Cytokinetics, Incorporated (Nasdaq: CYTK) today announced positive
data relating to aficamten from REDWOOD-HCM OLE
(
Randomized
Evaluation of
Dosing
With CK-274 in
Obstructive
Outflow
Disease in
HCM
Open
Label
Extension) and the results from two additional
analyses of omecamtiv mecarbil from GALACTIC-HF
(
Global
Approach to
Lowering
Adverse
Cardiac Outcomes
Through
Improving
Contractility in
Heart
Failure), all presented in
Late-Breaking Science Sessions at Heart Failure 2022, an
International Congress of the European Society of Cardiology. The
analysis from GALACTIC-HF related to low blood pressure has been
simultaneously published in the European Heart Journal.
“This first analysis from REDWOOD-HCM OLE showed
that ongoing treatment with aficamten, now out to 6 months,
resulted in sustained and substantial reductions in LVOT gradients,
as well as improvements in functional class and symptoms. Overall
safety and tolerability remain favorable, and all
patients enrolled remain on aficamten. We look forward to
sharing additional longer-term data later this year,” said Fady I.
Malik, M.D., Ph.D., Cytokinetics’ Executive Vice President of
Research & Development. “In addition, the analysis of patients
from GALACTIC-HF with lower blood pressure, often very challenging
to treat, showed that the treatment effect of omecamtiv mecarbil
was greater than in the overall population, blood pressure was not
adversely affected, and safety was similar to placebo in these
patients. In another analysis, the treatment effect of omecamtiv
mecarbil was also comparable in patients with or without tricuspid
regurgitation. These findings add to the growing body of evidence
demonstrating that patients with clinical features suggestive of
high-risk heart failure respond favorably to omecamtiv
mecarbil.”
REDWOOD-HCM OLE: First Long-Term Data
from Open Label Extension
Ahmad Masri, M.D., Assistant Professor of
Medicine, Division of Cardiovascular Medicine, School of Medicine,
Oregon Health & Science University, presented the first
long-term data from REDWOOD-HCM OLE. Patients enrolled in
REDWOOD-HCM OLE have completed participation in REDWOOD-HCM, the
Phase 2 clinical trial of aficamten. The primary endpoint is the
incidence of adverse events and left ventricular ejection fraction
(LVEF) <50%. Secondary endpoints include measures of the
long-term effects of aficamten on left ventricular outflow tract
gradient (LVOT-G), and assessments of steady state
pharmacokinetics. The trial also includes a cardiac magnetic
resonance imaging sub-study to assess changes in cardiac
morphology, function and fibrosis. All enrolled patients receive
aficamten. After entry into REDWOOD-HCM OLE, each patient started
at 5 mg once daily and underwent echocardiography-guided dose
titration approximately every two weeks during the first six weeks
and subsequently will continue to have study visits approximately
every twelve weeks thereafter.
Data from 38 patients enrolled in REDWOOD-HCM
OLE were presented today, including 30 patients treated for 12
weeks and 19 patients treated for 24 weeks. The data showed that
treatment with aficamten was associated with substantial reductions
in the average resting LVOT-G (mean change from baseline (SD) =
-32.6 (28) mmHg, p<0.0001 at 12 weeks, -32.8 (32.3) mmHg,
p=0.0003 at 24 weeks) and Valsalva LVOT-G (-42.7 (38.7) mmHg,
p<0.0001 at 12 weeks, -51.1 (35.3) mmHg, p<0.0001 at 24
weeks). These reductions started to occur within two weeks of
treatment, were sustained through 24 weeks of treatment, and were
achieved with only modest decreases in the average LVEF (-3.2 (4.2)
%, p=0.0038 at 24 weeks). Compared to baseline (47% Class II, 53%
Class III), New York Heart Association (NYHA) Functional Class was
improved in the majority of patients (p<0.0001 for improvement
by one or more NYHA class), and no patients had a worsening of NYHA
Class. At 12 weeks, 72% of patients improved by one class and 7%
improved by two classes; at 24 weeks 61% of patients improved by
one class and 17% improved by two classes. For patients reaching
Week 24, 56% were Class I and 39% were Class II. There were also
significant improvements in cardiac biomarkers including NTpro-BNP
(reduction of 70% from baseline, p<0.001) and cardiac troponin
(20% reduction, p=0.002). Treatment with aficamten was
well-tolerated with one temporary discontinuation due to LVEF
<50% and one temporary down-titration, neither related to drug.
Both patients remain on treatment with aficamten.
GALACTIC-HF: Patients with Low Blood
Pressure Treated with Omecamtiv Mecarbil
Have an Increased Treatment Effect
Marco Metra, M.D., Professor of Cardiology &
Director of the Institute of Cardiology, Department of Medical
& Surgical Specialties, Radiological Sciences & Public
Health, University & Civil Hospitals of Brescia, Italy
presented an analysis from GALACTIC-HF on the effect of treatment
with omecamtiv mecarbil in patients with HFrEF and low blood
pressure. Of 8,232 patients with available baseline data on blood
pressure, 1,473 patients (17.9%) had low systolic blood pressure
defined as ≤100 mmHg. All patients with low blood pressure had an
increased risk of cardiovascular death or heart failure events
compared to patients without low blood pressure. In patients with
low blood pressure, there was a greater treatment effect from
omecamtiv mecarbil on the primary composite endpoint of
cardiovascular death or first heart failure event than in patients
without low blood pressure such that there was an absolute risk
reduction of 9.8 events per 100 patient-years (hazard ratio, 0.81;
95% confidence interval [CI] 0.70, 0.94; interaction p=0.051).
Patients with low blood pressure treated with omecamtiv mecarbil
also experienced improvements in blood pressure over time as did
those treated with placebo. Additionally, the incidence of
treatment-emergent serious adverse events in patients with low
blood pressure who received omecamtiv mecarbil (RR 0.88; 95% CI
0.82, 0.95; p<0.001) and adjudicated first stroke (RR 0.31; 95%
CI 0.12, 0.79; p=0.009) was lower compared to placebo. Other
measures of safety and tolerability were also similar between
patients with low blood pressure and those without low blood
pressure.
GALACTIC-HF: Treatment Effect of
Omecamtiv Mecarbil on Primary Outcome
Consistent in Patients with or without Tricuspid
Regurgitation
Marianna Adamo, M.D., Interventional
Cardiologist, University of Brescia, Italy presented an analysis
from GALACTIC-HF on the impact of tricuspid regurgitation (TR) on
the effectiveness of omecamtiv mecarbil. Of 8,256 patients in
GALACTIC, 8,180 patients had data reported on TR, of which 6,476
(79%) had no TR, 919 (11%) had mild TR, and 785 (10%) had
moderate/severe TR. Compared to patients with no TR, patients with
moderate/severe TR were older (p=0.003), more often enrolled in an
inpatient setting (p<0.001), had higher incidence of atrial
fibrillation or flutter (p<0.001), were a worse NYHA functional
class (p<0.001), had higher heart rate (p<0.001), and had
worse cardiac biomarker levels including higher NT-proBNP and
higher cardiac troponin (p<0.001 for both). Baseline
moderate/severe TR was also associated with lower KCCQ Total
Symptom Scores, an indicator of lower quality of life. Patients
with moderate/severe TR in GALACTIC-HF experienced higher rates of
the primary composite endpoint, cardiovascular death, all-cause
death and heart failure events. The impact of moderate/severe TR on
heart failure events was more pronounced in outpatients and in
patients with higher LVEF, lower NT-proBNP and lower eGFR. The
treatment effect of omecamtiv mecarbil on the primary outcome was
consistent across patients with no TR, mild TR and moderate/severe
TR such that baseline TR did not modify the treatment effect
(interaction p=0.91).
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. 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 long-term
effects on cardiac structure and function. 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
symptoms including chest pain, dizziness, shortness of breath, or
fainting during physical activity. A subset of patients with HCM
are at high risk of progressive disease which can lead to atrial
fibrillation, stroke and death due to arrhythmias. There are no FDA
approved medical treatments that directly address the
hypercontractility that underlies HCM.
About Omecamtiv
Mecarbil
Omecamtiv mecarbil is an investigational,
selective, small molecule cardiac myosin activator, the first of a
novel class of myotropes1 designed to directly target the
contractile mechanisms of the heart, binding to and recruiting more
cardiac myosin heads to interact with actin during systole.
Omecamtiv mecarbil is designed to increase the number of active
actin-myosin cross bridges during each cardiac cycle and
consequently augment the impaired contractility that is associated
with heart failure with reduced ejection fraction (HFrEF).
Preclinical research has shown that omecamtiv mecarbil increases
cardiac contractility without increasing intracellular myocyte
calcium concentrations or myocardial oxygen consumption.2-4
The development program for omecamtiv mecarbil
is assessing its potential for the treatment of HFrEF. Positive
results from GALACTIC-HF, the first Phase 3 clinical trial of
omecamtiv mecarbil demonstrated a statistically significant effect
of treatment with omecamtiv mecarbil to reduce risk of the primary
composite endpoint of cardiovascular (CV) death or heart failure
events (heart failure hospitalization and other urgent treatment
for heart failure) compared to placebo in patients treated with
standard of care. No reduction in the secondary endpoint of time to
CV death was observed. Adverse events and treatment discontinuation
of study drug were balanced between treatment arms.
About Heart Failure
Heart failure is a grievous condition that
affects more than 64 million people worldwide5 about half of whom
have reduced left ventricular function.6,7 It is the leading
cause of hospitalization and readmission in people age 65 and
older.8,9 Despite broad use of standard treatments and advances in
care, the prognosis for patients with heart failure is poor.10 An
estimated one in five people over the age of 40 are at risk of
developing heart failure, and approximately 50 percent of people
diagnosed with heart failure will die within five years of initial
hospitalization.11,12 More than 2 million people in the U.S. are
estimated to have an ejection fraction <30%, indicating they may
have severe heart failure.13
About Cytokinetics
Cytokinetics is a late-stage 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 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 muscle function and contractility. Cytokinetics is
readying for the potential commercialization of omecamtiv mecarbil,
its cardiac muscle activator, following positive results from
GALACTIC-HF, a large, international Phase 3 clinical trial in
patients with heart failure. Cytokinetics is also developing
aficamten, a next-generation cardiac myosin inhibitor, currently
the subject of SEQUOIA-HCM, the Phase 3 clinical trial of aficamten
in patients with symptomatic obstructive hypertrophic
cardiomyopathy (HCM). Aficamten is also being evaluated in
non-obstructive HCM in Cohort 4 of the Phase 2 clinical trial,
REDWOOD-HCM. Cytokinetics is also developing reldesemtiv, an
investigational fast skeletal muscle troponin activator, currently
the subject of COURAGE-ALS, a Phase 3 clinical trial in patients
with amyotrophic lateral sclerosis (ALS). Cytokinetics continues
its over 20-year history of pioneering innovation in muscle biology
and related pharmacology focused to diseases of muscle dysfunction
and conditions of muscle weakness.
For additional information
about Cytokinetics, visit www.cytokinetics.com and follow
us on Twitter, 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 relating to any of our other clinical
trials, including statements relating to the potential benefits of
aficamten for patients with obstructive hypertrophic cardiomyopathy
and statements relating to the potential benefits of omecamtiv
mecarbil for patients with heart failure with reduced ejection
fraction. 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,
potential difficulties or delays in the development, testing,
regulatory approvals for trial commencement, progression or product
sale or manufacturing, or production of Cytokinetics' drug
candidates that could slow or prevent clinical development or
product approval; Cytokinetics' drug candidates may have adverse
side effects or inadequate therapeutic efficacy; the FDA or foreign
regulatory agencies may delay or limit Cytokinetics' ability to
conduct clinical trials; Cytokinetics may be unable to obtain or
maintain patent or trade secret protection for its intellectual
property; standards of care may change, rendering Cytokinetics'
drug candidates obsolete; and competitive products or alternative
therapies may be developed by others for the treatment of
indications Cytokinetics' drug candidates and potential drug
candidates may target. For further information regarding these and
other risks related to Cytokinetics' business, investors should
consult Cytokinetics' filings with the Securities and Exchange
Commission.
Contact:Cytokinetics Diane WeiserSenior Vice President,
Corporate Communications, Investor Relations(650) 624-3071
References:
- Psotka MA, Gottlieb SS, Francis GS et al. Cardiac Calcitropes,
Myotropes, and Mitotropes. JACC. 2019; 73:2345-53.
- Planelles-Herrero VJ, Hartman JJ, Robert-Paganin J. et al.
Mechanistic and structural basis for activation of cardiac myosin
force production by omecamtiv mecarbil. Nat Commun.
2017;8:190.
- Shen YT, Malik FI, Zhao X, et al. Improvement of cardiac
function by a cardiac myosin activator in conscious dogs with
systolic heart failure. Circ Heart Fail. 2010; 3: 522-27.
- Malik FI, Hartman JJ, Elias KA, Morgan BP, Rodriguez H, Brejc
K, Anderson RL, Sueoka SH, Lee KH, Finer JT, Sakowicz R. Cardiac
myosin activation: a potential therapeutic approach for systolic
heart failure. Science. 2011 Mar 18;331(6023):1439-43.
- James et al. GBD 2017 Disease and Injury Incidence and
Prevalence Collaborators. Lancet 2018; 392:
1789–858.
- Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline
for the Management of Heart failure: A Report of the American
College of Cardiology Foundation/American Heart Association Task
Force on Practice Guidelines. Circulation.
2013;128:e240-e327.
- Ponikowski P, Voors AA, Anker SD, et al. 2016
ESC guidelines for the diagnosis and treatment of acute and chronic
heart failure: The Task Force for the diagnosis and treatment of
acute and chronic heart failure of the European Society of
Cardiology (ESC). Developed with the special contribution of
the Heart Failure Association (HFA) of the ESC. Eur
Heart J. 2016;37:2129–2200.
- Roger VL. Epidemiology of Heart Failure. Circulation
Research. 2013;113:646-659, originally published August 29,
2013. Doi: 10.1161/CIRCRESAHA.113.300268.
- Kilgore M, Patel HK, Kielhorn A et al. Economic burden of
hospitalizations of Medicare beneficiaries with heart
failure. Risk Manag Healthc Policy. 2017; 10:
63-70.
- Jhund PS, MacIntyre K, Simpson CR, et al. Long-Term Trends in
First Hospitalization for Heart Failure and Subsequent Survival
Between 1986 and 2003. Circulation. 2009;119:515-523.
- Benjamin EJ, Virani SS, Callaway CW et al. Heart Disease and
Stroke Statistics—2018 Update: A Report From the American
Heart Association. Circulation. 2018;137:e67-e492.
- Roger VL, Weston SA, Redfield MM, et al. Trends in Heart
Failure Incidence and Survival in a Community-Based
Population. JAMA. 2004;292:344-350.
- Shannon M. Dunlay, Véronique L. Roger, Susan A. Weston,
Ruoxiang Jiang, and Margaret M. Redfield (Circ Heart Fail.
2012;5:720-726.); Olmsted County community cohort of HF patients
(1984 to 2009).
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