Long-term Safety and Tolerability Evaluation of Aficamten (CK-3773274) in Adults with Symptomatic Hypertrophic Cardiomyopathy: An Open-label Extension Study

The primary objective of this study is to determine the **safety** and **tolerability** of aficamten in patients with symptomatic hypertrophic cardiomyopathy (HCM). This is clinically relevant as it addresses the need for effective management of symptoms in HCM, a condition characterized by thickened heart muscle that can lead to heart failure and arrhythmias. Ensuring the safety and tolerability of aficamten is crucial for its potential use as a therapeutic option in this patient population.

Secondary objectives include assessing the long-term effects of aficamten on the left ventricular outflow tract gradient (LVOT-G) in patients with obstructive hypertrophic cardiomyopathy (oHCM). This evaluation is important as it may provide insights into the sustained impact of aficamten on cardiac function, potentially improving clinical outcomes for patients with oHCM by reducing the obstruction in the heart's outflow tract.

The clinical trial involves a total of **674 participants** diagnosed with **symptomatic hypertrophic cardiomyopathy (HCM)**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific criteria, including the completion of a previous Cytokinetics study investigating aficamten, and a left ventricular ejection fraction (LVEF) of 55% or greater. The trial includes a vulnerable population, indicating that special considerations are in place to ensure their safety and well-being. The general health status of participants is characterized by their ability to meet the inclusion criteria, and no specific lifestyle considerations such as diet or physical activity are highlighted in the available data.

The clinical trial is designed to evaluate the long-term safety and tolerability of **aficamten** in adults with symptomatic hypertrophic cardiomyopathy (HCM). This is an open-label, phase 4 study, which means that both the researchers and participants know which treatment is being administered. The trial is expected to run from June 2021 to June 2026, with a total duration of approximately five years. Participants will be involved in the study for a maximum treatment period of 240 weeks, during which they will receive aficamten in the form of a film-coated tablet, administered orally. The maximum daily dose is 20 mg, with a total maximum dose of 33,600 mg over the course of the study.

The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess the overall outcomes. The inclusion criteria require participants to have completed a previous Cytokinetics study involving aficamten, with a left ventricular ejection fraction (LVEF) of at least 55%. The primary endpoints focus on the incidence of adverse events (AEs), serious adverse events (SAEs), and any decrease in LVEF below 50%. Secondary endpoints include changes in baseline values related to left ventricular outflow tract gradient (LVOT-G) and LVEF.

Participants may be withdrawn from the study if they experience significant safety concerns or if they do not comply with the study protocol. The trial aims to provide valuable data on the long-term effects of aficamten in managing symptomatic HCM, contributing to the understanding of its safety profile and therapeutic potential.

The clinical trial involves the administration of **Aficamten**, a pharmaceutical product developed by Cytokinetics Inc. Aficamten is presented in the form of a **film-coated tablet** and is intended for **oral use**. The active substance in Aficamten is chemically derived and is identified by the chemical name (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, also known by the sponsor product code CK-3773274. The maximum daily dose of Aficamten is 20 mg, with a total maximum dose of 33,600 mg over a treatment period of up to 240 days. The trial aims to evaluate the safety and tolerability of Aficamten in patients with symptomatic **hypertrophic cardiomyopathy** (HCM).

In this study, Aficamten is the sole experimental medication being tested, and no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The administration of Aficamten is monitored to ensure participant compliance with the dosing schedule. The trial does not involve any pediatric formulations, and Aficamten is not classified as an orphan drug. The study is designed to provide a comprehensive assessment of the long-term effects of Aficamten in the target patient population.

The efficacy of **Aficamten** in the treatment of **Hypertrophic Cardiomyopathy (HCM)** will be assessed through a series of primary and secondary endpoints. The primary endpoints focus on the safety profile of the drug, including the incidence of reported adverse events (AEs), serious adverse events (SAEs), and the occurrence of left ventricular ejection fraction (LVEF) dropping below 50%. These parameters will be systematically collected and analyzed to determine the safety and tolerability of the treatment.

Secondary endpoints will evaluate the therapeutic impact of **Aficamten** by measuring changes from baseline in specific cardiac function parameters. These include the peak left ventricular outflow tract gradient (LVOT-G) at rest and with Valsalva provocation, as well as the proportion of patients achieving specific LVOT-G thresholds. Additionally, the time to first occurrence of these thresholds will be recorded. The assessments will be conducted at various timepoints throughout the trial, allowing for a comprehensive analysis of the drug's efficacy in improving cardiac function in patients with symptomatic HCM.