Cytokinetics, Incorporated (Nasdaq: CYTK) today announced that
additional 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), elaborating on dosing and safety data as well
as the effect of aficamten on exercise performance were presented
at Heart Failure 2024, an International Congress of the European
Society of Cardiology. The primary results from SEQUOIA-HCM were
also presented in the same Late Breaking Clinical Trial session at
the Congress and simultaneously published in the New England
Journal of Medicine.1
“These additional analyses from SEQUOIA-HCM
further illuminate the positive impact of treatment with aficamten
on measures of dosing, safety, efficacy and impact on quality of
life beyond the primary and secondary endpoints of the trial,” said
Stuart Kupfer, M.D., SVP, Chief Medical Officer. “Notably, the
dosing and safety data support dose down-titration in cases of low
left ventricular ejection fraction (LVEF), potentially enabling
ease of individualized dosing for patients treated with aficamten
and also may inform a tailored risk mitigation approach.”
Aficamten Demonstrates
Predictable Dosing with No Dose Interruptions Due to LVEF
<50%
Results from prespecified analyses from
SEQUOIA-HCM on dosing and measures of safety during treatment with
aficamten were presented by Caroline Coats, M.D., Ph.D., Lead
Clinician, West of Scotland Inherited Cardiac Conditions Service,
Honorary Senior Lecturer, School of Cardiovascular and Metabolic
Health, University of Glasgow. In SEQUOIA-HCM, there were no major
adverse cardiovascular events associated with treatment with
aficamten. Serious adverse events occurred in 8 (5.6%) patients in
the aficamten group and 13 (9.3%) patients in the placebo group,
none of which were determined to be related to study drug. There
was no difference in the incidence of adverse events by dose
strength. Over the duration of the 24-week double-blind treatment
period, patients treated with aficamten had a placebo-corrected
average change in left ventricular ejection fraction (LVEF) of
-4.8% (95% CI -6.3 to -3.2). This modest reduction in LVEF in
patients treated with aficamten resulted in large reductions in
left ventricular outflow tract gradient (LVOT-G).
Titration of patients to their individually
determined target dose of aficamten resulted in dose-related
increases in plasma drug concentrations with the majority of
patients achieving one of the two highest doses (15 mg in 35.0% and
20 mg in 48.6%). Following the completion of dose titration, during
the maintenance phase, plasma drug concentrations of aficamten
remained stable with low variability for the duration of the
treatment.
Overall, there was a low frequency of LVEF
<50% in SEQUOIA-HCM. LVEF determined by the core laboratory was
the prespecified analysis; 5 patients (3.5%) on aficamten compared
to 1 patient (0.7%) on placebo had LVEF <50%. One of the 5
patients on aficamten 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.
To enable same-day dose adjustments, the dosing
algorithm in SEQUOIA-HCM used site-interpreted LVEF and LVOT
gradients for dose adjustments per protocol as implemented by the
interactive Web-response system. There were 7 (4.9%) patients
treated with aficamten who underwent per-protocol dose reductions
for site-read LVEF <50%. Only one patient treated with aficamten
had both core laboratory and site-read LVEF <50%. There were no
dose interruptions and none of the patients treated with aficamten
experienced symptoms of heart failure due to systolic
dysfunction.
“The pharmacological properties that were
designed into aficamten appear to translate into the intended
clinical benefits. In SEQUOIA-HCM patients underwent dose titration
as early as two-weeks and achieved the maximal therapeutic effect
in the majority of patients while the occurrence of adverse event
was similar to placebo,” said Caroline Coats, M.D., Ph.D., Lead
Clinician, West of Scotland Inherited Cardiac Conditions Service,
Honorary Senior Lecturer, School of Cardiovascular and Metabolic
Health, University of Glasgow. “The favorable safety and
tolerability data from SEQUOIA-HCM affirm aficamten as a promising
potential treatment for obstructive HCM.”
Aficamten Improved
Novel Integrated Exercise Performance Metric; Improvements in
Exercise Performance Correlated with Improvements in Cardiac
Structure and Function
Results from a prespecified analysis of
cardiopulmonary exercise testing (CPET) metrics in SEQUOIA-HCM were
presented by Gregory Lewis, M.D., Jeffrey and Mary Ellen Jay Chair
and Section Head, Heart Failure Medical Director, Cardiopulmonary
Exercise Testing Laboratory, Professor of Medicine, Harvard Medical
School. In addition to significantly improving peak oxygen uptake
(pVO2), this prespecified analysis demonstrated that treatment with
aficamten for 24 weeks improved a novel integrated exercise
performance metric. Additionally, improvements in pVO2 were highly
correlated with improvements in other clinically important
measures.
To capture both maximal and submaximal exercise
performance (pVO2 and ventilatory efficiency [VE/VCO2],
respectively) an integrated CPET Z-score metric was developed that
combines the two measurements into a composite endpoint. It
integrates the effect of aficamten on exercise across the entire
test, representing a more complete view of the therapeutic effect
of aficamten on functional capacity. Aficamten substantially
improved overall performance of the integrated CPET Z-score by a
placebo-adjusted difference of 0.35 (95% CI, 0.25, 0.46;
p<0.001). Additionally, of patients treated with aficamten,
72.2% experienced an improvement in pVO2, compared to 43.8% of
patients treated with placebo. Among the patients treated with
aficamten, 27.8% had a large improvement (≥3.0 mL/kg/min) in pVO2,
21.8% had a moderate improvement (≥1.5 to <3.0 mL/kg/min) and
22.6% had a small improvement (0 to <1.5).
Furthermore, enhanced exercise performance was
shown to be correlated with improvements in clinically important
measures including Kansas City Cardiomyopathy Questionnaire
Clinical Summary Score (KCCQ-CSS) (p=0.001), New York Heart
Association (NYHA) Functional Class (p<0.001), resting LVOT-G
(p=0.003), Valsalva LVOT-G (p=0.001), NT-proBNP (p<0.001) and
high-sensitivity cardiac troponin I (p=0.010). Importantly, these
correlations demonstrate that the therapeutic effects of aficamten
manifest broadly and are interrelated.
“Measuring changes in peak oxygen uptake only
tells part of the story in HCM. Through this analysis we’ve
developed a novel integrated exercise performance metric that, in
addition to pVO2, is designed to take into account submaximal
exercise performance, which may represent patient exertion in
day-to-day activities,” said Gregory Lewis, M.D., Jeffrey and Mary
Ellen Jay Chair and Section Head, Heart Failure Medical Director,
Cardiopulmonary Exercise Testing Laboratory, Professor of Medicine,
Harvard Medical School. “Using this metric, which is designed to
assess the impact of aficamten across a range of exercise
intensities, we saw that the therapeutic effect of aficamten
spanned the range associated with meaningful daily activity. By
positively impacting cardiac function, aficamten enhanced overall
exercise performance, which is closely correlated with improvements
in several important measures of disease including cardiac
structure, function and symptoms, underscoring the potential
clinical significance of the beneficial effects of aficamten.”
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. 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.
SEQUOIA-HCM (Safety,
Efficacy, and Quantitative
Understanding of Obstruction
Impact of Aficamten in
HCM), was the pivotal Phase 3 clinical trial in
patients with symptomatic obstructive hypertrophic cardiomyopathy
(HCM). 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).
The treatment effect with aficamten was consistent across all
prespecified subgroups reflective of patient baseline
characteristics and treatment strategies, including patients
receiving or not receiving background beta-blocker therapy.
Statistically significant (p<0.0001) and clinically meaningful
improvements were also observed in all 10 prespecified secondary
endpoints. Aficamten was well-tolerated 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.
Overall, there were no instances of worsening heart failure or
treatment interruptions due to low LVEF.
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. 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.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 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 conditions that FDA or another regulatory body may
require in connection with the approval of aficamten. 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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