Ninerafaxstat Shows Promise in Phase 2 Trial for Cardiometabolic HFpEF Patients
核心洞察
Imbria Pharmaceuticals (搜索)' ninerafaxstat demonstrated statistically significant improvements in cardiac energetics, left ventricular reserve capacity, and exercise performance in patients with cardiometabolic HFpEF (搜索) in the Phase 2 IMPROVE-DiCE trial.
The partial fatty acid oxidation (搜索) inhibitor works by shifting the heart's metabolism from fatty acids to glucose, resulting in more efficient energy production and improved cardiac function both at rest and during exercise.
With HFpEF (搜索) prevalence expected to reach 8.5 million in the US by 2030 and limited treatment options available, ninerafaxstat's positive results support further development for HFpEF and adjacent cardiovascular indications.
Imbria Pharmaceuticals (搜索) has announced positive clinical results from Part 2 of the IMPROVE-DiCE Phase 2 trial, showing that ninerafaxstat improved multiple cardiac parameters in patients with cardiometabolic heart failure with preserved ejection fraction (搜索) (HFpEF (搜索)). The findings were presented at the American College of Cardiology's Annual Scientific Session & Expo (ACC.25) in Chicago.
The trial demonstrated that ninerafaxstat treatment for 12 weeks led to improvements in cardiac energetics, left ventricular reserve capacity, exercise capacity, and patient-reported heart failure symptoms in this difficult-to-treat patient population.
Key Clinical Findings
After 12 weeks of treatment, patients with cardiometabolic HFpEF (搜索) showed a statistically significant (P=0.02) increase from baseline in cardiac phosphocreatine to adenosine triphosphate (PCr/ATP) ratio, indicating improved cardiac energy reserves and meeting the trial's primary objective. Notably, patients with the most severe energy deficit at baseline showed the largest responses to ninerafaxstat.
The drug also demonstrated:
- Significant improvement in left ventricular systolic reserve capacity during exercise (P=0.03), reflecting an enhanced ability of the heart to increase stroke volume during physical activity
- An increase in 6-minute walk distance of approximately 14 meters (P=0.02)
- Statistically significant and clinically meaningful improvements in heart failure-related health status, measured by the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) in patients most symptomatically limited at baseline (~8 points; P=0.04)
"These findings validate the mechanistic rationale for targeting impaired myocardial energetics in HFpEF (搜索) and demonstrate ninerafaxstat's potential to restore resting cardiac energetics and enhance functional cardiac reserve," said Oliver Rider, MRCP(UK), DPhil (Oxon), Professor of Cardiovascular Medicine, University of Oxford. "Importantly, these results suggest ninerafaxstat could improve daily symptoms and physical capacity for people living with HFpEF, a condition with few effective treatments available today."
Addressing a Growing Medical Need
HFpEF (搜索) represents approximately 50% of all heart failure cases, with prevalence in the U.S. expected to rise to 8.5 million by 2030. Within the HFpEF population, at least 80% of patients have type 2 diabetes mellitus (搜索) and obesity, which are key drivers of the cardiometabolic HFpEF (搜索) phenotype.
"There are no current treatments aimed at targeting mitochondrial energy generation to improve patient symptoms, quality of life, and functional capacity," noted Jai Patel, MRCP(UK), Chief Medical Officer at Imbria. "We believe these validating results pave the way to support further investigation of ninerafaxstat in cardiometabolic HFpEF (搜索)."
Dr. Patel added that ninerafaxstat's unique therapeutic profile could potentially make a meaningful impact in cardiometabolic HFpEF (搜索) and pathophysiologically adjacent disease states such as non-obstructive hypertrophic cardiomyopathy (搜索) (nHCM (搜索)).
Mechanism of Action
Ninerafaxstat addresses cardiac disorders characterized by an imbalance of energy supply and demand in the heart. The drug works as a partial fatty acid oxidation (搜索) (pFOX) inhibitor, shifting the heart's metabolic preference from fatty acids toward glucose. This metabolic shift leads to more efficient mitochondrial energy generation, potentially improving cardiac function both at rest and during exercise.
The compound offers several practical advantages for patients and clinicians: it can be orally administered, requires no dose titration or monitoring, has no clinically significant drug-drug interactions, and can be used alongside standard cardiovascular treatments.
About the IMPROVE-DiCE Trial
IMPROVE-DiCE is a two-part Phase 2 clinical trial evaluating ninerafaxstat's safety, tolerability, and pharmacodynamic effects. It is the first clinical trial to utilize multi-nuclear spectroscopy, including state-of-the-art hyperpolarized MR spectroscopy and MRI, to quantify cardiac energetic, metabolic, and functional responses to a metabolic modulator in cardiovascular disease.
Part 1 of the trial, which enrolled pre-HFpEF (搜索) patients with type 2 diabetes and obesity, previously demonstrated normalization of cardiac energetics, significant reduction in cardiac steatosis, and improvements in left ventricular diastolic filling rate. These results were presented at the European Society of Cardiology Congress in August 2022.
Part 2 focused on symptomatic patients with cardiometabolic HFpEF (搜索), assessing ninerafaxstat's impact on cardiac energetics, cardiac reserve function, exercise capacity, and heart failure symptoms. The trial was conducted at the Oxford Centre for Clinical Magnetic Resonance Research, Radcliffe Department of Medicine at the University of Oxford, UK, under the leadership of Professor Oliver Rider.
HFpEF: A Challenging Cardiac Condition
HFpEF (搜索) is characterized by the heart's inability to pump blood adequately without pathological increases in filling pressures at rest or during exertion. Like other forms of heart failure, HFpEF is associated with cardiac energy deficiency resulting from impaired mitochondrial energy generation.
This energy deficit leads to impaired cardiac functional reserve during physical activity and is associated with exercise-induced pulmonary congestion. Patients typically experience exertional breathlessness, fatigue, and markedly reduced exercise capacity, resulting in severely impaired quality of life.
Despite its significant morbidity and mortality, HFpEF (搜索) has few evidence-based therapies. The cardiometabolic HFpEF (搜索) phenotype, driven by chronic cardiometabolic stress from type 2 diabetes and obesity, is rapidly becoming the most prevalent form of this condition.
The positive results from the IMPROVE-DiCE trial suggest that ninerafaxstat could potentially address this significant unmet medical need by targeting the fundamental energetic impairment underlying HFpEF (搜索) pathophysiology.