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Clinical Trial
. 2025 Jun 1;10(6):609-616.
doi: 10.1001/jamacardio.2025.0103.

Novel Controlled Metabolic Accelerator for Obesity-Related HFpEF: The HuMAIN-HFpEF Randomized Clinical Trial

Ambarish Pandey  1 , Gregory D Lewis  2 , Barry A Borlaug  3 , Sanjiv J Shah  4 , Andrew J Sauer  5 , Sheldon Litwin  6   7 , Kavita Sharma  8 , Diane K Jorkasky  9 , Elizabeth A Tarka  10 , Shaharyar M Khan  11 , Dalane W Kitzman  12
Affiliations
Clinical Trial

Novel Controlled Metabolic Accelerator for Obesity-Related HFpEF: The HuMAIN-HFpEF Randomized Clinical Trial

Ambarish Pandey et al. JAMA Cardiol. .

Abstract

Importance: Excess body fat plays a pivotal role in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). HU6 is a novel, controlled metabolic accelerator that enhances mitochondrial uncoupling resulting in increased metabolism and fat-specific weight loss.

Objective: To assess efficacy and safety of HU6 in reducing body weight, improving peak volume of oxygen consumption (VO2) and body composition among patients with obesity-related HFpEF.

Design, setting, and participants: The Exploratory Phase 2A, Double-Blind, Placebo-Controlled Dose Escalation Study of Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of HU6 for Subjects With Obese HFpEF (HuMAIN-HFpEF) trial was a multicenter, dose-escalation randomized clinical trial among patients with chronic stable HFpEF and obesity. Data were analyzed from July to October 2024.

Intervention: HU6 treatment for 19 weeks, starting at 150 mg per day and potentially up titrated to 450 mg per day based on safety and tolerability vs placebo.

Main outcomes and measures: The primary end point was change in body weight.

Results: Of 66 participants randomized (mean [SD] age, 64.5 [12] years; 38 female [58%]; mean [SD] weight, 110.9 [22.4] kg), 56 completed the trial. HU6 (vs placebo) significantly decreased weight (between-group difference, -2.86 kg; 95% CI, -4.68 to -1.04 kg; P = .003), total fat mass (between-group difference, -2.96 kg; 95% CI, -4.50 to -1.42 kg; P < .001), and percentage visceral fat (between-group difference,-1.3%; 95% CI, -2.1 to -0.5%; P = .003), with no significant loss of muscle mass. There were no statistically significant changes in peak VO2, 6-minute walk distance, Kansas City Cardiomyopathy Questionnaire score, high-sensitivity C-reactive protein level, N-terminal pro-brain natriuretic peptide level, or diastolic function. Serious adverse events were noted in 5 participants (4 in the HU6 group; 1 in the placebo group), including 1 death, all judged unrelated to treatment.

Conclusions and relevance: Among patients with obesity-related HFpEF, treatment with HU6 for 19 weeks led to modest but statistically significant weight loss without significant changes in peak VO2. Larger trials of longer duration are warranted to determine whether longer-term administration of HU6 can improve exercise function, quality of life, and cardiovascular outcomes in this increasingly common disorder.

Trial registration: ClinicalTrials.gov Identifier: NCT05284617.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Pandey reported receiving grants from Rivus Pharma; personal fees from Rivus Pharma for serving as a committee member; receiving research support from the National Institutes of Health (NIH), American Heart Association (AHA), Roche Diagnostics, Ultromics, Applied Therapeutics, and Gilead Sciences; receiving honoraria as an advisor/consultant for Tricog Health Inc, Lilly USA, Rivus Pharma, Cytokinetics, Roche Diagnostics, Axon therapies, Medtronic, Edward Lifesciences, Science37, Novo Nordisk, Bayer, Merck, Sarfez Pharmaceuticals, and Emmi Solutions; receiving nonfinancial support from Pfizer and Merck; and serving as a consultant for Palomarin Inc with stocks compensation. Dr Lewis reported receiving grants and advisory board fees from Rivus; grants from Amgen, consulting fees from Cytokinetics, grants from Applied Therapeutics and Imbria, consulting fees from Edwards, and grants from Pfizer, NIH, and AHA outside the submitted work. Dr Borlaug reported receiving grants from Rivus Pharma during the conduct of the study. Dr Shah reported receiving consulting fees from Rivus Pharma during the conduct of the study. Dr Sauer reported receiving grants from Rivus Pharma during the conduct of the study. Dr Litwin reported receiving grants from Rivus Pharma and consultant fees from Axon, Eli Lilly, Corvia, Novo Nordisk, and Alleviant outside the submitted work. Dr Sharma reported receiving grants from Amgen; advisory board/consulting fees from Rivus Pharma, Alleviant, AstraZeneca, Bayer, Edwards LifeSciences, Novartis, and Novo Nordisk outside the submitted work. Dr Jorkasky reported receiving stock options from Rivus Pharma outside the submitted work. Dr Tarka reported receiving consultant fees from Rivus Pharma during the conduct of the study. Dr Khan reported being an employee of Rivus Pharma and having a patent for heart failure with preserved ejection fraction pending as a Rivus employee. Dr Kitzman reported receiving grants and personal fees from Rivus Pharma, Novo Nordisk, AstraZeneca, Pfizer, and Bayer; personal fees from Corvia and Boehringer Ingelheim; and stock ownership in Gilead. No other disclosures were reported.

References

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