IMPROVE-DiCE, a 2-Part, Open-Label, Phase 2a Trial Evaluating the Safety and Effectiveness of Ninerafaxstat in Patients With Cardiometabolic Syndromes
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.
Article Details
Authors (25)
Moritz J. Hundertmark
Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom (M.J.H., S.M.B., C.P., A.G.S., A.J.L., J.G., F.M., J.A.H., L.V., S.N., D.J.T., O.J.R.).
Sarah M. Birkhoelzer
Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom (M.J.H., S.M.B., C.P., A.G.S., A.J.L., J.G., F.M., J.A.H., L.V., S.N., D.J.T., O.J.R.).
Clara Portwood
Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom (M.J.H., S.M.B., C.P., A.G.S., A.J.L., J.G., F.M., J.A.H., L.V., S.N., D.J.T., O.J.R.).
Adrienne G. Siu
Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom (M.J.H., S.M.B., C.P., A.G.S., A.J.L., J.G., F.M., J.A.H., L.V., S.N., D.J.T., O.J.R.).
Violet Matthews
Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom (V.M., R.S.).
Andrew J. Lewis
Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom (M.J.H., S.M.B., C.P., A.G.S., A.J.L., J.G., F.M., J.A.H., L.V., S.N., D.J.T., O.J.R.).
James Grist
Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom (M.J.H., S.M.B., C.P., A.G.S., A.J.L., J.G., F.M., J.A.H., L.V., S.N., D.J.T., O.J.R.).
Ferenc Mózes
Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom (M.J.H., S.M.B., C.P., A.G.S., A.J.L., J.G., F.M., J.A.H., L.V., S.N., D.J.T., O.J.R.).
John A. Henry
Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom (M.J.H., S.M.B., C.P., A.G.S., A.J.L., J.G., F.M., J.A.H., L.V., S.N., D.J.T., O.J.R.).
Jai Patel
Imbria Pharmaceuticals, Boston, MA (J.P., P.C., A.Y.).
Paul Chamberlin
Imbria Pharmaceuticals, Boston, MA (J.P., P.C., A.Y.).
Rizwan Sarwar
Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom (V.M., R.S.).
Arash Yavari
Imbria Pharmaceuticals, Boston, MA (J.P., P.C., A.Y.).
Hakim-Moulay Dehbi
Prashant Rao
Beth Israel Deaconess Medical Ctr, Boston, Massachusetts, United States
Xu Shi
Shuning Zheng
Jeremy M. Robbins
Robert E. Gerszten
Michael P. Frenneaux
Imperial College London (M.P.F.).
Ladislav Valkovič
Jack J.J.J. Miller
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark (J.J.J.J.M.).
Stefan Neubauer
Damian J. Tyler
Oliver J. Rider
Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom (M.J.H., S.M.B., C.P., A.G.S., A.J.L., J.G., F.M., J.A.H., L.V., S.N., D.J.T., O.J.R.).