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

Maron MS 1 , Mahmod M 2 , Abd Samat AH 2 , Choudhury L 3 , Massera D 4 , Phelan DMJ 5 Show all authors , Cresci S 6 , Martinez MW 7 , Masri A 8 , Abraham TP 9 , Adler E 10 , Wever-Pinzon O 11 , Nagueh SF 12 , Lewis GD 13 , Chamberlin P 14 , Patel J 14 , Yavari A 14 , Dehbi HM 14 , Sarwar R 14 , Raman B 2 , Valkovič L 2 , Neubauer S 2 , Udelson JE 15 , Watkins H 16

Affiliations 

  • 1 Hypertrophic Cardiomyopathy Center, Lahey Hospital and Medical Center, Burlington, Massachusetts, USA. Electronic address: [email protected]
  • 2 Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
  • 3 Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  • 4 Hypertrophic Cardiomyopathy Program, Leon H. Charney Division of Cardiology, NYU Langone Health, New York, New York, USA
  • 5 Sanger Heart and Vascular Institute, Atrium Health, Charlotte, North Carolina, USA
  • 6 Center for Cardiovascular Research, Washington University School of Medicine in St Louis, St Louis, Missouri, USA
  • 7 Division of Cardiology, Atlantic Health System, Morristown, New Jersey, USA
  • 8 Hypertrophic Cardiomyopathy Center, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, USA
  • 9 Division of Cardiology, University of California-San Francisco, San Francisco, California, USA
  • 10 Division of Cardiovascular Medicine, Department of Medicine, University of California-San Diego, La Jolla, California, USA
  • 11 Division of Cardiovascular Medicine, Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, Utah, USA
  • 12 Methodist DeBakey Heart and Vascular Center, Houston, Texas, USA
  • 13 Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
  • 14 Imbria Pharmaceuticals, Boston, Massachusetts, USA
  • 15 Division of Cardiology, Tufts Medical Center, Boston, Massachusetts, USA
  • 16 Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
J Am Coll Cardiol, 2024 May 28;83(21):2037-2048.
PMID: 38599256 DOI: 10.1016/j.jacc.2024.03.387

Abstract

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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