obstructive hypertrophic cardiomyopathy
(HCM). The results from SEQUOIA-HCM show that treatment with
aficamten significantly improved exercise capacity compared to
placebo, increasing peak oxygen uptake (pVO2) measured by
cardiopulmonary exercise testing (CPET) by a least square mean
difference (95% CI) of 1.74 (1.04 - 2.44) mL/kg/min (p=0.000002).
The treatment effect with aficamten was consistent across all
prespecified subgroups reflective of patient baseline
characteristics and treatment strategies, including patients
receiving or not receiving background beta-blocker therapy.
Statistically significant (p<0.0001) and clinically meaningful
improvements were also observed in all 10 prespecified secondary
endpoints. Aficamten was well-tolerated with an adverse event
profile comparable to placebo. Treatment emergent serious adverse
events occurred in 8 (5.6%) and 13 (9.3%) patients on aficamten and
placebo, respectively. Core echocardiographic left ventricular
ejection fraction (LVEF) was observed to be <50% in 5 patients
(3.5%) on aficamten compared to 1 patient (0.7%) on placebo. There
were no instances of worsening heart failure or treatment
interruptions due to low LVEF.
Aficamten is also currently being evaluated in
MAPLE-HCM, a Phase 3 clinical trial of aficamten as monotherapy
compared to metoprolol as monotherapy in patients with obstructive
HCM, ACACIA-HCM, a Phase 3 clinical trial of aficamten in patients
with non-obstructive HCM, CEDAR-HCM, a clinical trial of aficamten
in a pediatric population with obstructive HCM, and FOREST-HCM, an
open label extension clinical study of aficamten in patients with
hypertrophic cardiomyopathy (HCM). Aficamten received Breakthrough
Therapy Designation for the treatment of symptomatic obstructive
HCM from the U.S. Food & Drug Administration (FDA) as well as
the National Medical Products Administration (NMPA) in China.
About Hypertrophic
Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is a disease
in which the heart muscle (myocardium) becomes abnormally thick
(hypertrophied). The thickening of cardiac muscle leads to the
inside of the left ventricle becoming smaller and stiffer, and thus
the ventricle becomes less able to relax and fill with blood. This
ultimately limits the heart’s pumping function, resulting in
reduced exercise capacity and symptoms including chest pain,
dizziness, shortness of breath, or fainting during physical
activity. HCM is the most common monogenic inherited cardiovascular
disorder, with approximately 280,000 patients diagnosed in the
U.S., however, there are an estimated 400,000-800,000 additional
patients who remain undiagnosed.1,2,3 Two-thirds of patients with
HCM have obstructive HCM (oHCM), where the thickening of the
cardiac muscle leads to left ventricular outflow tract (LVOT)
obstruction, while one-third have non-obstructive HCM (nHCM), where
blood flow isn’t impacted, but the heart muscle is still thickened.
People with HCM are at high risk of also developing cardiovascular
complications including atrial fibrillation, stroke and mitral
valve disease.4 People with HCM are at risk for potentially fatal
ventricular arrhythmias and it is one of the leading causes of
sudden cardiac death in younger people or athletes.5 A subset of
patients with HCM are at high risk of progressive disease leading
to dilated cardiomyopathy and heart failure necessitating cardiac
transplantation.
About Cytokinetics
Cytokinetics is a late-stage, specialty
cardiovascular biopharmaceutical company focused on discovering,
developing and commercializing first-in-class muscle activators and
next-in-class muscle inhibitors as potential treatments for
debilitating diseases in which cardiac muscle performance is
compromised. As a leader in muscle biology and the mechanics of
muscle performance, the company is developing small molecule drug
candidates specifically engineered to impact myocardial muscle
function and contractility. Cytokinetics is preparing for
regulatory submissions for aficamten, its next-in-class cardiac
myosin inhibitor, following positive results from SEQUOIA-HCM, the
pivotal Phase 3 clinical trial in obstructive hypertrophic
cardiomyopathy. Aficamten is also currently being evaluated in
MAPLE-HCM, a Phase 3 clinical trial of aficamten as monotherapy
compared to metoprolol as monotherapy in patients with obstructive
HCM, ACACIA-HCM, a Phase 3 clinical trial of aficamten in patients
with non-obstructive HCM, CEDAR-HCM, a clinical trial of aficamten
in a pediatric population with obstructive HCM, and FOREST-HCM, an
open label extension clinical study of aficamten in patients with
hypertrophic cardiomyopathy (HCM). Cytokinetics is also developing
omecamtiv mecarbil, a cardiac muscle activator, in patients with
heart failure. Additionally, Cytokinetics is developing CK-586, a
cardiac myosin inhibitor with a mechanism of action distinct from
aficamten for the potential treatment of HFpEF, and CK-136, a
cardiac troponin activator for the potential treatment HFrEF and
other types of heart failure, such as right ventricular failure
resulting from impaired cardiac contractility.
For additional information about Cytokinetics,
visit www.cytokinetics.com and follow us on X, LinkedIn, Facebook
and YouTube.
Forward-Looking Statements
This press release contains forward-looking
statements for purposes of the Private Securities Litigation Reform
Act of 1995 (the “Act”). Cytokinetics disclaims any
intent or obligation to update these forward-looking statements and
claims the protection of the Act’s Safe Harbor for forward-looking
statements. Examples of such statements include, but are not
limited to, statements express or implied relating to the
properties or potential benefits of aficamten or any of our other
drug candidates and our ability to fully enroll CEDAR-HCM. Such
statements are based on management’s current expectations, but
actual results may differ materially due to various risks and
uncertainties, including, but not limited to the risks related to
Cytokinetics’ business outlines in Cytokinetics’ filings with
the Securities and Exchange Commission. Forward-looking
statements are not guarantees of future performance, and
Cytokinetics’ actual results of operations, financial condition and
liquidity, and the development of the industry in which it
operates, may differ materially from the forward-looking statements
contained in this press release. Any forward-looking statements
that Cytokinetics makes in this press release speak only
as of the date of this press
release. Cytokinetics assumes no obligation to update its
forward-looking statements whether as a result of new information,
future events or otherwise, after the date of this press
release.
CYTOKINETICS® and the CYTOKINETICS and C-shaped logo are
registered trademarks of Cytokinetics in the U.S. and certain other
countries.
Contact:Cytokinetics Diane WeiserSenior Vice
President, Corporate Affairs(415) 290-7757
References:
- CVrg: Heart Failure 2020-2029, p 44; Maron et al. 2013 DOI:
10.1016/S0140-6736(12)60397-3; Maron et al 2018
10.1056/NEJMra1710575
- Symphony Health 2016-2021 Patient Claims Data DoF;
- Maron MS, Hellawell JL, Lucove JC, Farzaneh-Far R, Olivotto I.
Occurrence of Clinically Diagnosed Hypertrophic Cardiomyopathy in
the United States. Am J Cardiol. 2016; 15;117(10):1651-1654.
- Gersh, B.J., Maron, B.J., Bonow, R.O., Dearani, J.A., Fifer,
M.A., Link, M.S., et al. 2011 ACCF/AHA guidelines for the diagnosis
and treatment of hypertrophic cardiomyopathy. A report of the
American College of Cardiology Foundation/American Heart
Association Task Force on practice guidelines. Journal of the
American College of Cardiology and Circulation, 58, e212-260.
- Hong Y, Su WW, Li X. Risk factors of sudden cardiac death in
hypertrophic cardiomyopathy. Current Opinion in Cardiology. 2022
Jan 1;37(1):15-21
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