Amgen (NASDAQ:AMGN) and Cytokinetics, Inc. (NASDAQ:CYTK) today
announced The Lancet published results from a Phase 2 clinical
trial evaluating omecamtiv mecarbil in patients with chronic heart
failure. The COSMIC-HF (Chronic Oral Study of Myosin Activation to
Increase Contractility in Heart Failure) trial met its primary
pharmacokinetic objective and showed statistically significant
improvements in all pre-specified secondary measures of cardiac
function in the treatment group receiving pharmacokinetic-based
dose titration. The results were initially presented as a
Late-Breaking Clinical Trial at the American Heart Association
(AHA) Scientific Sessions 2015.1
“Data from COSMIC-HF underscore the potential of
omecamtiv mecarbil for the treatment of chronic heart failure, a
disease that remains a growing healthcare problem worldwide,” 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
findings from COSMIC-HF support the therapeutic hypothesis that
directly improving cardiac systolic function with a cardiac myosin
activator may reverse abnormal structural changes and neurohormonal
activation associated with the progression of heart failure.”
The trial, which evaluated 448 patients with
chronic heart failure and left ventricular systolic dysfunction,
showed that dose titration controlled patient exposure to omecamtiv
mecarbil. Patients were randomized 1:1:1 to receive either placebo
or treatment with omecamtiv mecarbil dosed as 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 pharmacokinetic-based dose titration
strategy was designed to maintain patient exposure to omecamtiv
mecarbil in the targeted plasma concentration range. Approximately
53 percent of patients in the dose titration group were escalated
to a dose of 50 mg twice daily.
Following 20 weeks of treatment, statistically
significant improvements were observed in all 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<0.0001), stroke volume increased by
3.6 mL (p=0.0217) and heart rate decreased by 3.0 beats per min
(p=0.0070). Left ventricular end-systolic and end-diastolic
dimensions decreased by 1.8 mm (p=0.0027) and 1.3 mm (p=0.0128),
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=0.0069). In pre-specified exploratory
analyses of the dose titration group, placebo-corrected reductions
in NT-proBNP persisted four weeks after stopping omecamtiv
mecarbil, decreasing further to 1306 pg/mL (p=0.0006). The data
also showed increases in fractional shortening at week 20 compared
to placebo in the dose titration group.
“The mechanism of action for omecamtiv mecarbil
is novel and these data reinforce its potential as a new therapy
for the millions of patients living with heart failure around the
world,” said Sean E. Harper, M.D., executive vice president of
Research and Development at Amgen. “In collaboration with our
partners Cytokinetics and Servier, we look forward to initiating
our Phase 3 clinical trial program for omecamtiv mecarbil where we
will learn if the improvements in cardiac function observed in the
COSMIC-HF study translate into improved cardiovascular outcomes for
patients.”
“Results from COSMIC-HF provide further
validation for the pharmacodynamic effects of omecamtiv mecarbil
and show its potential to reverse ventricular enlargement in
patients living with chronic heart failure,” said Robert I. Blum,
President and CEO at Cytokinetics. “We look forward to advancing
omecamtiv mecarbil into its Phase 3 program designed to investigate
correlations between cardiac function and clinical
outcomes.”
Adverse events (AEs), including serious AEs, in
patients on omecamtiv mecarbil were comparable to placebo. The
incidence of adjudicated deaths (3 percent died on placebo, 1
percent died on omecamtiv mecarbil 25 mg twice daily, 2 percent
died on omecamtiv mecarbil dose titration), myocardial infarction
(1 percent on placebo, 0 percent on omecamtiv mecarbil 25 mg twice
daily, 1 percent on omecamtiv mecarbil dose titration) and unstable
angina (0 percent on placebo, 1 percent on omecamtiv mecarbil 25 mg
twice daily, 0 percent on omecamtiv mecarbil dose titration) was
similar. Other cardiac AEs were generally balanced between placebo
and active treatment groups. In patients receiving omecamtiv
mecarbil 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 adjudicated as an
episode of myocardial ischemia or infarction.
About Heart FailureHeart
failure is a grievous condition that affects more than 23 million
people worldwide,2,3 about half of whom have reduced left
ventricular function.4,5 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 DesignCOSMIC-HF
(Chronic Oral Study of Myosin Activation to Increase Contractility
in Heart Failure) was 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 oral modified-release
formulations of omecamtiv mecarbil 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 pharmacokinetic-based
dose titration strategy was designed to maintain patient exposure
to omecamtiv mecarbil in a targeted plasma concentration range;
approximately 53 percent of patients in the dose titration group
were escalated to a dose of 50 mg twice daily.
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 NT-proBNP (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.11-13
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. Servier has exercised an exclusive option
granted by Amgen for the commercialization of omecamtiv mecarbil in
Europe, as well as the Commonwealth of Independent States,
including Russia.
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.14 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 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 troponin
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, subject to an option held by Astellas
Pharma Inc. Cytokinetics is also collaborating with Astellas to
develop CK-2127107, a fast skeletal muscle activator, for the
potential treatment of spinal muscular atrophy, chronic obstructive
pulmonary disease and ALS. Cytokinetics is collaborating with Amgen
Inc. to develop omecamtiv mecarbil, a novel cardiac muscle
activator, for the potential treatment of heart failure. 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 http://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
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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;
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References
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Activation to Increase Contractility in Heart Failure (COSMIC-HF):
Results from a Double-blind, Randomized, Placebo-controlled,
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- Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile
of heart failure. Nat Rev Cardiol. 2011;8(1):30-41.
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epidemiology of heart failure: public and private health
burden. Eur Heart J. 1998;19 (Suppl
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for the Management of Heart failure: A Report of the American
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ESC guidelines for the diagnosis and treatment of acute and chronic
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the Heart Failure Association (HFA) of the ESC. Eur
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http://www.cdc.gov/nchs/data/nhsr/nhsr005.pdf. Accessed September
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Patients in the Medicare Fee-for-Service Program. NEJM.
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- 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.
- 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
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JAMA. 2004;292:344-350.
- Malik FI, Hartman JJ, Elias KA, et al. Cardiac myosin
activation: a potential therapeutic approach for systolic heart
failure. Science. 2011;331(6023):1439-1443.
- 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.
- Malik FI, Morgan BP. Cardiac myosin activation part 1: From
concept to clinic. J Mol Cell Cardiol. 2011;51:454-461.
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Accessed September 2016.
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