Ninerafaxstat, novel medication for HNOCM targeting myocardial energetics

Impaired myocardial energetics is a probable cause of symptoms and exercise limitation in hypertrophic non obstructive cardiomyopathy (HNOCM). Ninerafaxstat is a novel cardiac mitotrope which enhances cardiac energetics. Mitotropes are medications which aim to improve cardiac performance by acting at the level of mitochondrial energy production [1]. Abnormalities in the function of sarcomere increases the energy cost of force production in hypertrophic cardiomyopathy and results in an energy deficient state which can be exacerbated by deficient oxygen delivery to the hypertrophied cardiac muscle as a result of microvascular ischemia. This can also adversely affect diastolic myocardial relaxation which is a heavily energy dependent process and cause symptoms in HCM.

Ninerafaxstat is a partial fatty acid oxidation inhibitor and acts by direct competitive inhibition of 3-ketoacyl CoA thiolase, the last enzyme in the mitochondrial long chain fatty acid beta oxidation pathway. Inhibition of beta oxidation shifts cardiac energy mechanism from free fatty acid oxidation to glucose oxidation, which requires less amount of oxygen per molecule of ATP generated, a boon in oxygen deficient states. Ninerafaxstat is a prodrug with three metabolites which are metabolically active as per preclinical studies. Ninerafaxstat by improving myocardial energy efficiency could improve exercise tolerance as a result of enhanced myocardial relaxation, better filling and stroke volume during exertion in HNOCM.

A study involving 67 patients with HNOCM across 12 centers published in the Journal of American College of Cardiology evaluated the effect of ninerafaxstat. This was a phase 2 clinical trial. Serious adverse events were noted in 11.8% of the ninerafaxstat group and 6.1% of the placebo group. They concluded that in symptomatic HNOCM, this novel medication targeting myocardial energetics was safe and well tolerated. It was associated with better exercise performance and health status among those with most symptomatic limitation. Their findings would support further assessment of ninerafaxstat in a Phase 3 clinical trial, with more number of patients [1].

Reference

1. Psotka MA, Gottlieb SS, Francis GS, Allen LA, Teerlink JR, Adams KF Jr, Rosano GMC, Lancellotti P. Cardiac Calcitropes, Myotropes, and Mitotropes: JACC Review Topic of the Week. J Am Coll Cardiol. 2019 May 14;73(18):2345-2353. doi: 10.1016/j.jacc.2019.02.051. PMID: 31072579.
2. Maron MS, Mahmod M, Abd Samat AH, Choudhury L, Massera D, Phelan DMJ, Cresci S, Martinez MW, Masri A, Abraham TP, Adler E, Wever-Pinzon O, Nagueh SF, Lewis GD, Chamberlin P, Patel J, Yavari A, Dehbi HM, Sarwar R, Raman B, Valkovič L, Neubauer S, Udelson JE, Watkins H. Safety and Efficacy of Metabolic Modulation With Ninerafaxstat in Patients With Nonobstructive Hypertrophic Cardiomyopathy. J Am Coll Cardiol. 2024 Apr 1:S0735-1097(24)06684-1. doi: 10.1016/j.jacc.2024.03.387. Epub ahead of print. PMID: 38599256.