Primary objectives:To determine the safety and tolerability of CK-3773274 in patients with symptomatic HCMSecondary objectives:- To describe the concentration-response relationship of CK-3773274 on the resting and post-Valsalva LVOT-G on…
ID
Source
Brief title
Condition
- Myocardial disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Patient incidence of reported adverse events (AEs)
- Patient incidence of reported serious adverse events (SAEs)
- Patient incidence of left ventricular ejection fraction (LVEF) <50%
Secondary outcome
- Slope of the relationship of the plasma concentration of CK-3773274 to the
change from baseline in the resting LVOT-G
- Slope of the relationship of the plasma concentration of CK-3773274 to the
change from baseline in the post-Valsalva LVOT-G
- Change from baseline in resting and post-Valsalva LVOT-G over time as a
function of dose
- Change from baseline in resting and post-Valsalva LVOT-G to Week 10
- Slope of the relationship of the plasma concentration of CK-3773274 to the
change from baseline in the resting LVEF
- Observed maximum plasma concentration (Cmax) and trough plasma concentration
(Ctrough) for CK-3773274 during dosing
Background summary
This is the first patient study of CK-3773274, a small molecule, allosteric
inhibitor of cardiac myosin being developed as a chronic oral treatment for
patients with hypertrophic cardiomyopathy (HCM).
Hypertrophic Cardiomyopathy
HCM results from pathogenic genetic mutations, often affecting the genes
encoding the proteins of the cardiac sarcomere, such as myosin (Maron B J
2018). Histologic features include myofibrillar disarray, myocyte hypertrophy
and interstitial fibrosis. Clinically, HCM is characterized by left ventricular
(LV) hypertrophy unexplained by loading conditions and a nondilated LV with
preserved or increased ejection fraction (Gersh 2011). Imaging studies of
patients with HCM show hypertrophied LV walls, enhanced ventricular
contractility, normal end-diastolic LV volume, reduced end-systolic volume,
impaired diastolic compliance and often left atrial enlargement (Marian 2017).
From population-based insurance claims and national health system data, the
prevalence of clinically identified individuals with HCM in the US and EU is
approximately 1:2000 and 1:3195 (Maron M S 2016; Husser 2018; Magnusson 2017;
Pujades-Rodriguez 2018).
Approximately 70% of patients with phenotypic HCM will demonstrate an element
of LVOT obstruction (Maron M S 2006). The mechanisms for developing obstruction
are well defined and involve a complex interplay between alterations in
ventricular flow between asymmetric septal hypertrophy and the mitral valve
leaflets. The result is abnormal systolic contact with the mitral valve
leaflets (most commonly the anterior leaflet) and the development of an LVOT
gradient (LVOT-G). By nature, oHCM is a dynamic condition with variable
systolic gradients. In the setting of reduced afterload or reduced preload,
symptoms change depending on the gradient and often worsen during exertion.
Additional clinical manifestations of HCM include an elevated risk for
ventricular fibrillation and sudden cardiac death; heart failure syndrome due
to diastolic dysfunction; chest pain due to microvascular ischemia;
palpitations and stroke due to atrial fibrillation; syncope and presyncope due
to either ventricular arrhythmias or an abnormal blood pressure response to
exercise; and, in a minority of patients, progression to systolic heart failure.
Contemporary management strategies for oHCM have resulted in the majority of
patients achieving normal or near-normal longevity and improved morbidity;
however, there has been little progress with the development of novel
pharmacotherapies. Current medical treatment consists of beta-blockers,
verapamil, diltiazem and disopyramide as recommended in the 2014 European
Society of Cardiology and in the 2011 American College of Cardiology Foundation
/ American Heart Association guidelines for the diagnosis and management of
HCM. For patients with advanced symptomatic disease unresponsive to
medications, septal reduction therapies (surgical myectomy or percutaneous
alcohol ablation of the septum) can provide effective LVOT-G reduction (Elliott
2014; Gersh 2011; Ponikowski 2016). A subgroup of patients, who have been
resuscitated from sudden cardiac death or who are at risk of sudden cardiac
death, may undergo placement of an implantable cardioverter defibrillator (ICD)
(Kristensen 2014). For those patients with HCM with end-stage disease who have
both significant systolic impairment and diastolic dysfunction, cardiac
transplantation may be the only treatment option (Gersh 2011). Disease-related
mortality is most often attributable to sudden cardiac death, heart failure,
and embolic stroke.
The remaining 30% of patients with HCM do not have LVOT obstruction, either at
rest or with physiologic provocation (ie Valsalva maneuver or exercise) and are
categorized as nHCM. Of note, patients with nHCM experience a higher burden of
life-threatening ventricular arrhythmias (sustained ventricular tachycardia or
ventricular fibrillation) compared to patients with resting or latent
obstruction but have a similar risk of developing heart failure and all-cause
mortality compared to patients with resting oHCM. Treatment options for
patients with nHCM are limited and while there may be some benefit of
beta-blockers and calcium channel blockers, the evidence for these therapies is
minimal. Patients with severe heart failure symptoms may require heart
transplantation.
Mutations in over a dozen genes encoding sarcomere-associated proteins cause
HCM. MYH7 and MYBPC3, encoding β-myosin heavy chain and myosin-binding protein
C, respectively, are the two most common genes involved, together accounting
for approximately 50% of the HCM families (Elliott 2014). Mechanistically,
mutations in HCM appear to increase the net power generation in the sarcomere
in vitro (Chuan 2012; Sommese 2013; Spudich 2016; Toepfer 2019). The findings
in these studies are consistent with the underlying myocardial pathophysiology
of the LV in patients with HCM being hypercontractile with diminished
compliance (Wilson 1967).
These nonclinical investigations have enhanced our understanding of the
molecular pathogenesis of HCM and have stimulated efforts designed to identify
cardiac myosin modulators that can target the underlying mechanism of
hypercontractility in obstructive HCM.
CK3773274
CK-3773274, a small molecule, allosteric inhibitor of cardiac myosin is being
developed as a chronic oral treatment for patients with HCM. CK-3773274 is
designed to reduce the hypercontractility that underlies the pathophysiology of
HCM in the cardiac sarcomere. The intended pharmacologic effect is reduction in
force produced by the cardiac sarcomere that seems to drive the disease,
improving diastolic function and also reducing LVOT obstruction in those
patients with oHCM.
CK-3773274 has been studied in a Phase 1 study of healthy adult participants.
This Phase 2 study will be the first investigation of CK-3773274 in patients
with HCM.
Study objective
Primary objectives:
To determine the safety and tolerability of CK-3773274 in patients with
symptomatic HCM
Secondary objectives:
- To describe the concentration-response relationship of CK-3773274 on the
resting and post-Valsalva LVOT-G on echocardiogram over 10 weeks of treatment
in patients with oHCM (Cohorts 1, 2, 3 only)
- To describe the dose response relationship on LVOT-G (resting and Valsalva)
of CK-3773274 in patients with symptomatic oHCM (Cohorts 1, 2, 3 only)
- To evaluate the concentration-response relationship of CK-3773274 on resting
left ventricular ejection fraction (LVEF) over 10 weeks of treatment in
patients with HCM.
- To evaluate the plasma concentrations of CK-3773274 in patients with HCM
For exploratory objectives refer to the protocol.
Study design
This is a Phase 2, multi-center, dose finding study in patients with
symptomatic HCM. Four sequential cohorts will be enrolled. The first two
cohorts will enroll patients with oHCM randomized 2:1 to CK-3773274 or placebo.
Patients in Cohorts 1 and 2 will receive up to three escalating doses of
CK-3773274 or placebo based on echocardiographic guidance. Cohort 3 will enroll
patients with oHCM whose background HCM therapy includes disopyramide (patients
on disopyramide are excluded from Cohorts 1, 2, and 4). Cohort 4 will enroll
patients with nHCM. In the third and fourth cohorts, all patients will be
assigned CK-3773274 and will receive up to three escalating doses of CK-3773274
based on echocardiographic guidance. Overall, the treatment duration will be 10
weeks with a 4-week follow-up period after the last dose.
Intervention
In Cohorts 1 and 2, subjects will receive CK-3773274 or placebo. In Cohorts 3
and 4, subjects will receive CK-3773274. CK-3773274 is administered as an oral
tablet at doses of 5-30 mg per day.
Study burden and risks
Risks and side effects observed with CK-3773274
CK-3773274 has the potential to reduce heart pumping function too much. This
has been observed in a few study subjects with no other side effect and
improved after the study medicine dose was reduced or discontinued. Since
CK-3773274 is a research medicine, there may be other risks that are unknown.
All medicines have the potential risk of an allergic reaction, which if not
treated promptly, could become life threatening.
Risks from study procedures
Risks and discomforts that subjects may experience from the study procedures
include:
Heart Monitoring Device:
An ambulatory monitoring device (about the size of a deck of cards) will be
used to monitor your heartbeat. The small device attaches to your chest with
an adhesive bandage. You may be asked to shave a part of your chest prior to
placing the device, which may cause irritation. In rare instances, the adhesive
bandage may cause skin irritation. Also, wearing the device may be
uncomfortable, such as during sleep. You may take a shower while wearing the
device.
Electrocardiogram (ECG):
Occasionally there may be some minor skin irritation from the adhesive tabs of
the wire electrodes.
Echocardiogram:
The technician will spread gel on the subject*s chest and then press a device
known as a transducer firmly against the skin. The subject may feel some mild
discomfort during the process.
350 Oyster Point Boulevard -
South San Francisdo CA 94080
US
350 Oyster Point Boulevard -
South San Francisdo CA 94080
US
Listed location countries
Age
Inclusion criteria
Males and females between 18 and 85 years of age at Screening.
Body weight is >=45 kg at Screening.
Diagnosed with HCM per the following criteria:
• Has LV hypertrophy with non-dilated LV chamber in the absence of other
cardiac disease.
• Has minimal wall thickness >=15 mm (minimal wall thickness >=13 mm is
acceptable with a positive family history of HCM or with a known
disease-causing gene mutation).
Adequate acoustic windows for echocardiography.
For Cohorts 1,2 and 3 has LVOT-G during screening as follows:
• Resting gradient >=50 mmHg
OR
• Resting gradient >=30 mmHg and <50 mmHg with post-Valsalva LVOT G >=50 mmHg
LVEF >=60% at screening.
New York Heart Association (NYHA) Class II or III at Screening.
Patients on beta-blockers, verapamil, diltiazem, or ranolazine should have been
on stable doses for >4 weeks prior to Randomization and anticipate remaining on
the same medication regimen during the study.
For Cohort 3: Patients must be taking disopyramide. Patients should have been
on stable disopyramide doses for >4 weeks prior to screening and anticipate
remaining on the same medication regimen during the study.
For Cohort 4 has resting and post-Valsalva LVOT-G <30 mmHg at the time of
screening.
For Cohort 4 has elevated NT-proBNP >300 pg/mL at the time of screening.
A full listing can be found in Protocol section 5.
Exclusion criteria
- Aortic stenosis or fixed subaortic obstruction.
- Known infiltrative or storage disorder causing cardiac hypertrophy that
mimics HCM (eg, Noonan syndrome, Fabry disease, amyloidosis).
- History of LV systolic dysfunction (LVEF <45%) at any time during their
clinical course.
- Documented history of current obstructive coronary artery disease (>70%
stenosis in one or more epicardial coronary arteries) or documented history of
myocardial infarction.
- Has been treated with septal reduction therapy (surgical myectomy or
percutaneous alcohol septal ablation) or has plans for either treatment during
the study period (Cohorts 1, 2, and 3 only). Patients having undergone septal
reduction therapy > 12 months prior to screening who remain symptomatic from
nHCM, and who meet all other criteria for inclusion, may be enrolled in Cohort
4.
- For Cohorts 1, 2 and 4: Has been treated with disopyramide or antiarrhythmic
drugs that have negative inotropic activity within 4 weeks prior to screening.
For Cohort 3, use of disopyramide is required.
- Paroxysmal atrial fibrillation or flutter documented during the Screening
period.
- Paroxysmal or permanent atrial fibrillation requiring rhythm restoring
treatment (eg, direct-current cardioversion, ablation procedure, or
antiarrhythmic therapy) <=6 months prior to screening. (This exclusion does not
apply if atrial fibrillation has been treated with anticoagulation and
adequately rate-controlled for >6 months.)
- History of syncope or sustained ventricular tachyarrhythmia with exercise
within 6 months prior to Screening.
- Has received prior treatment with CK3773274 or is currently receiving
mavacamten.
- For Cohort 4: has any documented history of LVOT-G >= 30 mmHg at rest, with
Valsalva, or with exercise (for subjects who have had prior septal reduction
therapy, this exclusion criteria only applies to gradients detected following
septal reduction therapy).
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-002785-12-NL |
| CCMO | NL71785.078.19 |