Cytokinetics, Incorporated (Nasdaq: CYTK) today announced that data
from a secondary analysis of GALACTIC-HF (
Global
Approach to
Lowering
Adverse
Cardiac Outcomes
Through
Improving
Contractility in
Heart
Failure) assessing the effect of omecamtiv
mecarbil on clinical outcomes in relationship to patient baseline
ejection fraction 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 College of Cardiology 70th Annual
Scientific Session & Expo (ACC.21) and were simultaneously
published in the Journal of the American College of Cardiology.1
“These results build on our previous observation
that the treatment effect of omecamtiv mecarbil grows progressively
stronger in patients with lower ejection fraction, the very
patients who are at the highest risk for heart failure
hospitalization and cardiovascular death,” said John Teerlink, M.D.
“Given that these severe heart failure patients are often unable to
tolerate guideline-directed medical therapy and are left with few
treatment options, omecamtiv mecarbil may provide an opportunity to
improve their systolic function and keep them out of the hospital.
In addition, omecamtiv mecarbil has no adverse effect on heart
rate, blood pressure, kidney function or blood potassium levels,
suggesting it can be added without interfering with
guideline-directed medical therapy.”
“Despite excellent background therapy, heart
failure patients are still in need of additional options as
evidenced by the increasingly high event rates as baseline ejection
fraction falls,” said Fady I. Malik, M.D., Ph.D., Cytokinetics’
Executive Vice President of Research & Development. “The data
presented today underscore the potential value that omecamtiv
mecarbil may have in reducing the clinical and economic burden of
severe heart failure. We look forward to further analyses of
GALACTIC-HF in the coming months and to advancing toward our goal
of an NDA submission in the U.S. for omecamtiv mecarbil in the
second half of 2021.”
GALACTIC-HF: Secondary
Analysis
GALACTIC-HF enrolled 8,256 patients who were at
risk of hospitalization and death, despite being well treated on
standard of care therapy. As previously reported, 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 heart
failure events (heart failure hospitalization and other urgent
treatment for heart failure) or cardiovascular (CV) death compared
to placebo in patients treated with standard of care (hazard ratio,
0.92; 95% confidence interval [CI] 0.86, 0.99; p=0.025). No
reduction in the secondary endpoint of time to CV death was
observed in the overall population. 1 Supplemental analyses
indicated that the effect of omecamtiv mecarbil on the primary
composite endpoint was consistent across most prespecified
subgroups, with a progressively larger treatment effect of
omecamtiv mecarbil with decreasing EF (interaction p = 0.004). This
secondary analysis further investigates the influence of EF on the
observed treatment effects.
The analysis evaluated the effect of patient
treatment with omecamtiv mecarbil based on quartiles of baseline EF
defined as EF ≤22%, EF 23-28%, EF 29-32% and EF ≥33% as well as
considering baseline EF as a continuous variable. The incidence of
the primary outcome of first heart failure event or cardiovascular
death increased with decreasing ejection fraction; in the lowest
LVEF quartile (EF ≤22%) the incidence (35.6 per 100 patient-years)
was almost 80% greater than in the highest EF quartile (EF ≥33%; 20
per 100 patient-years). Treatment with omecamtiv mecarbil
demonstrated a 15% (HR 0.85; 95% CI 0.74-0.97; p = 0.016)
and 17% (HR 0.83; 95% CI 0.73-0.95; p = 0.005) relative
risk reduction in the lower two quartiles, respectively, compared
to no difference in the upper two quartiles.
Analysis of ejection fraction as a continuous
variable demonstrated a progressively larger treatment effect of
omecamtiv mecarbil with decreasing ejection fraction (Figure A,
interaction p = 0.013 by EF quartile). Accordingly, the absolute
treatment effect on the primary composite endpoint also increased
between the patients treated with placebo and omecamtiv mecarbil as
baseline ejection fraction decreased (Figure B) such that in the
lowest ejection fraction quartile, there was an absolute reduction
of 7.4 events per 100 patient-years, with a number-needed-to-treat
of 11.8 patients necessary to prevent an event over three
years.
Figure A accompanying this
announcement is available at
https://www.globenewswire.com/NewsRoom/AttachmentNg/1d595e71-7590-4988-8f2d-d3c5d1ca17ba
Figure B accompanying this
announcement is available at
https://www.globenewswire.com/NewsRoom/AttachmentNg/1716ac6d-a536-44ab-86ae-f160660037ee
The beneficial effect of treatment with
omecamtiv mecarbil on the primary composite endpoint was driven
predominantly by the reduction in heart failure events. To
determine the significance of EF subgroup differences, a test of
the interaction effect revealed that EF was a significant modifier
of this treatment effect (interaction p = 0.004 by EF quartile,
interaction p = 0.001 by EF as continuous variable). Treatment with
omecamtiv mecarbil demonstrated a 19% (HR 0.81; 95% CI 0.70-0.93)
and 17% (HR 0.84; 95% CI 0.72-0.98) relative risk reduction in the
lower two quartiles, respectively, compared to no difference in the
upper two quartiles.
A greater reduction in NT-proBNP was also
observed with omecamtiv mecarbil in patients with lower EF, with a
22% reduction (p < 0.001) in the lowest EF quartile, and a 3%
reduction in the highest quartile (p = 0.54; interaction p <
0.001). NT-proBNP is a biomarker of ventricular wall stress, where
higher levels reflect more severe heart failure.
As previously noted, treatment with omecamtiv
mecarbil resulted in a small reduction in heart rate (treatment
difference of 1.1 to 1.9 bpm across the EF quartiles) and increase
in troponin I (median 3-5 ng/L across the EF quartiles; limit of
detection, 6 ng/L; upper reference limit, 40 ng/L), though
these results did not differ by EF quartile. There were no
significant differences in systolic blood pressure, serum
potassium, or creatinine or the incidence of adverse events between
the omecamtiv mecarbil and placebo treated groups between EF
quartiles.
GALACTIC-HF: Trial Design and
Primary Results
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. 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). No
reduction in the secondary endpoint of time to CV death was
observed in the overall population. The effect on the primary
endpoint was observed without evidence of an increase in the
overall rates of myocardial ischemic events, ventricular
arrhythmias or death from cardiovascular or all causes.
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) and 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 More than 2 million people in the U.S. are
estimated to have an ejection fraction <30%, indicating they may
have severe heart failure.15
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 engaging with regulatory authorities
in preparation for a U.S. NDA submission of omecamtiv mecarbil, its
novel cardiac muscle activator, following positive results from
GALACTIC-HF, a large, international Phase 3 clinical trial in
patients with heart failure. Cytokinetics is conducting
METEORIC-HF, a second Phase 3 clinical trial of omecamtiv mecarbil.
Cytokinetics is also developing CK-274, a next-generation cardiac
myosin inhibitor, for the potential treatment of hypertrophic
cardiomyopathies (HCM). Cytokinetics is conducting REDWOOD-HCM, a
Phase 2 clinical trial of CK-274 in patients with obstructive HCM.
Cytokinetics is also developing reldesemtiv, a fast skeletal muscle
troponin activator for the potential treatment of ALS and other
neuromuscular indications following conduct of FORTITUDE-ALS and
other Phase 2 clinical trials. The company is preparing for the
potential advancement of reldesemtiv to a Phase 3 clinical trial in
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, 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 timing
and likelihood of any regulatory submissions or approval of
omecamtiv mecarbil, Cytokinetics' 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' 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:CytokineticsDiane WeiserSenior Vice
President, Corporate Communications, Investor Relations(415)
290-7757
References
- Teerlink JR., Diaz R., Felker GM., et al. Effect of Ejection
Fraction on Clinical Outcomes in Patients treated with Omecamtiv
Mecarbil in GALACTIC-HF. JACC. 2021
- 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.
- 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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