Cytokinetics, Incorporated (Nasdaq: CYTK) today announced
additional 48-week data from 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), at the 73rd Annual American College of
Cardiology (ACC) Scientific Session taking place from April 6, 2024
–April 8, 2024 in Atlanta, GA.
FOREST-HCM enrolled 213 patients with
obstructive HCM from May 28, 2021 through October 31, 2023.
Previously presented data from 17 patients who had been enrolled
through 48 weeks in FOREST-HCM showed that prolonged treatment with
aficamten was associated with significant and sustained reductions
in left ventricle outflow tract gradient (LVOT-G), and improvements
in symptoms and cardiac biomarkers. The updated data set presented
at ACC in Atlanta focuses on 46 patients from FOREST-HCM that had
completed 48 weeks of follow-up at the time of the current interim
analysis.
At Week 48, 75% of these patients were receiving
the 15 mg or 20 mg dose of aficamten. Treatment with aficamten for
48 weeks resulted in substantial and sustained reductions in
average resting LVOT-G (mean change from baseline (SD) = -39.6 mmHg
(34), p<0.0001) and Valsalva LVOT-G (mean change from baseline
(SD) = -53.2 mmHg (38.6), p<0.0001). Statistically significant
improvements in New York Heart Association (NYHA) Functional Class
from baseline were observed, with 82.2% of patients improving by ≥1
NYHA class with no instances of worsening NYHA class. Additionally,
there were significant improvements in NT-proBNP, a biomarker of
cardiac wall stress, with an average decrease of 63% from baseline
to week 48 (p<0.001). Treatment with aficamten also resulted in
statistically significant improvements in measures of cardiac
structure and function including decreases in maximum wall
thickness (mean change from baseline (SE) = -0.12 cm (0.02),
p<0.0001), left atrial volume index (mean changes from baseline
(SE) = -3.5 mL/m2 (0.98), p=0.0008) and lateral E/e’ (mean change
from baseline (SE) = -2.2 (0.92), p=0.02). While 19 of these 46
patients in FOREST-HCM met guideline eligibility criteria for
septal reduction therapy (SRT) at baseline, only one patient
remained eligible for SRT after six months of treatment with
aficamten, representing a 94% reduction in SRT-eligibility.
In FOREST-HCM, aficamten appears to be
well-tolerated, with no treatment-related serious adverse events
(SAEs). There was a modest reduction in left ventricular ejection
fraction (LVEF) from baseline to Week 48 (mean change from baseline
(SD) = -5.1 mg (5.9), p<0.0001). As has been previously
reported, three patients underwent dose down-titration due to LVEF
<50%. Two patients were asymptomatic, and one dose
down-titration occurred due to recurrent alcohol-induced atrial
fibrillation.
“These data from FOREST-HCM continue to
reinforce the efficacy and safety of longer-term treatment with
aficamten for patients with obstructive HCM, demonstrating
significant improvements in patient symptom burden and cardiac
function while also improving the overall architecture of the
heart,” said Fady I. Malik, M.D., Ph.D., Cytokinetics’ Executive
Vice President of Research & Development. “In light of the
positive results from SEQUOIA-HCM, the pivotal Phase 3 clinical
trial of aficamten, we are pleased to see this additional clinical
evidence that reinforces our intended next-in-class profile and
that may enable aficamten to become the cardiac myosin inhibitor of
choice among physicians and patients with HCM.”
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
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 show that treatment with
aficamten significantly improved exercise capacity compared to
placebo, increasing peak oxygen uptake (pVO2) measured by
cardiopulmonary exercise testing (CPET) by a least square mean
difference (95% CI) of 1.74 (1.04 - 2.44) mL/kg/min (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 8 (5.6%) and 13 (9.3%) 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. There
were no instances of worsening heart failure or treatment
interruptions due to low LVEF.
Aficamten is currently the subject of two
ongoing Phase 3 clinical trials: MAPLE-HCM
(Metoprolol vs Aficamten in
Patients with LVOT Obstruction on
Exercise Capacity in HCM),
evaluating aficamten as monotherapy compared to metoprolol as
monotherapy in patients with obstructive HCM, and ACACIA-HCM
(Assessment Comparing
Aficamten to Placebo on Cardiac
Endpoints In Adults with
Non-Obstructive HCM), evaluating aficamten in
patients with symptomatic non-obstructive 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 two
ongoing Phase 3 clinical trials: MAPLE-HCM, evaluating aficamten as
monotherapy compared to metoprolol as monotherapy in patients with
obstructive HCM and ACACIA-HCM, evaluating aficamten in patients
with non-obstructive 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 and 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. 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 CYTOKINETICS and 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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