Safety and Efficacy of Metabolic Modulation With Ninerafaxstat in Patients With Nonobstructive Hypertrophic Cardiomyopathy

Martin S. Maron, Masliza Mahmod, Azlan Helmy Abd Samat, Lubna Choudhury, Daniele Massera, Dermot M.J. Phelan, Sharon Cresci, Matthew W. Martinez, Ahmad Masri, Theodore P. Abraham, Eric Adler, Omar Wever-Pinzon, Sherif F. Nagueh, Gregory D. Lewis, Paul Chamberlin, Jai Patel, Arash Yavari, Hakim Moulay Dehbi, Rizwan Sarwar, Betty RamanLadislav Valkovič, Stefan Neubauer, James E. Udelson, Hugh Watkins

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Background: In nonobstructive hypertrophic cardiomyopathy (nHCM), there are no approved medical therapies. Impaired myocardial energetics is a potential cause of symptoms and exercise limitation. Ninerafaxstat, a novel cardiac mitotrope, enhances cardiac energetics. Objectives: This study sought to evaluate the safety and efficacy of ninerafaxstat in nHCM. Methods: Patients with hypertrophic cardiomyopathy and left ventricular outflow tract gradient <30 mm Hg, ejection fraction ≥50%, and peak oxygen consumption <80% predicted were randomized to ninerafaxstat 200 mg twice daily or placebo (1:1) for 12 weeks. The primary endpoint was safety and tolerability, with efficacy outcomes also assessed as secondary endpoints. Results: A total of 67 patients with nHCM were enrolled at 12 centers (57 ± 11.8 years of age; 55% women). Serious adverse events occurred in 11.8% (n = 4 of 34) in the ninerafaxstat group and 6.1% (n = 2 of 33) of patients in the placebo group. From baseline to 12 weeks, ninerafaxstat was associated with significantly better VE/VCO2 (ventilatory efficiency) slope compared with placebo with a least-squares (LS) mean difference between the groups of −2.1 (95% CI: −3.6 to −0.6; P = 0.006), with no significant difference in peak VO2 (P = 0.90). The Kansas City Cardiomyopathy Questionnaire Clinical Summary Score was directionally, though not significantly, improved with ninerafaxstat vs placebo (LS mean 3.2; 95% CI: −2.9 to 9.2; P = 0.30); however, it was statistically significant when analyzed post hoc in the 35 patients with baseline Kansas City Cardiomyopathy Questionnaire Clinical Summary Score ≤80 (LS mean 9.4; 95% CI: 0.3-18.5; P = 0.04). Conclusions: In symptomatic nHCM, novel drug therapy targeting myocardial energetics was safe and well tolerated and associated with better exercise performance and health status among those most symptomatically limited. The findings support assessing ninerafaxstat in a phase 3 study.

Original languageEnglish (US)
Pages (from-to)2037-2048
Number of pages12
JournalJournal of the American College of Cardiology
Issue number21
StatePublished - May 28 2024


  • cardiac energetics
  • clinical trial
  • exercise capacity
  • health status
  • ninerafaxstat
  • nonobstructive hypertrophic cardiomyopathy

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


Dive into the research topics of 'Safety and Efficacy of Metabolic Modulation With Ninerafaxstat in Patients With Nonobstructive Hypertrophic Cardiomyopathy'. Together they form a unique fingerprint.

Cite this