Cytokinetics, Incorporated (Nasdaq: CYTK) today announced that the
primary results from SEQUOIA-HCM (
Safety,
Efficacy, and
Quantitative
Understanding of
Obstruction
Impact of
Aficamten in
HCM), the pivotal Phase 3 clinical trial of
aficamten in patients with symptomatic obstructive hypertrophic
cardiomyopathy (HCM), were presented by Martin Maron, M.D.,
Director, Hypertrophic Cardiomyopathy Center, Lahey Hospital and
Medical Center, and Principal Investigator of SEQUOIA-HCM, in a
Late Breaking Clinical Trial session at Heart Failure 2024, an
International Congress of the European Society of Cardiology, and
simultaneously published in the New England Journal of Medicine.1
SEQUOIA-HCM enrolled 282 patients with
obstructive HCM. The baseline characteristics of patients in
SEQUOIA-HCM were well-matched between treatment groups and
consistent with a symptomatic patient population that had high
resting and post-Valsalva gradients (mean [SD]; 55.1 [29.6] and
83.1 [32.3] mmHg, respectively) reflective of substantial burden of
disease. Background therapies consisted of beta-blockers (61.3%),
calcium channel blockers (28.7%), and disopyramide (12.8%), with
combination background therapies permitted.
The results from SEQUOIA-HCM showed that
treatment with aficamten for 24 weeks significantly improved
exercise capacity compared to placebo, increasing peak oxygen
uptake (pVO2) measured by cardiopulmonary exercise testing (CPET)
by 1.8 ml/kg/min compared to baseline in patients treated with
aficamten versus 0.0 ml/kg/min in patients treated with placebo
(least square mean (LSM) difference [95% CI] of 1.74 mL/kg/min
[1.04 - 2.44]; p=0.000002) (Figure 1).
The treatment effect of aficamten was consistent
across all prespecified subgroups, including age, sex, patient
baseline characteristics, and in patients receiving or not
receiving background beta-blocker therapy (Figure 2).
Statistically significant improvements were
observed in all 10 prespecified secondary endpoints, with
functional and symptomatic improvements occurring within two weeks
of initiating treatment with aficamten and sustained throughout the
treatment period. Compared to baseline, at Week 24 patients treated
with aficamten experienced significant improvements in
post-Valsalva left ventricular outflow tract gradient (LVOT-G) with
an LSM difference of -50 mmHg (p<0.0001) versus placebo.
Aficamten also substantially reduced the burden of symptoms
compared with placebo, with a significant improvement observed in
Kansas City Cardiomyopathy Questionnaire Clinical Summary Score
(KCCQ-CSS) (LSM difference = 7 points; p<0.0001) and with 34% of
patients experiencing ≥1 class improvement in New York Heart
Association (NYHA) Functional Class (p<0.0001) (Figure 3).
Treatment with aficamten substantially reduced the proportion of
patients eligible for septal reduction therapy (SRT). Among those
eligible for SRT at baseline, over the duration of 24 weeks of
treatment, patients receiving aficamten spent 78 fewer days
eligible for SRT compared with those treated with placebo
(p<0.0001). Additionally, from baseline to Week 24, treatment
with aficamten reduced NT-proBNP, a biomarker of cardiac wall
stress, by 80% relative to placebo (Figure 4).
The prespecified exploratory responder analysis
in SEQUOIA-HCM showed that treatment with aficamten improved both
exercise capacity and symptoms, with 60 (42%) of 142 patients
treated with aficamten achieving the composite responder endpoint
of (1) ≥1.5 mL/kg/min increase in pVO2 and ≥1 NYHA Functional Class
improvement, or (2) ≥3.0 mL/kg/min increase in pVO2 and no
worsening of NYHA Functional Class, compared to 19 (14%) of 140
patients treated with placebo, equating to a placebo-corrected
difference of 28.7% (95% CI, 18.8, 38.6; p<0.0001).
“The results from SEQUOIA-HCM demonstrate that
treatment with aficamten is associated with statistically
significant, rapid and sustained improvements in exercise capacity,
symptoms, cardiac function and cardiac biomarkers in patients with
obstructive HCM,” said Fady I. Malik, M.D., Ph.D.,
Cytokinetics’ Executive Vice President of Research &
Development. “With no treatment interruptions due to low LVEF,
aficamten appeared safe and well-tolerated. We believe these
results are strongly supportive of the potential approval of
aficamten, and we look forward to submitting regulatory filings in
both the U.S. and Europe later this year. I would like to thank the
patients, investigator teams, and our staff for their tireless work
to bring these results forward.”
“These results are remarkable, not only because
of the magnitude of effect on clinical measures of disease, but
also for the consistency observed across patient subgroups,
including patients taking beta-blockers at baseline, which in
real-world practice represents a large portion of patients with
obstructive HCM,” said Martin Maron, M.D., Director, Hypertrophic
Cardiomyopathy Center, Lahey Hospital and Medical Center, and
Principal Investigator of SEQUOIA-HCM. “If approved, aficamten is a
potentially transformational treatment which may reliably and
safely address the most important treatment goals in obstructive
HCM including relieving limiting symptoms and enhancing exercise
capacity resulting in substantial improvements in quality of
life.”
Aficamten was well-tolerated in SEQUOIA-HCM with
an adverse event profile comparable to placebo. Treatment emergent
serious adverse events occurred in 5.6% and 9.3% of patients on
aficamten and placebo, respectively. Core echocardiographic left
ventricular ejection fraction (LVEF) was observed to be <50% in
5 patients (3.5%) on aficamten compared to 1 patient (0.7%) on
placebo. One of the 5 patients on aficamten with low LVEF had LVEF
<40% following infection with COVID-19 but did not interrupt
treatment as the site-read LVEF remained greater than 40% and the
patient did not have symptoms of heart failure due to systolic
dysfunction. Overall, there were no instances of worsening heart
failure or treatment interruptions due to low LVEF.
Investor Event and Webcast Information
Cytokinetics will host an investor event and
conference call on May 13, 2024 at 4:00 PM Western European Summer
Time (11:00 AM Eastern Time). The event will be held at the Pestana
Palace Lisboa Hotel in Lisbon, Portugal in the Lusitano II room.
The event will be simultaneously webcast and will be accessible in
the Investors & Media section of Cytokinetics’ website.
Interested parties must register to attend in person or online at
https://cytokinetics-SEQUOIA-HCM-investor-event.open-exchange.net/registration.
Registered attendees may access the virtual event platform by
visiting the Investor & Media section of the Cytokinetics
website at www.cytokinetics.com. A link to the webcast replay will
be archived on the Cytokinetics website until November 13,
2024.
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 if approved. 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.
About the Broad Phase 3 Clinical Trials
Program for Aficamten
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), the pivotal
Phase 3 clinical trial in patients with symptomatic obstructive
hypertrophic cardiomyopathy (HCM). Aficamten is 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 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. 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.
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 in the
U.S., however, there are an estimated 400,000-800,000 additional
patients who remain undiagnosed.2,3,4 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.5 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.6 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 first-in-class muscle activators and
next-in-class muscle inhibitors 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. 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, and CK-136, a cardiac troponin activator for
the potential treatment HFrEF and other types of heart failure,
such as right ventricular failure resulting from impaired cardiac
contractility.
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, and the labeling or
post-marketing obligations that may be required by FDA or any other
regulatory body in the United States or abroad as a condition to
regulatory approval. 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:
- Maron, MS, et al. Aficamten for Symptomatic Obstructive
Hypertrophic Cardiomyopathy. N Engl J Med. DOI:
10.1056/NEJMoa2401424
- 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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