Amgen (NASDAQ:AMGN) and Cytokinetics Incorporated (NASDAQ:CYTK)
today announced the presentation of data from the expansion phase
of COSMIC-HF (Chronic Oral Study of Myosin Activation to Increase
Contractility in Heart Failure), a Phase 2 trial evaluating
omecamtiv mecarbil in patients with chronic heart failure, in a
Late-Breaking Clinical Trial session at the American Heart
Association (AHA) Scientific Sessions 2015 in Orlando, Fla. The
trial met its primary pharmacokinetic objective and demonstrated
statistically significant improvements in all pre-specified
secondary measures of cardiac function in the treatment group
employing pharmacokinetic-based dose titration. Omecamtiv mecarbil,
a novel investigational cardiac myosin activator, enhances cardiac
function by increasing cardiac contractility and is being developed
for the potential treatment of heart failure.1,2
The expansion phase of COSMIC-HF was designed to
evaluate the pharmacokinetics, pharmacodynamics, safety and
tolerability of oral omecamtiv mecarbil in 448 patients with
chronic heart failure and left ventricular systolic dysfunction.
Patients were randomized 1:1:1 to receive either placebo or
treatment with omecamtiv mecarbil 25 mg twice daily or a dose
titration group where 25 mg twice daily dosing could be increased
to 50 mg twice daily depending on plasma concentrations of
omecamtiv mecarbil after two weeks of treatment with the 25 mg
dose. Data from the expansion phase showed that dose titration
controlled patient exposure to omecamtiv mecarbil. Approximately 60
percent of patients in the dose titration group escalated dosing to
50 mg twice daily.
Following 20 weeks of treatment, statistically
significant improvements were observed in pre-specified secondary
endpoint measures of cardiac function in the dose titration group,
compared to placebo. Systolic ejection time increased by 25.0 msec
(p<0.001), stroke volume increased by 3.63 mL (p=0.022) and
heart rate decreased by 2.97 beats per min (p=0.007). Left
ventricular end-systolic and end-diastolic dimensions decreased by
1.79 mm (p=0.003) and 1.29 mm (p=0.013), respectively, and were
associated with statistically significant reductions in left
ventricular end-systolic and end-diastolic volumes. N-terminal
pro-brain natriuretic peptide (NT-proBNP) decreased by 970 pg/mL
(p=0.007). Additionally, in the 25 mg twice daily group, there were
statistically significant increases in systolic ejection time and
stroke volume and a decrease in NT-proBNP. All changes are from
baseline compared to placebo. The pharmacodynamic effects of
omecamtiv mecarbil were generally dose dependent and larger in
patients that received oral dosing with 50 mg twice daily.
Adverse events (AEs), including serious AEs, in
patients on omecamtiv mecarbil were comparable to placebo. The
incidence of adjudicated deaths (2.7 percent died on placebo, 1.4
percent died on omecamtiv mecarbil), myocardial infarction (1.34
percent on placebo, 0.34 percent on omecamtiv mecarbil) and
unstable angina (0 percent on placebo, 0.34 percent on omecamtiv
mecarbil) was similar. Other cardiac AEs were generally balanced
between placebo and active treatment groups. In the omecamtiv
mecarbil groups, compared to placebo, cardiac troponin increased by
0.001 ng/mL and 0.006 ng/mL (median change from baseline at week
20) in the 25 mg twice daily group and dose titration group,
respectively. Events of increased troponin (n=278 across all
treatment groups) were independently adjudicated and none were
determined to be myocardial ischemia or infarction.
“Heart failure remains a large and growing
problem for the global health care community. The results from
COSMIC-HF suggest chronic dosing of omecamtiv mecarbil may have a
favorable and meaningful impact on cardiac function and
remodeling,” said John Teerlink, M.D., professor of Clinical
Medicine at the University of California San Francisco and director
of Heart Failure at the San Francisco Veterans Affairs Medical
Center. “The magnitude of cardiac effects observed in this trial
are impressive and could potentially translate into improvements in
clinical outcomes.”
“The improvements observed in cardiac function
with omecamtiv mecarbil in the COSMIC-HF trial are promising,” said
Sean E. Harper, M.D., executive vice president of Research and
Development at Amgen. “Omecamtiv mecarbil is a unique
investigational therapy for heart failure patients, and we continue
to review the data with Cytokinetics and leading heart failure
experts to better understand the potential role of this novel
medicine.”
“Data from COSMIC-HF highlight the potential of
cardiac myosin activation for the treatment of heart failure
patients,” said Robert I. Blum, president and CEO at Cytokinetics.
“It’s particularly gratifying to see the consistency of effect with
chronic omecamtiv mecarbil therapy across important
echocardiographic measures of cardiac function.”
Heart failure is a common condition that affects
more than 23 million people worldwide,3,4 about half of whom have
reduced left ventricular function.5 It is the leading cause of
hospitalization and readmission in people age 65 and older.6,7
Despite broad use of standard treatments and advances in care, the
prognosis for patients with heart failure is poor.8 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.9,10
COSMIC-HF Trial Design
COSMIC-HF (Chronic Oral Study of Myosin Activation to Increase
Contractility in Heart Failure) is a double-blind, randomized,
placebo-controlled, multicenter, Phase 2 trial designed to evaluate
an oral formulation of omecamtiv mecarbil in chronic heart failure
patients with reduced ejection fraction. The trial consisted of two
parts, a dose escalation phase and a larger and longer expansion
phase. The dose escalation phase, which completed in 2013, assessed
the pharmacokinetics and tolerability of three oral
modified-release formulations of omecamtiv mecarbil and was used to
select one formulation for further evaluation in the expansion
phase. In the dose escalation phase, 96 patients were randomized
1:1:1:1 to placebo or one of three omecamtiv mecarbil oral
modified-release formulations in two cohorts (25 mg twice daily or
50 mg twice daily). Each patient cohort was followed for 35
days.
The expansion phase evaluated 448 chronic heart
failure patients with reduced ejection fraction who were dosed with
the selected oral formulation of omecamtiv mecarbil for 20 weeks
and followed for a total of 24 weeks. Patients were randomized
1:1:1 to receive either placebo or treatment with omecamtiv
mecarbil 25 mg twice daily or 25 mg with dose escalation to 50 mg
twice daily depending on plasma concentrations of omecamtiv
mecarbil after two weeks of treatment. The primary endpoints for
the expansion phase were to assess the maximum and pre-dose plasma
concentration of omecamtiv mecarbil. The secondary endpoints were
to assess changes from baseline in systolic ejection time, stroke
volume, left ventricular end-systolic diameter, left ventricular
end-diastolic diameter, heart rate and N-terminal pro-brain
natriuretic peptide (a biomarker associated with the severity of
heart failure) at week 20, as well as the safety and tolerability
of omecamtiv mecarbil including incidence of adverse events from
baseline to week 24.
COSMIC-HF was not designed to assess the impact
of omecamtiv mecarbil on cardiovascular outcomes in heart failure
patients.
COSMIC-HF was conducted by Amgen in
collaboration with Cytokinetics.
About Omecamtiv Mecarbil
Omecamtiv mecarbil is a novel cardiac myosin activator. Cardiac
myosin is the cytoskeletal motor protein in the cardiac muscle cell
that is directly responsible for converting chemical energy into
the mechanical force resulting in cardiac contraction. Cardiac
myosin activators are thought to accelerate the rate-limiting step
of the myosin enzymatic cycle and shift the enzymatic cycle in
favor of the force-producing state. Preclinical research has shown
that cardiac myosin activators increase contractility in the
absence of changes in intracellular calcium in cardiac
myocytes.1,2,11
Omecamtiv mecarbil is being developed by Amgen
in collaboration with Cytokinetics. Amgen holds an exclusive,
worldwide license to omecamtiv mecarbil and related compounds,
subject to Cytokinetics’ specified development and
commercialization rights. Additionally, Les Laboratoires Servier
obtained an exclusive option to commercialize omecamtiv mecarbil in
Europe.
About Amgen
CardiovascularBuilding on more than three decades of
experience in developing biotechnology medicines for patients with
serious illnesses, Amgen is dedicated to addressing important
scientific questions to advance care and improve the lives of
patients with cardiovascular disease, the leading cause of
morbidity and mortality worldwide.12 Amgen's research into
cardiovascular disease, and potential treatment options, is part of
a growing competency at Amgen that utilizes human genetics to
identify and validate certain drug targets. Through its own
research and development efforts, as well as partnerships, Amgen is
building a robust cardiovascular portfolio consisting of several
approved and investigational molecules in an effort to address a
number of today's important unmet patient needs, such as high
cholesterol and heart failure.
About AmgenAmgen is committed
to unlocking the potential of biology for patients suffering from
serious illnesses by discovering, developing, manufacturing and
delivering innovative human therapeutics. This approach begins by
using tools like advanced human genetics to unravel the
complexities of disease and understand the fundamentals of human
biology.
Amgen focuses on areas of high unmet medical
need and leverages its biologics manufacturing expertise to strive
for solutions that improve health outcomes and dramatically improve
people's lives. A biotechnology pioneer since 1980, Amgen has grown
to be one of the world's leading independent biotechnology
companies, has reached millions of patients around the world and is
developing a pipeline of medicines with breakaway potential.
For more information, visit www.amgen.com and
follow us on www.twitter.com/amgen.
About CytokineticsCytokinetics
is a late-stage biopharmaceutical company focused on discovering,
developing and commercializing first-in-class muscle activators as
potential treatments for debilitating diseases in which muscle
performance is compromised and/or declining. As a leader in muscle
biology and the mechanics of muscle performance, the company is
developing small molecule drug candidates specifically engineered
to increase muscle function and contractility. Cytokinetics’ lead
drug candidate is tirasemtiv, a fast skeletal muscle activator, for
the potential treatment of ALS. Tirasemtiv has been granted orphan
drug designation and fast track status by the U.S. Food and Drug
Administration and orphan medicinal product designation by the
European Medicines Agency for the potential treatment of ALS.
Cytokinetics retains the right to develop and commercialize
tirasemtiv. Cytokinetics is collaborating with Amgen Inc. to
develop omecamtiv mecarbil, a novel cardiac muscle activator, for
the potential treatment of heart failure. Cytokinetics is
collaborating with Astellas Pharma Inc. to develop CK-2127107, a
fast skeletal muscle activator, for the potential treatment of
spinal muscular atrophy. Amgen holds an exclusive license worldwide
to develop and commercialize omecamtiv mecarbil and Astellas holds
an exclusive license worldwide to develop and commercialize
CK-2127107. Both licenses are subject to Cytokinetics’ specified
development and commercialization participation rights. For
additional information about Cytokinetics, visit
www.cytokinetics.com.
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Cytokinetics Forward-Looking
StatementsThis 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
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research and development activities, including the significance and
utility of COSMIC-HF clinical trial results and the
potential progression of omecamtiv mecarbil to Phase 3 development;
and the properties and potential benefits of Cytokinetics' drug
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CONTACT: Amgen, Thousand Oaks Kristen Davis,
805-447-3008 (media) Kristen Neese, 805-313-8267 (media) Arvind
Sood, 805-447-1060 (investors)
CONTACT: Cytokinetics, South San FranciscoDiane
Weiser, 415-290-7757 (investors and media)
References
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- 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(4):522-527.
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of heart failure. Nat Rev Cardiol. 2011;8:30-41.
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First Hospitalization for Heart Failure and Subsequent Survival
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- Mozaffarian D, Benjamin EJ, Go AS, et al. Heart Disease and
Stroke Statistics—2015 Update: A Report From the American Heart
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- Rogers VL, Weston SA, Redfield MM, et al. Trends in Heart
Failure Incidence and Survival in a Community-Based Population.
JAMA. 2004;292:344-350.
- Malik FI, Morgan BP. Cardiac myosin activation part 1: From
concept to clinic. J Mol Cell Cardiol. 2011;51:454-461.
- World Health Organization. Cardiovascular diseases (CVDs) fact
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Accessed November 2015.
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