dose-finding study to evaluate the safety, tolerability, pk, and pd of ck-3773274 in adults with hcm

Conditions: Hypertrophic Cardiomyopathy (HCM)

Summary: 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).

Keywords: ck-3773274 ck-274 obstructive hypertrophic cardiomyopathy ohcm redwood-hcm non-obstructive hypertrophic cardiomyopathy nhcm hypertrophic cardiomyopathy hcm aficamten