Cytokinetics, Incorporated (Nasdaq: CYTK) today announced the
primary results from GALACTIC-HF (
Global
Approach to
Lowering
Adverse
Cardiac Outcomes
Through
Improving
Contractility in
Heart
Failure), the Phase 3 event-driven cardiovascular
outcomes clinical trial of omecamtiv mecarbil. The results were
presented by John Teerlink, M.D., Professor of Medicine, University
of California San Francisco, Director of Heart Failure, San
Francisco Veterans Affairs Medical Center and Executive Committee
Chair, GALACTIC-HF, in a Late Breaking Clinical Trial session at
the American Heart Association (AHA) Scientific Sessions 2020, and
were simultaneously published in the New England Journal of
Medicine.1
GALACTIC-HF, one of the largest Phase 3 global
cardiovascular outcomes trials in heart failure ever conducted,
enrolled 8,256 patients who were at risk of hospitalization and
death, despite being well treated on standard of care therapy.
After a median duration of follow-up of 21.8 months, the trial
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. A
first primary endpoint event occurred in 1,523 of 4,120 patients
(37.0%) in the omecamtiv mecarbil group and in 1,607 of 4,112
patients (39.1%) in the placebo group (hazard ratio, 0.92; 95%
confidence interval [CI] 0.86, 0.99; p=0.025). This effect was
observed without evidence of an increase in the overall rates of
myocardial ischemic events, ventricular arrhythmias or death from
cardiovascular or all causes.
The statistically significant reduction in the
composite of heart failure events or cardiovascular deaths, without
significant imbalances in the overall incidence of adverse events
across treatment arms, was observed in one of the broadest and most
diverse range of patients enrolled in a contemporary heart failure
trial. GALACTIC-HF included both inpatients and outpatients, and
with a high representation of participants with moderate to severe
heart failure symptoms as well as lower ejection fraction, systolic
blood pressure and renal function.
No reduction in the secondary endpoint of time
to CV death was observed. Death from cardiovascular causes occurred
in 808 (19.6%) patients treated with omecamtiv mecarbil and 798
patients (19.4%) assigned to placebo (hazard ratio, 1.01; 95% CI,
0.92 to 1.11; p=0.86). The pre-specified analysis of change from
baseline to week 24 in the KCCQ total symptom score by
randomization setting (inpatient mean difference [95% CI]: 2.50
[0.54, 4.46], outpatient mean difference: -0.46 [-1.40, 0.48],
joint P = 0.028) did not meet the significance threshold of P=0.002
based upon the multiplicity control testing procedure. No other
secondary endpoints were met in accordance with the prespecified
statistical analysis.
The effect of omecamtiv mecarbil was consistent
across most prespecified subgroups and with a potentially greater
treatment effect suggested in patients with a lower left
ventricular ejection fraction (LVEF ≤28%, n=>4,000, hazard
ratio, 0.84; 95% CI 0.77, 0.92; interaction p=0.003). Omecamtiv
mecarbil also significantly decreased NT-proBNP concentrations by
10% (95% CI 6-14%) at Week 24 compared to placebo.
“Heart failure remains a growing clinical and
economic burden as our global population continues to age,” said
John Teerlink, M.D. “Results from GALACTIC-HF demonstrate that the
selective cardiac myosin activator omecamtiv mecarbil, which
previously had been shown to improve cardiac performance, can
meaningfully improve patient outcomes. The results also suggest
that heart failure patients from a large pre-specified subgroup
with more severely reduced systolic function may benefit more from
this novel investigational medicine, and is an observation aligned
with its primary pharmacologic effect to increase cardiac
function.”
“We are pleased that GALACTIC-HF, a landmark
clinical trial that enrolled one of the broadest range of both
inpatients and outpatients studied in contemporary heart failure
trials, demonstrated a positive effect on its overall primary
efficacy endpoint and that treatment with omecamtiv mecarbil may
especially benefit those with more reduced ejection fraction
without an imbalance in the overall incidence of adverse events,”
said Fady I. Malik, M.D., Ph.D., Cytokinetics’ Executive Vice
President of Research & Development. “We look forward to
continuing to discuss next steps in this program with Amgen to
inform a potential path forward.”
The overall safety profile of omecamtiv mecarbil
in GALACTIC-HF appears to be consistent with data from previous
trials. Adverse events and treatment discontinuation of study drug
were balanced between the treatment arms. In general, the overall
rates of myocardial ischemia, ventricular arrhythmias and death
were similar between treatment and placebo groups. Additionally,
there was no significant difference in the change in systolic blood
pressure between baseline and at 24 or 48 weeks between the
omecamtiv mecarbil and placebo groups. There was a small but
significant decrease in heart rate in participants assigned to
omecamtiv mecarbil compared to placebo at both timepoints. Median
cardiac troponin I concentration increased 4 ng/L (95% CI 3-5;
limit of detection, 6 ng/L) from baseline with omecamtiv mecarbil
compared to placebo.
Investor/Media Event
Cytokinetics will host an investor and media
event on November 13, 2020 at 1:00 PM ET that will be
simultaneously webcast and can be accessed at
https://wsw.com/webcast/cc/cytk/1388034 as well as from the
Investors & Media section of Cytokinetics’ website
at www.cytokinetics.com. An archived replay of the virtual
event will be available via Cytokinetics’ website
until November 13, 2021.
GALACTIC-HF: Trial Design
GALACTIC-HF,2 (Global Approach to Lowering
Adverse Cardiac Outcomes Through Improving Contractility in Heart
Failure), one of the largest Phase 3 global cardiovascular outcomes
studies in heart failure ever conducted, enrolled 8,256 patients in
35 countries across 945 sites with HFrEF, New York Heart
Association (NYHA) class II-IV, left ventricular ejection fraction
(LVEF) ≤35%, elevated natriuretic peptides and either current
hospitalization for heart failure or history of hospitalization or
emergency department visit for heart failure within a year.
Patients were randomized to either oral placebo or a starting dose
of 25 mg omecamtiv mecarbil twice daily (maintenance dose of 50 mg,
37.5 mg, or 25 mg twice daily) guided by pharmacokinetic-guided
dose selection. A blood test, the QMS Omecamtiv Mecarbil
Immunoassay (the OM Test) was used to measure plasma levels of
omecamtiv mecarbil in each patient in order to guide selection of
the appropriate maintenance dose.
The primary composite endpoint of this
double-blind, placebo-controlled, event-driven trial was time to CV
death or first heart failure event (heart failure hospitalization
and other urgent treatment for heart failure). Secondary endpoints
were: time to CV death, patient reported outcomes (measured by
Kansas City Cardiomyopathy Questionnaire [KCCQ] Total Symptom Score
[TSS]), time to first heart failure hospitalization and time to
all-cause death.
About Omecamtiv Mecarbil and the Phase 3
Clinical Trials Program
Omecamtiv mecarbil is an investigational
selective cardiac myosin activator, the first of a novel class of
myotropes3 designed to directly target the contractile mechanisms
of the heart, binding to and recruiting more cardiac myosin heads
to interact with actin during systole. Preclinical research has
shown that omecamtiv mecarbil increases cardiac contractility
without increasing intracellular myocyte calcium concentrations or
myocardial oxygen consumption.4-6 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.
Omecamtiv mecarbil is being developed for the
potential treatment of heart failure with reduced ejection fraction
(HFrEF) under a collaboration between Amgen and Cytokinetics, with
funding and strategic support from Servier. Omecamtiv mecarbil is
the subject of a comprehensive Phase 3 clinical trials program
composed of GALACTIC-HF and METEORIC-HF (Multicenter Exercise
Tolerance Evaluation of Omecamtiv Mecarbil Related to Increased
Contractility in Heart Failure), a Phase 3 clinical trial designed
to evaluate the effect of treatment with omecamtiv mecarbil
compared to placebo on exercise capacity.
About Heart Failure
Heart failure is a grievous condition that
affects more than 64 million people worldwide7 about half of whom
have reduced left ventricular function.8,9 It is the leading
cause of hospitalization and readmission in people age 65 and
older.10, 11 Despite broad use of standard treatments and advances
in care, the prognosis for patients with heart failure is poor.12
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.13,14
About Cytokinetics and Amgen
Collaboration
In 2006, Cytokinetics and Amgen entered into a
strategic alliance to discover, develop and commercialize novel
small molecule therapeutics designed to activate the cardiac
sarcomere for the potential treatment of heart failure. Omecamtiv
mecarbil is being developed by Amgen in collaboration with
Cytokinetics, with funding and strategic support from Servier.
Amgen holds an exclusive, worldwide license to omecamtiv mecarbil
and related compounds, subject to Cytokinetics’ specified
development and commercialization rights. Cytokinetics is eligible
for pre-commercialization and commercialization milestone payments
and royalties that escalate based on increasing levels of annual
net sales of products commercialized under the agreement.
Cytokinetics has co-invested with Amgen in the Phase 3 development
program of omecamtiv mecarbil in exchange for increased royalties
from Amgen on worldwide sales of omecamtiv mecarbil outside Japan
and co-promotion rights in institutional care settings in North
America. Amgen has also entered an alliance with Servier for
exclusive commercialization rights for omecamtiv mecarbil in Europe
as well as the Commonwealth of Independent States, including
Russia. Servier contributes funding for development and provides
strategic support to the program.
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 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 impact muscle function and
contractility. Cytokinetics is collaborating with Amgen Inc.
(Amgen) to develop omecamtiv mecarbil, a novel cardiac muscle
activator. Omecamtiv mecarbil is the subject of an international
clinical trials program in patients with heart failure including
GALACTIC-HF, of which topline results were recently reported, and
METEORIC-HF, which is ongoing. Amgen holds an exclusive worldwide
license to develop and commercialize omecamtiv mecarbil with a
sublicense held by Servier for commercialization in Europe and
certain other countries. Cytokinetics is developing reldesemtiv, a
fast skeletal muscle troponin activator (FSTA) for the potential
treatment of ALS and other neuromuscular indications following
conduct of FORTITUDE-ALS and other Phase 2 clinical trials. The
company is considering potential advancement of reldesemtiv to
Phase 3 pending ongoing regulatory interactions. Cytokinetics is
collaborating with Astellas Pharma Inc. (Astellas) to research,
develop and commercialize other novel mechanism skeletal sarcomere
activators (not including FSTAs). Licenses held by Amgen and
Astellas are subject to specified co-development and
co-commercialization rights of Cytokinetics. Cytokinetics is also
developing CK-274, a novel cardiac myosin inhibitor that company
scientists discovered independent of its collaborations, for the
potential treatment of hypertrophic cardiomyopathies. Cytokinetics
has granted Ji Xing Pharmaceuticals Limited an exclusive license to
develop and commercialize CK-274 in China and Taiwan, in accordance
with Cytokinetics’ planned global registration programs.
Cytokinetics is conducting REDWOOD-HCM, a Phase 2 clinical trial of
CK-274 in patients with obstructive HCM. 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 the GALACTIC-HF clinical trial;
statements relating to the METEORIC-HF clinical trial; the
potential benefits of omecamtiv mecarbil, including its
ability to represent a novel therapeutic strategy to increase
cardiac muscle function and restore cardiac performance; the
potential approval of omecamtiv mecarbil by the FDA or any other
regulatory authority; Cytokinetics' and its partners' research
and development activities; the design, timing, results,
significance and utility of preclinical and clinical results; and
the properties and potential benefits
of Cytokinetics' other drug candidates. 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' or
its partners' ability to conduct clinical
trials; Cytokinetics may be unable to obtain or maintain
patent or trade secret protection for its intellectual property;
the nature of Amgen's decisions with respect to the design,
initiation, conduct, timing and continuation of development
activities for omecamtiv mecarbil; standards of care may
change, rendering Cytokinetics' drug candidates obsolete;
competitive products or alternative therapies may be developed by
others for the treatment of
indications Cytokinetics' drug candidates and potential
drug candidates may target; and risks and uncertainties relating to
the timing and receipt of payments from its partners, including
milestones and royalties on future potential product sales
under Cytokinetics' collaboration agreements with such
partners. For further information regarding these and other risks
related to Cytokinetics' business, investors should
consult Cytokinetics' filings with the Securities
and Exchange Commission.
Contact:CytokineticsDiane WeiserSenior Vice
President, Corporate Communications, Investor Relations(415)
290-7757
References
- Teerlink J et al. NEJM. 2020
- Teerlink JR., Diaz R., Felker GM., et al. Omecamtiv Mecarbil in
Chronic Heart Failure With Reduced Ejection Fraction:
Rationale and Design of GALACTIC-HF. JACC Heart
Fail. 2020 Apr; 8(4):329-340. doi:
10.1016/j.jchf.2019.12.001.Epub 2020 Feb 6.
- 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.
An infographic accompanying this announcement is available
at https://www.globenewswire.com/NewsRoom/AttachmentNg/f899c63c-8605-44cf-8c16-c9ab93640611
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