Targeting Myocardial Energetics in Nonobstructive Hypertrophic Cardiomyopathy (nHCM): The Role of Ninerafaxstat

Non-obstructive hypertrophic cardiomyopathy (nHCM) is a condition that has significant therapeutic challenges due to its complicated pathophysiology. Beta-blockers (BB) and calcium channel blockers (CCB) are the existing treatment modalities that offer limited symptom relief and fail to address underlying metabolic deficits. This review evaluates emerging targeted therapies, focusing on ninerafaxstat, a cardiac metabolic modulator that inhibits 3-ketoacyl-CoA thiolase (3-KAT) to shift myocardial substrate utilization from fatty acids to glucose, thereby improving energy efficiency. Clinical trials of novel agents, including myosin inhibitors (aficamten, mavacamten) and metabolic modulators, highlight ninerafaxstat's unique potential. The Phase 2 IMPROVE-HCM trial demonstrated improved ventilatory efficiency (VE/VCO2 slope: -2.1, P=0.005), reduced left atrial remodeling (-0.9 mm, P=0.01), and enhanced quality of life in severe subgroups, with a favorable safety profile. Unlike myosin inhibitors, which reduce hypercontractility but not energy deficits, ninerafaxstat directly resolves metabolic dysfunction, synergizing with sarcomere-targeted therapies for dual-pathway efficacy. While myosin inhibitors (e.g., REDWOOD-HCM, MAVERICK-HCM) show robust biomarker improvements, ninerafaxstat addresses the core energy mismatch driving nHCM progression. Innovative gene therapies (MyPEAK-1) and exercise programs broaden the range of available treatments. Ninerafaxstat represents a paradigm shift toward precision medicine in nHCM, offering a metabolic foundation for combination strategies. Future Phase 3 trials must validate long-term benefits on functional capacity, metabolic markers, arrhythmia risk, and survival, positioning ninerafaxstat as a cornerstone therapy for restoring cardiac energetics in nHCM.