Safety and Efficacy of Ninerafaxstat in Nonobstructive HCM

Quick Takes

  • In this phase 2 trial, ninerafaxstat was well tolerated in patients with nonobstructive HCM.
  • Use of ninerafaxstat was associated with a trend towards an improvement in patient-reported health status measures and functional capacity and decrease in NT-proBNP and LA size.

Study Questions:

What is the safety and tolerability of ninerafaxstat in patients with symptomatic, nonobstructive hypertrophic cardiomyopathy (nHCM)?


The IMPROVE-HCM study was a phase 2, multicenter, randomized, placebo-controlled, double-blind trial performed across 12 centers. Adults with nHCM and peak oxygen consumption (pVO2) ≤80% predicted, end-diastolic left ventricular (LV) wall thickness ≥15 mm (or ≥13 mm with family history of HCM or a pathogenic sarcomeric mutation), and absent resting and/or exercise-provokable gradient with LV ejection fraction (LVEF) ≥50% were enrolled. Patients were randomized to 200 mg ninerafaxstat twice daily or placebo. Endpoints included treatment-emergent adverse events. Efficacy endpoints included maximal and submaximal exercise capacity, O2 uptake recovery kinetics, LV diastolic function, LV systolic function, symptoms and patient-reported health status (Kansas City Cardiomyopathy Questionnaire), and biomarkers.


The trial included 67 patients with a mean age of 57 years, 55% were female, and 59% had New York Heart Association class II symptoms. Treatment-emergent side effects occurred in 12% of patients in the ninerafaxstat group and 6% in the placebo group. Patients on ninerafaxstat were more likely to experience nausea, hypokalemia, chest discomfort, and fatigue. Ninerafaxstat use was not associated with change in LVEF at 12 weeks compared to placebo. Patient-reported health status measures trended towards improvement with ninerafaxstat but did not reach statistical significance. pVO2 uptake was no different between the two groups but ventilatory efficiency slope was better with ninerafaxstat. Ninerafaxstat use was associated with a nonsignificant decrease in N-terminal pro–B-type natriuretic peptide (NT-proBNP) and statistically significant decrease in left atrial (LA) size from baseline to week 12. Measures of diastolic function were no different between the two groups.


In a phase 2 randomized, controlled trial, a novel cardiac mitotrope, ninerafaxstat, was associated with favorable changes in patient-reported health status, functional capacity, and LA dimension in patients with nHCM.


The last few years have seen major advances in management of patients with obstructive HCM with the advent of myosin inhibitors. However, patients with nHCM continue to have no treatment options apart from beta-blockers or calcium channel blockers that are frequently not effective. nHCM is characterized by abnormal bioenergetics with increased use of free fatty acids that are a less efficient energy source, leading to diastolic dysfunction. Ninerafaxstat is a novel cardiac mitotrope that inhibits mitochondrial fatty acid oxidation shifting towards glucose metabolism for energy. This phase 2 trial suggests that the drug was largely well tolerated with a higher incidence of nausea, chest pain, fatigue, and hypokalemia. Ninerafaxstat use was associated with a trend towards reduction in NT-proBNP, LA size, and improvement in patient-reported health status and functional capacity. A larger phase 3 study will provide additional data on efficacy endpoints.

Clinical Topics: Heart Failure and Cardiomyopathies

Keywords: Exercise Tolerance, Hypertrophic Cardiomyopathy, Novel Agents

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