Ninerafaxstat in the Treatment of Diabetic Cardiomyopathy and Nonobstructive Hypertrophic Cardiomyopathy

Ninerafaxstat is a novel mitotrope under investigation in 2 large clinical trials: IMPROVE-DiCE (a phase IIa trial investigating ninerafaxstat) and IMPROVE-hypertrophic cardiomyopathy (HCM). IMPROVE-DiCE is a single-center, open-label, phase 2a trial investigating the effectiveness of ninerafaxstat in diabetic cardiomyopathy. Ninerafaxstat significantly improved phosphocreatine/adenosine triphosphate median by 32% (P < 0.01) and reduced myocardial triglyceride content by 34% (P = 0.026). Magnetic resonance imaging (MRI) analysis showed improved left ventricular peak circumferential diastolic strain rate by 15% (P < 0.047) and peak left ventricular filling rate by 11% (P < 0.05). Pyruvate dehydrogenase flux was increased in 7 of 9 patients (P = 0.08), consistent with improved glucose utilization. IMPROVE-HCM (ninerafaxstat safe, effective for nonobstructive hypertrophic cardiomyopathy patients) is a phase 2, multicenter, randomized controlled and double-blinded study. From baseline to 12 weeks, ninerafaxstat was associated with a significantly improved ventilatory efficiency slope compared with placebo (P = 0.006). In a post hoc analysis with 35 patients with baseline Kansas City Cardiomyopathy Questionnaire score ≤80, changes in ventilatory efficiency slope favored ninerafaxstat versus placebo (P = 0.02). Left atrial size, a surrogate marker of diastolic dysfunction, was significantly decreased in patients on ninerafaxstat versus placebo (P = 0.01). These findings support a larger phase 3 study in symptomatic nonobstructive HCM patients to further investigate ninerafaxstat. Several drugs that also improve glucose utilization including fatty acid oxidation inhibitors, carnitine palmitoyltransferase I inhibitors, and glucagon-like peptide-1 receptor agonists are presently under investigation in clinical trials.