Cytokinetics, Incorporated (Nasdaq: CYTK) today announced that new
data related to the safety and long-term use of aficamten were
presented in a Late Breaking Clinical Trial presentation and oral
presentation at the European Society of Cardiology Congress 2024 in
London, UK. The presentations included an integrated safety
analysis from three clinical studies of aficamten and an analysis
of the withdrawal of standard of care medications in patients
treated with aficamten in FOREST-HCM (
Follow-up,
Open-Label,
Research
Evaluation of
Sustained
Treatment with Aficamten in
HCM),
the open label extension clinical study of aficamten in patients
with hypertrophic cardiomyopathy (HCM).
“The emerging safety profile of aficamten
observed across three clinical trials representing 206 patient
years of exposure to aficamten provides a rationale for how
aficamten may translate to real-world use as a cardiac myosin
inhibitor of choice,” said Stephen Heitner, M.D., Vice President,
Head of Clinical Research. “We’re encouraged by the promising
safety and tolerability profile for aficamten as well as the
observation that patients successfully withdrew background standard
of care medications, with many able to simplify their treatment
regimen to disease-specific monotherapy with aficamten. These
findings were in an open-label setting, at the discretion of the
patient and physician, and did not impact the safety or efficacy of
aficamten. We look forward to results of MAPLE-HCM, the Phase 3
clinical trial assessing the potential superiority of aficamten as
monotherapy compared to metoprolol, which we expect to disclose in
the first half of next year.”
Integrated Safety Analysis from Three
Clinical Trials of Aficamten
Reinforces Robust Safety Profile
Ahmad Masri, M.D., M.S., Director of the
Hypertrophic Cardiomyopathy Center at Oregon Health and Science
University presented data from an integrated safety analysis of
aficamten across the Phase 2 clinical trial, REDWOOD-HCM
(Randomized Evaluation of
Dosing With CK-274 in
Obstructive Outflow
Disease in HCM), the Phase 3
clinical trial, SEQUOIA-HCM (Safety,
Efficacy, and Quantitative
Understanding of Obstruction
Impact of Aficamten in
HCM), and FOREST-HCM, the open-label extension
clinical study of aficamten. Patients with obstructive HCM who
received at least one dose of aficamten or placebo were included in
this analysis. A total of 283 patients received at least one dose
of aficamten and 153 patients received at least one dose of
placebo. Overall, treatment with aficamten was well-tolerated with
an adverse event profile similar to placebo. Across all three
clinical studies, 11 patients (3.9%) experienced incidents of left
ventricular ejection fraction (LVEF) <50%, but none were
associated with clinical heart failure, and all were successfully
managed by dose down-titration. Additionally, of the 1,588 total
echocardiograms performed on patients treated with aficamten during
the maintenance phases of each clinical study, only 0.7% of
echocardiograms that were performed impacted the clinical
management of patients and led to a reduction in dose. There were
no dose interruptions and no treatment discontinuations in these
three clinical studies of aficamten due to decreased LVEF.
Additionally, among patients treated with
aficamten and compared to placebo, there was a low incidence of new
onset atrial fibrillation and myocardial infarction. The rate of
syncope events was also similar between groups (Table 1). This
integrated safety analysis reinforces the safety profile of
aficamten as relates to the potential management of HCM in a
real-world setting.
Table 1. Integrated Safety Analysis |
|
Cumulativeaaficamten-treated
pool |
Placebo-controlled poolb |
|
Aficamten |
Aficamten |
Placebo |
Number of participants |
283 |
170 |
153 |
LVEF <50%c, n (%) |
11 (3.9) |
9 (5.3) |
1 (0.7) |
LVEF <50% with clinical heart failure |
0 |
0 |
1 (0.7) |
Atrial fibrillation |
12 (4.2) |
4 (2.4) |
5 (3.3) |
New onset |
5 (1.8) |
1 (0.6) |
3 (2.0) |
Recurrent |
7 (2.5) |
3 (1.8) |
2 (1.3) |
Stroke |
3 (1.1) |
1 (0.6) |
1 (0.7) |
Myocardial infarction |
1 (0.4) |
0 |
1 (0.7) |
Syncope |
4 (1.4) |
3 (1.8) |
5 (3.3) |
Death |
0 |
0 |
0 |
a Parent and extension studies. b Placebo-controlled pool of
REDWOOD-HCM and SEQUOIA-HCM. c Site read. |
Withdrawal of SoC Medications Does Not Negatively Impact
Efficacy or Safety of Aficamten
in Patients with Obstructive HCM
Dr. Masri also presented data from an analysis
related to the withdrawal of standard of care (SoC) medications in
patients with obstructive HCM in FOREST-HCM. Of the 145 patients
with obstructive HCM who completed at least 24 weeks of treatment
with aficamten at the time of this analysis, 136 (93.8%) were
receiving SoC medications including beta blockers, calcium channel
blockers and disopyramide. Withdrawal of SoC medications was
attempted at the discretion of the investigator in 64 (47%)
patients, while a comparator group of 72 (53%) patients did not
undergo SoC withdrawal. Successful withdrawal was defined as at
least a 50% dose-reduction in one medication relative to baseline.
Among patients who attempted withdrawal of SoC medications, 59
(92%) were successful, including 38 (64%) patients who discontinued
at least one SoC medication and 27 (71%) patients who achieved and
maintained monotherapy with aficamten. Following successful
withdrawal of SoC medications, 23 (39%) patients underwent dose
up-titration with aficamten.
Among those who attempted withdrawal of SoC
medications, there were no statistically significant differences in
the treatment effect of aficamten post-withdrawal compared to
pre-withdrawal on resting left ventricular outflow tract gradient
(LVOT-G), Valsalva LVOT-G, change in LVEF, New York Heart
Association (NYHA) Functional Class, Kansas City Cardiomyopathy
Questionnaire Clinical Summary Score (KCCQ-CSS), high-sensitivity
cardiac troponin I (hs-cTnI) and NT-proBNP. There were no
differences in the efficacy of aficamten between the group of
patients who attempted SoC withdrawal and the control group of
patients who did not attempt SoC withdrawal. Further, no
differences in safety profile emerged, with similar rates of
adverse events, instances of LVEF <50% and new onset atrial
fibrillation between groups. These data suggest that aficamten may
be tolerated and effective as monotherapy in patients with
obstructive HCM and warrants further evaluation.
Conference Call and Webcast
Cytokinetics will host a conference call on
September 3, 2024 at 8:00 AM Eastern Time that will be
simultaneously webcast and can be accessed from the Investors &
Media section of Cytokinetics’ website at www.cytokinetics.com. The
live audio of the conference call can also be accessed by telephone
by registering in advance at the following link:
Cytokinetics ESC Investor Conference Call. Upon
registration, participants will receive a dial-in number and a
unique passcode to access the call. An archived replay of the
webcast will be available via Cytokinetics’ website for six
months.
About
Aficamten
Aficamten is an investigational selective, small
molecule cardiac myosin inhibitor discovered following an extensive
chemical optimization program that was conducted with careful
attention to therapeutic index and pharmacokinetic properties and
as may translate into next-in-class potential in clinical
development. Aficamten was designed to reduce the number of active
actin-myosin cross bridges during each cardiac cycle and
consequently suppress the myocardial hypercontractility that is
associated with hypertrophic cardiomyopathy (HCM). In preclinical
models, aficamten reduced myocardial contractility by binding
directly to cardiac myosin at a distinct and selective allosteric
binding site, thereby preventing myosin from entering a force
producing state.
The development program for aficamten is
assessing its potential as a treatment that improves exercise
capacity and relieves symptoms in patients with HCM as well as its
potential long-term effects on cardiac structure and function.
Aficamten was evaluated in SEQUOIA-HCM (Safety,
Efficacy, and Quantitative
Understanding of Obstruction
Impact of Aficamten in
HCM), a positive pivotal Phase 3 clinical trial in
patients with symptomatic obstructive hypertrophic cardiomyopathy
(HCM). Aficamten received Breakthrough Therapy Designation for the
treatment of symptomatic obstructive HCM from the U.S. Food &
Drug Administration (FDA) as well as the National Medical Products
Administration (NMPA) in China. Cytokinetics expects to submit a
New Drug Application (NDA) to the FDA in Q3 2024 and a Marketing
Authorization Application (MAA) to the European Medicines Agency
(EMA) in Q4 2024.
Aficamten is also currently being evaluated
in MAPLE-HCM, a Phase 3 clinical trial of aficamten as
monotherapy compared to metoprolol as monotherapy in patients with
obstructive HCM, ACACIA-HCM, a Phase 3 clinical trial
of aficamten in patients with non-obstructive HCM, and
CEDAR-HCM, a clinical trial of aficamten in a pediatric
population with obstructive HCM, and FOREST-HCM, an open-label
extension clinical study of aficamten in patients with
HCM.
About Hypertrophic
Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is a disease
in which the heart muscle (myocardium) becomes abnormally thick
(hypertrophied). The thickening of cardiac muscle leads to the
inside of the left ventricle becoming smaller and stiffer, and thus
the ventricle becomes less able to relax and fill with blood. This
ultimately limits the heart’s pumping function, resulting in
reduced exercise capacity and symptoms including chest pain,
dizziness, shortness of breath, or fainting during physical
activity. HCM is the most common monogenic inherited cardiovascular
disorder, with approximately 280,000 patients diagnosed, however,
there are an estimated 400,000-800,000 additional patients who
remain undiagnosed in the U.S.1,2,3 Two-thirds of patients with HCM
have obstructive HCM (oHCM), where the thickening of the cardiac
muscle leads to left ventricular outflow tract (LVOT) obstruction,
while one-third have non-obstructive HCM (nHCM), where blood flow
isn’t impacted, but the heart muscle is still thickened. People
with HCM are at high risk of also developing cardiovascular
complications including atrial fibrillation, stroke and mitral
valve disease.4 People with HCM are at risk for potentially fatal
ventricular arrhythmias and it is one of the leading causes of
sudden cardiac death in younger people or athletes.5 A subset of
patients with HCM are at high risk of progressive disease leading
to dilated cardiomyopathy and heart failure necessitating cardiac
transplantation.
About Cytokinetics
Cytokinetics is a late-stage, specialty
cardiovascular biopharmaceutical company focused on discovering,
developing and commercializing muscle biology-directed drug
candidates as potential treatments for debilitating diseases in
which cardiac 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 myocardial muscle function and contractility.
Cytokinetics is preparing for regulatory submissions for aficamten,
its next-in-class cardiac myosin inhibitor, following positive
results from SEQUOIA-HCM, the pivotal Phase 3 clinical trial in
obstructive hypertrophic cardiomyopathy which were published in the
New England Journal of Medicine. Aficamten is also currently being
evaluated in MAPLE-HCM, a Phase 3 clinical trial of aficamten as
monotherapy compared to metoprolol as monotherapy in patients with
obstructive HCM, ACACIA-HCM, a Phase 3 clinical trial of aficamten
in patients with non-obstructive HCM, CEDAR-HCM, a clinical trial
of aficamten in a pediatric population with obstructive HCM, and
FOREST-HCM, an open-label extension clinical study of aficamten in
patients with HCM. Cytokinetics is also developing omecamtiv
mecarbil, a cardiac muscle activator, in patients with heart
failure. Additionally, Cytokinetics is developing CK-586, a cardiac
myosin inhibitor with a mechanism of action distinct from aficamten
for the potential treatment of HFpEF.
For additional information about Cytokinetics,
visit www.cytokinetics.com and follow us on X, 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 express or implied relating to the
properties or potential benefits of aficamten or any of our other
drug candidates, our ability to obtain regulatory approval for
aficamten for the treatment of obstructive hypertrophic
cardiomyopathy or any other indication from FDA or any other
regulatory body in the United States or abroad, the labeling or
post-marketing conditions that FDA or another regulatory body may
require in connection with the approval of aficamten, and our
ability release the data from MAPLE-HCM in the first half of 2025.
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 the risks related to
Cytokinetics’ business outlines in Cytokinetics’ filings with
the Securities and Exchange Commission. Forward-looking
statements are not guarantees of future performance, and
Cytokinetics’ actual results of operations, financial condition and
liquidity, and the development of the industry in which it
operates, may differ materially from the forward-looking statements
contained in this press release. Any forward-looking statements
that Cytokinetics makes in this press release speak only
as of the date of this press
release. Cytokinetics assumes no obligation to update its
forward-looking statements whether as a result of new information,
future events or otherwise, after the date of this press
release.
CYTOKINETICS® and the C-shaped logo are
registered trademarks of Cytokinetics in the U.S. and certain other
countries.
Contact:Cytokinetics Diane WeiserSenior Vice
President, Corporate Affairs(415) 290-7757
References:
- CVrg: Heart Failure 2020-2029, p 44; Maron et al. 2013 DOI:
10.1016/S0140-6736(12)60397-3; Maron et al 2018
10.1056/NEJMra1710575
- Symphony Health 2016-2021 Patient Claims Data DoF;
- Maron MS, Hellawell JL, Lucove JC, Farzaneh-Far R, Olivotto I.
Occurrence of Clinically Diagnosed Hypertrophic Cardiomyopathy in
the United States. Am J Cardiol. 2016; 15;117(10):1651-1654.
- Gersh, B.J., Maron, B.J., Bonow, R.O., Dearani, J.A., Fifer,
M.A., Link, M.S., et al. 2011 ACCF/AHA guidelines for the diagnosis
and treatment of hypertrophic cardiomyopathy. A report of the
American College of Cardiology Foundation/American Heart
Association Task Force on practice guidelines. Journal of the
American College of Cardiology and Circulation, 58, e212-260.
- Hong Y, Su WW, Li X. Risk factors of sudden cardiac death in
hypertrophic cardiomyopathy. Current Opinion in Cardiology. 2022
Jan 1;37(1):15-21
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