Efficacy and Safety Evaluation of Aficamten in Pediatric Patients with Symptomatic Obstructive Hypertrophic Cardiomyopathy: A Phase 2/3 Randomized, Double-blind, Placebo-controlled Trial

Trial ID: 2024-511377-30-00
Protocol: CY 6023
Sponsor: Cytokinetics Inc.

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Diseases & Conditions

Hypertrophic cardiomyopathy

Objectives

The primary objective of this study is to assess the effect of **aficamten** compared with placebo on the change from baseline in Valsalva left ventricular outflow tract gradient (LVOT-G) in pediatric participants with symptomatic obstructive hypertrophic cardiomyopathy (oHCM). This is clinically relevant as it aims to evaluate the potential of aficamten to alleviate the obstruction in the heart's outflow tract, which is a critical factor in the management of oHCM. Additionally, the study seeks to determine the safety of aficamten in this population, which is essential for ensuring the therapeutic viability of the drug in pediatric patients.

Secondary objectives include: - Assessing the effect of aficamten compared with placebo on change from baseline in resting LVOT-G. - Evaluating the pharmacokinetics (PK) of aficamten. - Evaluating the effect of aficamten compared with placebo on cardiac biomarker levels. - Evaluating the effect of aficamten compared with placebo on the New York Heart Association (NYHA) Functional Classification. - Assessing the long-term effects of aficamten on LVOT-G. - Assessing the effect of aficamten on functional outcomes.

Participants

The clinical trial involves a total of **56 participants** diagnosed with **symptomatic obstructive hypertrophic cardiomyopathy** (oHCM). The study population comprises both male and female subjects, specifically targeting an age range of 12 to less than 18 years. Participants are required to have a body weight of at least 45 kg for the initial cohort, with subsequent inclusion of those weighing at least 35 kg after a safety assessment. The trial population was selected based on specific echocardiographic criteria confirming left ventricular hypertrophy with a nondilated chamber, and a left ventricular ejection fraction (LVEF) of 60% or higher. Participants are expected to have a New York Heart Association (NYHA) Class of II or higher at screening. The study includes individuals on stable doses of beta blockers, verapamil, diltiazem, or disopyramide for more than four weeks prior to randomization. The trial also considers the safety of aficamten in pediatric participants, with a focus on those who have completed the initial period of the study. The selection process ensures the inclusion of a vulnerable population, with careful monitoring of their health status throughout the trial.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study with an open-label extension to evaluate the efficacy and safety of **aficamten** in a pediatric population with symptomatic obstructive hypertrophic cardiomyopathy. The trial is structured in two phases: Phase 2 and Phase 3, with the primary objective of assessing the effect of aficamten compared to placebo on the change from baseline in Valsalva left ventricular outflow tract gradient (LVOT-G) and determining the safety profile of aficamten in the target population. The trial is expected to commence recruitment on January 1, 2025, and conclude by March 31, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, body weight, and echocardiographic parameters. The trial will include multiple follow-up visits to monitor the participants' response to treatment and any adverse events. The primary endpoint will be evaluated at Week 12, with secondary endpoints assessed at 12-week intervals throughout the open-label extension phase. The end-of-study visit will mark the completion of the trial for each participant.

The expected duration of participant involvement is up to 64 weeks, depending on the phase of the trial they are enrolled in. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it necessary for their safety. The trial will utilize a placebo comparator, with aficamten administered in the form of a film-coated tablet, taken orally. The maximum daily dose of aficamten is set at 20 mg, with a total maximum treatment period of 64 weeks.

Treatment

The clinical trial involves the administration of **Aficamten**, a chemical compound with the active substance name **Aficamten**. The pharmaceutical form of Aficamten is a **film-coated tablet**, and it is administered orally. The maximum daily dose of Aficamten is 20 mg, with a total maximum dose of 8120 mg over a treatment period of 64 days. The compound is chemically synthesized and is identified by the sponsor product code CK-3773274. The trial aims to evaluate the efficacy and safety of Aficamten in a pediatric population with symptomatic obstructive hypertrophic cardiomyopathy.

In addition to Aficamten, the study includes a **placebo** treatment, which is a tablet placebo designed to match the 5 mg Aficamten tablet. The placebo serves as a comparator treatment in the randomized, double-blind, placebo-controlled phase of the trial. The placebo does not contain any active substance and is used to assess the effect of Aficamten by providing a control for comparison. The placebo is administered in the same manner as Aficamten, ensuring that the study maintains blinding and minimizes bias.

Efficacy

The efficacy of Aficamten in the treatment of symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in a pediatric population will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint for Period 1 is the change in Valsalva left ventricular outflow tract gradient (LVOT-G) while maintaining left ventricular ejection fraction (LVEF) ≥ 55% from baseline to Week 12. Additionally, the incidence of adverse events (AEs) and serious adverse events (SAEs) will be monitored through the end of the study.

Secondary endpoints include changes in resting LVOT-G from baseline to Week 12, as well as pharmacokinetic parameters such as observed Ctrough, Cmax, tmax, and AUCtau for Aficamten. Biomarker levels, including NT-proBNP and high-sensitivity cardiac troponin I (hs-cTnI), will also be evaluated for changes from baseline to Week 12. The New York Heart Association (NYHA) Functional Class will be assessed for changes and the proportion of participants with at least one class improvement from baseline to Week 12 will be recorded.

In the open-label extension (OLE) phase, changes in peak LVOT-G at rest and with Valsalva provocation will be measured at 12-week intervals from Week 14 through the end of treatment. The proportion of participants achieving specific LVOT-G and LVEF thresholds will be tracked, and time to first occurrence of these thresholds will be documented. Changes in NYHA Functional Class and the proportion of participants with at least one class improvement from Week 14 to the end of treatment will also be evaluated.

Inclusion and Exclusion Criteria

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Inclusion Criteria

P1: Males and females between 12 and < 18 years of age at screening and at Day 1.
P1: Body weight ≥ 45 kg for the initial cohort and then body weight ≥ 35 kg after at least 10 participants in the initial cohort have undergone dose titration up to Week 4 without observed events of LVEF < 50% at the starting dose of 5 mg qd.
P1: Diagnosed with oHCM per the following criteria, confirmed at the time of 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 (Ommen 2020)>2.5 in the absence of family history or Z-score (Ommen 2020)>2 in the presence of positive family history or positive genetic test. Core laboratory confirmation of LVEF ≥60% AND Valsalva LVOT-G ≥50mmHg.
P1: 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).
P1: New York Heart Association (NYHA) Class ≥ II at screening.
P1: Adequate acoustic windows for echocardiography.
P1: Participants on beta blockers, verapamil, diltiazem, or disopyramide should have been on stable doses or more than 4 weeks prior to randomization.
P2: 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.
P2: LVEF ≥ 55% after washout.
P3: completed period 2

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Exclusion Criteria

P1: 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).
P1: Has received prior treatment with aficamten or mavacamten.
P1: Currently listed for heart transplantation or anticipated to be listed for heart transplantation in the next 12 months.
P1: Does not assent/consent to participate in the CMR substudy.
P1: Inability to tolerate CMR without sedation.
P1: Has an ICD or cardiac pacemaker.
P1: History of LV systolic dysfunction (LVEF < 45%) or stress cardiomyopathy at any time during their clinical course.
P1: 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).
P1: Hypersensitivity to aficamten or any of the excipients
P1: 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.
P1: History of paroxysmal or persistent atrial fibrillation or atrial flutter.
P1: History of syncope, symptomatic ventricular arrhythmia, or sustained ventricular tachyarrhythmia within 3 months prior to screening.
P1: 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.
P1: 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]).
P1: 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.
P1: Implantable cardioverter defibrillator (ICD) implantation within 6 weeks of screening or planned ICD implantation during the trial period.