IMPROVE-DiCE, a 2-Part, Open-Label, Phase 2a Trial Evaluating the Safety and Effectiveness of Ninerafaxstat in Patients With Cardiometabolic Syndromes
Year: 2025
Type: article
Study design: Clinical Trial
Abstract: BACKGROUND: We report IMPROVE-DiCE (Improve Diabetic Cardiac Energetics), a 2-part open-label, phase 2a trial evaluating the safety and effectiveness of ninerafaxstat, a novel therapeutic designed to enhance cardiac energetics. Between May and September 2021, part 1 enrolled patients with type 2 diabetes and obesity without heart failure with preserved ejection fraction (HFpEF). Between January 2023 and June 2024, part 2 enrolled patients with type 2 diabetes, obesity, and HFpEF. METHODS: Forty-two participants received 200 mg ninerafaxstat twice daily (part 1, n=21, 43% women, 72±0.5 years of age, 4–8 weeks; part 2, n=21, 29% women, 71±6 years of age, 12 weeks). Myocardial energetics (phosphocreatine-to-ATP ratio [PCr/ATP], primary outcome) and function (rest and dobutamine stress) were assessed before and after treatment using magnetic resonance imaging, 31 P- and 1 H magnetic resonance spectroscopy. In part 1, hyperpolarized [1- 13 C]pyruvate magnetic resonance spectroscopy to assess in vivo pyruvate dehydrogenase flux (n=9) and plasma metabolomics and proteomics were also performed. RESULTS: In part 1, in patients with diabetes and obesity but without HFpEF, the heart was characterized by impaired pyruvate dehydrogenase flux, reduced PCr/ATP, triglyceride deposition, and diastolic impairment. Treatment with ninerafaxstat was associated with improved PCr/ATP (+0.39±0.49 [95% CI, 0.16–0.62]; Cohen’s d , 0.79; P =0.002) and lower myocardial triglyceride (by 34%, P =0.03). In part 2, in patients with diabetes, obesity, and symptomatic HFpEF, the heart was characterized by reduced PCr/ATP, diastolic impairment, and failure of systolic augmentation to exercise. Consistently, treatment with ninerafaxstat was associated with improvement in PCr/ATP (+0.15±0.25 [95% CI, 0.03–0.26]; Cohen’s d , 0.60; P =0.02), improved systolic augmentation to exercise (+1.4 L/min, P =0.04), improved exercise capacity (6-minute walk distance +16 m, P =0.02), and improved New York Heart Association class symptom burden. CONCLUSIONS: These mechanistic phase 2a study results show that ninerafaxstat is safely tolerated and improves myocardial energetics in participants with obesity and diabetes without or with clinically manifest HFpEF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04826159.
Source: Circulation
Authors: Moritz J. Hundertmark, Sarah M. Birkhoelzer, Clara Portwood, Adrienne G. Siu, Violet Matthews, Andrew J. Lewis, James Grist, Ferenc Mózes, John A. Henry, Jai Patel, Paul Chamberlin, Rizwan Sarwar, Arash Yavari, Hakim-Moulay Dehbi, Prashant Rao, Xu Shi, Shuning Zheng, Jeremy M. Robbins, Robert E. Gerszten, Michael P. Frenneaux, Ladislav Valkovič, Jack J.J.J. Miller, Stefan Neubauer, Damian J. Tyler, Oliver J. Rider
Institutions: University of Bern, University Hospital of Bern, John Radcliffe Hospital, University of Oxford, Oxford University Hospitals NHS Trust, University of Birmingham, University College London, Beth Israel Deaconess Medical Center, Imperial College London, Slovak Academy of Sciences, Institute of Measurement Science of the Slovak Academy of Sciences, Aarhus University
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4417454528