Data provide first human validation of cardiac energetics modulation as a therapeutic target in cardiometabolic heart disease, including heart failure with preserved ejection fraction (HFpEF)

In IMPROVE-DiCE, treatment with ninerafaxstat was associated with improvements in cardiac energetics, systolic reserve function, exercise capacity, and heart failure symptoms

Imbria Pharmaceuticals, Inc. (“Imbria”), a clinical-stage company developing transformational cardiovascular disease therapeutics, today announced that full results from the Phase 2a IMPROVE-DiCE clinical trial of ninerafaxstat have been published in Circulation, one of the world’s leading cardiovascular research journals. The peer-reviewed data demonstrated that treatment with ninerafaxstat was associated with improvements in myocardial energy metabolism, enhanced cardiac function, and favorable tolerability in patients with type 2 diabetes mellitus (T2DM), obesity, and heart failure with preserved ejection fraction (HFpEF).

“People with diabetes and obesity who develop HFpEF often struggle with fatigue and shortness of breath. Available treatment options remain limited and do not adequately address the fundamental energetic deficits driving this disease,” said Oliver Rider, MRCP(UK), DPhil (Oxon), principal investigator of the IMPROVE-DiCE trial and Professor of Cardiovascular Medicine, University of Oxford. “The significant improvements in cardiac energy metabolism and exercise capacity seen with ninerafaxstat are encouraging and support further investigation of this promising new therapeutic approach.”

IMPROVE-DiCE was a two-part, open-label Phase 2a clinical trial evaluating the safety, tolerability, and mechanistic effects of ninerafaxstat in patients with metabolic conditions known to impair cardiac energetics (e.g., T2DM, obesity, and HFpEF). The trial employed advanced, multi-modal cardiac imaging, including multi-nuclear MR spectroscopy and exercise stress imaging, to directly quantify myocardial energetics, metabolism, and cardiac functional reserve at baseline and after 12 weeks of treatment.

Patients exhibited markedly impaired cardiac energetics at baseline, measured by the phosphocreatine to ATP (PCr/ATP) ratio. Treatment with ninerafaxstat resulted in a significant improvement in this ratio, meeting the trial’s primary endpoint and validating the underlying mechanistic hypothesis. Ninerafaxstat is one of the few pharmacological interventions shown to improve energetics in any form of heart failure, and one of the first to do so in HFpEF.

In patients with cardiometabolic HFpEF, 12 weeks of treatment with ninerafaxstat was associated with:

• Significant improvements in systolic augmentation during exercise, a central feature of HFpEF, including:
  • ~188% mean increase in left ventricular (LV) stroke volume augmentation (p=0.04)
  • ~42% mean increase in LV cardiac output augmentation (p=0.04)
• Improvements in patient-reported symptoms, including:
  • Significant improvement in Patient Global Impression of Disease Severity (p=0.0143)
  • Reduced heart failure symptom burden, measured by physician-reported NYHA class (p=0.04)
• Improved functional capacity, including:
  • A significant increase in six-minute walk distance (6MWD) by ~14 m (p=0.02)

Ninerafaxstat was generally well tolerated across both parts of the trial. No adverse changes were observed in blood glucose, heart rate, blood pressure, heart rhythm, or left ventricular ejection fraction.

“The IMPROVE-DiCE trial provides novel human evidence that ninerafaxstat has the potential to improve how patients with metabolic diseases such as HFpEF feel and function,” said Albert Kim, MD, PhD, FACC, FHRS, Chief Medical Officer of Imbria. “These data build on our mechanistic findings in patients with non-obstructive hypertrophic cardiomyopathy and further strengthen the rationale for directly targeting impaired cardiac energetics. We look forward to advancing clinical development in HFpEF while continuing our ongoing Phase 2b FORTITUDE-HCM clinical trial.”  

The IMPROVE-DiCE trial results further support ninerafaxstat as a promising therapy that directly targets myocardial energy deficiency, with potential to improve myocardial metabolism, energetics, and function in patients with cardiometabolic heart disease. The full trial results and supplementary analyses are available in Circulation: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.125.074041