A Study to Evaluate the Effect of Aficamten in Pediatric Patients With Symptomatic Obstructive Hypertrophic Cardiomyopathy (oHCM).

A Phase 2/3 Multicenter, Randomized, Double-Blind, Placebo-Controlled and Open-Label Extension Trial to Evaluate the Efficacy and Safety of Aficamten in a Pediatric Population With Symptomatic Obstructive Hypertrophic Cardiomyopathy

The purpose of this study is to evaluate the efficacy, safety and pharmacokinetics of aficamten in a pediatric population with symptomatic obstructive hypertrophic cardiomyopathy (oHCM).

The overall objective of the trial is to determine the efficacy, safety, and tolerability of administration of aficamten in adolescents (12 to < 18 years old) and children (6 to < 12 years old) with symptomatic oHCM. Adolescents and children will be studied in a staged approach involving established favorable pharmacodynamic and safety profiles of aficamten in adolescents followed by further pharmacokinetic modeling to inform the dosing regimen in children.

The 12 to <18 years old cohort has enrolled all participants and is no longer recruiting, the 6 to < 12 year old cohort is not yet recruiting.

The trial will consist of 3 periods:

1. Period 1 is the randomized, double-blind, placebo-controlled treatment period that will assess the efficacy, safety and tolerability of aficamten in pediatric participants.
2. Period 2 is the open-label extension trial that will assess the long-term safety of aficamten in pediatric participants, and further assess efficacy and tolerability.
3. Period 3 is the long-term extension trial that will assess the long-term safety of aficamten in pediatric participants, and further assess efficacy and tolerability.

Inclusion Criteria:

• Period 1: Treatment Period

  • Males and females between 12 and < 18 years of age at screening and at Day 1.
  • Body weight ≥ 35 kg
  • Diagnosed with oHCM based on the following at screening:

• Left ventricular (LV) hypertrophy with nondilated LV chamber in the absence of other cardiac disease.

• Core laboratory confirmation of LV end-diastolic wall thickness that meets a threshold of:

  • Z-score > 2.5 in the absence of family history OR
  • Z-score > 2 in the presence of positive family history or positive genetic test.

• Core laboratory confirmation of LVEF ≥ 60% AND Valsalva LVOT-G ≥ 50 mmHg.

  • oHCM of sarcomeric origin confirmed by genetic testing or, if unable to confirm by genetic testing, oHCM of sarcomeric origin may be presumed in the absence of history of metabolic disorders, mitochondrial cardiomyopathies, neuromuscular disease, malformation syndromes, infiltrative diseases/inflammation, and endocrine disorders (such as Fabry's disease, Noonan syndrome with left ventricular hypertrophy, and amyloid-cardiomyopathy).
  • New York Heart Association (NYHA) Class ≥ II at screening.
  • Adequate acoustic windows for echocardiography.
  • Participants on beta blockers, verapamil, diltiazem, or disopyramide should have been on stable doses for more than 4 weeks prior to randomization.

• Period 2: Open-Label Extension

  • Completed Period 1. If unable to complete Period 1 due to circumstances not related to compliance or safety, the Medical Monitor may review and determine eligibility.
  • LVEF ≥ 55% after washout

• Period 3: Long-term Extension

  • Completed Period 2

Exclusion Criteria:

• Period 1: Treatment Period

Any of the following criteria will exclude potential participants from the trial:

• Significant valvular heart disease.

  • Moderate or severe valvular aortic stenosis or fixed subaortic obstruction.
  • Mitral regurgitation that is greater than mild in severity and not due to systolic anterior motion of the mitral valve (per judgment of Principal Investigator or designee).
  • Evidence of fixed left-sided obstruction (eg, subaortic membrane, aortic valve stenosis, or coarctation of the aorta).

• History of LV systolic dysfunction (LVEF < 45%) or stress cardiomyopathy at any time during their clinical course.

• History of congenital heart disease other than oHCM (may be enrolled if not hemodynamically significant in the judgement of the Principal Investigator and study Medical Monitor).

• Has been treated with SRT (surgical myectomy or percutaneous alcohol septal ablation) within the preceding 6 months or has plans for either treatment during the trial period.

• History of paroxysmal or persistent atrial fibrillation or atrial flutter.

• History of syncope, symptomatic ventricular arrhythmia, or sustained ventricular tachyarrhythmia within 3 months prior to screening.

• History or evidence of any other clinically significant disorder, malignancy, active infection, other condition, or disease that, in the opinion of the Principal Investigator (or designee) or the Medical Monitor, would pose a risk to participant safety or interfere with the trial evaluation, procedures, or completion.

• Current or previous use of drugs known to cause cardiomyopathy (eg, anthracyclines, monoclonal antibodies [trastuzumab], alkylating agents [cyclophosphamide], and tyrosine kinase inhibitors [sunitinib and imatinib]).

• Currently participating in another investigational device or drug trial or received an investigational device or drug < 1 month (or 5 half-lives for drugs, whichever is longer) prior to screening.

• Implantable cardioverter defibrillator (ICD) implantation within 6 weeks of screening or planned ICD implantation during the trial period.

• Has received prior treatment with aficamten or mavacamten.

• Currently listed for heart transplantation or anticipated to be listed for heart transplantation in the next 12 months.