Hypertrophic cardiomyopathy (HCM)

HCM -related fatal and disabling events are most often attributable to sudden cardiac death, heart failure, and embolic stroke.

HCM is the most common inherited cardiovascular disorder, and its prevalence is likely underestimated due to the current limitations of early screening. HCM is estimated to affect at least 1 in 200 people, with obstructive (either at rest or with provocation) HCM accounting for approximately 2/3 of cases and non-obstructive HCM for approximately 1/3 of cases in clinical practice. It is a leading cause of death in young adults and athletes. HCM-related fatal and disabling events are most often attributable to sudden cardiac death, heart failure, and embolic stroke. Sudden cardiac death is the common cause of death in young HCM patients between 10 to 35 years old, while heart failure and stroke due to HCM-related atrial fibrillation represent the common cause of death in middle-aged and elderly patients, respectively. The annual mortality rate for HCM patients in hospitals is 2% to 4%.

Patients with symptomatic oHCM are generally offered pharmacotherapy with non-HCM-specific agents such as 𝛽-blockers, verapamil, diltiazem and disopyramide based on clinicians’ experience; however, these medications do not target the underlying pathology (i.e., hypercontractility) and provide only symptomatic relief with variable effectiveness and risks of significant adverse effects. For oHCM patients with a left ventricular outflow tract pressure gradient (LVOT-G) of ≥50 mm Hg either at rest or with provocation who also have severe symptoms refractory to medical therapy, septal reduction therapies (such as surgical myectomy or percutaneous alcohol septal ablation) can be effective, but these invasive procedures carries risks of complications including death.

Aficamten is an investigational selective, small molecule cardiac myosin inhibitor from Cytokinetics, Incorporated (Nasdaq: CYTK), discovered following an extensive chemical optimization program that was conducted with careful attention to therapeutic index and pharmacokinetic properties and as may translate into next-in-class potential in clinical development. Aficamten was designed to reduce the number of active actin-myosin cross bridges during each cardiac cycle and consequently suppress the myocardial hypercontractility that is associated with hypertrophic cardiomyopathy (HCM). In preclinical models, aficamten reduced myocardial contractility by binding directly to cardiac myosin at a distinct and selective allosteric binding site, thereby preventing myosin from entering a force producing state.

In July 2020, CORXEL entered into a license and collaboration agreement with Cytokinetics, a late-stage biopharmaceutical company headquartered in California, pursuant to which Cytokinetics has granted to CORXEL an exclusive license to develop and commercialize aficamten (formerly known as CK-274) in the Greater China territory. In December 2023, CORXEL announced positive results from the China cohort of SEQUOIA-HCM, the pivotal phase 3 clinical trial of aficamten in patients with obstructive hypertrophic cardiomyopathy. In March 2024, CORXEL announced that the Center for Drug Evaluation (CDE) of the National Medical Products Administration of the PRC (NMPA) has approved the Clinical Trial Application (CTA) for the China cohort of ACACIA-HCM, a Phase 3 clinical trial of aficamten in patients with symptomatic non-obstructive hypertrophic cardiomyopathy (nHCM).

The development program for aficamten is assessing its potential as a treatment that improves exercise capacity and relieves symptoms in patients with HCM as well as its potential long-term effects on cardiac structure and function. Aficamten received Breakthrough Therapy Designation for the treatment of symptomatic obstructive HCM from the U.S. Food & Drug Administration (FDA) as well as the National Medical Products Administration (NMPA) in China.

Reference: 

• The Joint Committee of Cardiomyopathy Specialty Alliance, National Center for Cardiovascular Diseases/Cardiovascular Precision Medicine Branch of China International Exchange and Promotive Association for Medical and Health Care. 2023 Guideline for Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy. Chinese Circulation Journal, 2023, 38: 1.

• Chinese Heart Failure Association of Chinese Medical Doctor Association, National Heart Failure Committee, Editorial Board of Chinese Journal of Heart Failure and Cardiomyopathy. 2022 Chinese guideline on hypertrophic cardiomyopathy. Chin J Heart Fail & Cardiomyopathy, 2022, 6(2): 80-103

• Heart failure committee of Chinese medical association, Editorial board of the Chinese journal of heart failure and cardiomyopathy. 2017 Guidelines of hypertrophic cardiomyopathy management in China. Chin J Heart Fail & Cardiomyopathy. 2017; 1(2): 65-86.

• Ommen SR et al. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy. Circulation. 2020 Dec 22;142(25): e533-e557.

• Cytokinetics website.