Item 8.01. Other Events.
Today, November 15, 2021, Cytokinetics, Incorporated (the "Company" or
"Cytokinetics") announced that additional results from GALACTIC-HF (Global
Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in
Heart Failure), the Phase 3 clinical trial evaluating omecamtiv mecarbil in
patients with heart failure with reduced ejection fraction ("HFrEF"), were
presented by Dr. 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, at the
American Heart Association ("AHA") Scientific Sessions 2021.
In addition, preclinical data were presented at the AHA Scientific Sessions by
Ivan Luptak, M.D., Ph.D., Assistant Professor of Medicine, Boston University
School of Medicine, on a closely related analog to CK-3828136 ("CK-136"), the
company's novel, selective cardiac troponin activator which is in development
for the potential treatment of diseases associated with impaired cardiac
contractility, such as HFrEF, right ventricular heart failure, and others.
Treatment with Omecamtiv Mecarbil Associated with Significant Reduction in Risk
of Stroke in GALACTIC-HF
Additional analyses presented from GALACTIC-HF focused on the effect of
treatment with omecamtiv mecarbil on the risk of stroke in patients with HFrEF.
Among patients enrolled in the trial, 754 (9.2%) had a history of stroke. These
patients were older, more likely to be non-white, and were more likely to have
atrial fibrillation/flutter, hypertension, diabetes mellitus, ischemic heart
disease, worse New York Heart Association ("NYHA") functional class, and higher
baseline NT-proBNP or troponin compared to patients with no history of stroke. A
total of 194 non-fatal and fatal strokes were reported in GALACTIC-HF.
Multivariate predictors of the incidence of first stroke in GALACTIC-HF included
non-white race, history of stroke or percutaneous coronary intervention, and
elevated baseline troponin or systolic blood pressure. The treatment effect of
omecamtiv mecarbil on the primary composite endpoint of cardiovascular death or
heart failure events was similar in patients with a history of stroke (hazard
ratio 0.86; 95% confidence interval (CI) 0.70, 1.07; p=0.18) and in patients
without a history of stroke (hazard ratio 0.93; 95% CI 0.87, 1.00; p=0.06;
interaction p-value=0.40). However, among all patients who received omecamtiv
mecarbil, the risk of first fatal or non-fatal stroke was reduced by 35% (hazard
ratio 0.65; 95% CI 0.49, 0.87; p=0.004), and the risk of fatal stroke was
reduced by 44% (hazard ratio 0.56; 95% CI 0.31, 0.99; p=0.048). Treatment with
omecamtiv mecarbil was associated with greater reductions in stroke for patients
with a history of stroke, reducing the risk by 77% (n=754, hazard ratio 0.23;
95% CI 0.09, 0.56; interaction p-value=0.001), as well as in patients with a
history of atrial fibrillation, reducing the risk by 51% (n=3475, hazard ratio
0.49, CI 0.32, 0.76; p=0.001). Treatment with omecamtiv mecarbil also
demonstrated a reduction in new onset atrial fibrillation/flutter (no atrial
fibrillation/flutter present at screening: n=5987, hazard ratio 0.70, CI 0.50,
0.99; p=0.044; no history of atrial fibrillation/flutter: n=4757, hazard ratio
0.60, CI 0.37, 1.00; p=0.048). This reduction in stroke may be related to the
reduction in adverse events of atrial fibrillation/flutter, as well as
improvements in atrial and ventricular function that have been observed in
GALACTIC-HF and previous clinical trials of omecamtiv mecarbil. These findings
may have implications for the clinical impact of omecamtiv mecarbil and suggest
that it has a potential added benefit of decreasing the risk of stroke in
patients with HFrEF.
Cardiac Troponin Activator Increases Contractility Without Negative Impacts on
Myocardial Energetics
New preclinical data investigated the effects on cardiac contractility and
energetics on a closely related analog to CK-136, a cardiac troponin activator
referred to as TA1. Several in vitro, ex vivo and in vivo studies demonstrated
that TA1 increased myocardial contractility by sensitizing the sarcomere to
calcium without impairing diastolic function or depleting the cardiac energy
reserve. In bovine cardiac myofibrils and human cardiac microtissues, TA1
increased the calcium sensitivity of sarcomere function dose dependently.
Similarly, TA1 increased calcium sensitivity and maximal tension ex vivo in
mouse cardiac fibers, and in anesthetized normal rats, TA1 also dose dependently
increased fractional shortening, a measure of cardiac contractility. Finally,
assessments of isolated perfused rat hearts by 31P NMR spectroscopy comparing
TA1 to dobutamine, a calcitrope that increases cardiac output, both TA1 and
dobutamine similarly increased rate pressure product, but unlike dobutamine, TA1
did not worsen cardiac energetics, elevate left ventricular end-diastolic
pressure ("LVEDP") or raise heart rate. Magnetization transfer experiments also
confirmed that the higher force generation from TA1 did not come at a cost of
higher ATP consumption, as compared to dobutamine. Together, these data suggest
that cardiac troponin activation increases cardiac contractility without causing
a negative impact on calcium cycling, diastolic function or contractile reserve.
Because energy depletion has been associated with worse long-term survival in
heart failure, these results suggest cardiac troponin activation may have
application in diseases associated with decreased cardiac contractility. These
findings were also published online in Circulation: Heart Failure1 in
conjunction with their presentation.
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
was 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. 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 and includes GALACTIC-HF and METEORIC-HF, a Phase 3
clinical trial designed to evaluate the effect of treatment with omecamtiv
mecarbil compared to placebo on exercise capacity.
About CK-136
CK-136 is an investigational, selective, small molecule cardiac troponin
activator. In preclinical models, CK-136 increases myocardial contractility by
binding to cardiac troponin through an allosteric mechanism that sensitizes the
cardiac sarcomere to calcium, facilitating more actin-myosin cross bridge
formation during each cardiac cycle, thereby resulting in increased myocardial
contractility. Similar to cardiac myosin activation, preclinical research has
shown that cardiac troponin activation does not change the calcium transient of
cardiac myocytes. The development program for CK-136 is assessing its potential
for the treatment of diseases associated with impaired cardiac contractility,
such as HFrEF, right ventricular heart failure, and others.
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 preparing 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 aficamten, a
next-generation cardiac myosin inhibitor, for the potential treatment of
hypertrophic cardiomyopathies ("HCM"). The company has announced positive
results from Cohorts 1 and 2 in REDWOOD-HCM, a Phase 2 clinical trial of
aficamten in patients with obstructive HCM. Cytokinetics is conducting start-up
activities for SEQUOIA-HCM, the Phase 3 clinical trial of aficamten in patients
with obstructive HCM. Cytokinetics is also developing reldesemtiv, a fast
skeletal muscle troponin activator, currently the subject of COURAGE-ALS, a
Phase 3 clinical trial in patients with 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.
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 potential benefits of omecamtiv mecarbil, aficamten
or CK-136,statements relating to the potential submission or approval of an NDA
for omecamtiv mecarbil, statements relating to the timing of a potential
commercial launch of omecamtiv mecarbil, and statements relating to the timing
of the commencement or completion of the SEQUOIA-HCM clinical trial.
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.
###
References
1. He H, Baka T, Balschi J, Motani AS, Nguyen KK, Liu Q, Slater R, Rock B,
Wang C, Hale C, Karamanlidis G, Hartman JJ, Malik FI, Reagan JD, Luptak I.
A novel small molecule troponin activator increases cardiac contractile
function without negative impact on energetics. Circ Heart Failure. 2021.
2. Psotka MA, Gottlieb SS, Francis GS et al. Cardiac Calcitropes, Myotropes,
and Mitotropes. JACC. 2019; 73:2345-53.
3. 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.
4. 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.
5. 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.
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