Dose-finding Study to Evaluate the Safety, Tolerability, PK, and PD of CK-3773274 in Adults With HCM

This study is being performed to understand the effect of different doses of CK-3773274 on patients with hypertrophic cardiomyopathy (HCM).


Eligibility Criteria:
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 left ventricular (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
* 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
* 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.

Exclusion Criteria

* Aortic stenosis or fixed subaortic obstruction.
* Known infiltrative or storage disorder causing cardiac hypertrophy that mimics oHCM (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).
* Has any ECG abnormality considered by the investigator to pose a risk to patient safety (eg, second degree atrioventricular block type II).
* 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 CK-3773274 or 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).