Our Science

Addressing a Primary Driver of Cardiometabolic Disease: Obesity

Obesity is an unprecedented epidemic that is driving cardiometabolic diseases – the leading cause of death and disability worldwide. As a chronic disease rooted in metabolic dysfunction, obesity can lead to serious cardiometabolic diseases, such as liver disease (MASH) and heart failure (HFpEF).

Currently approved GLP-1 receptor agonists have delivered benefits to individuals living with obesity and resulting diseases, however discontinuation rates are high and approximately 75% of patients stop treatment within 2 years¹. Further, around 40% of the total weight loss from GLP-1s is lean muscle², which is critical for long-term function and metabolic health. After stopping treatment, patients regain weight rapidly³, mostly in the form of fat, leaving them worse off than when they started⁴. Obesity and resulting cardiometabolic diseases are chronic diseases and require a chronic treatment that delivers sustainable weight loss.

Harnessing a Natural Metabolic Process for Sustained, Fat-Selective, Muscle-Preserving Weight Loss

CMAs are oral, investigational small molecules designed to induce sustained, fat-selective, muscle-preserving weight loss. CMAs safely harness a natural process called mitochondrial uncoupling, which accounts for approximately 20-40% of caloric consumption and significantly contributes to basal metabolic rate. By safely harnessing this natural process with a precision approach, Rivus’ CMAs have been shown to selectively reduce fat throughout the body while preserving muscle mass.

Watch Rivus’ Chief Scientific Officer Shaharyar Khan, PhD,
explain how CMAs differ from current obesity treatments.

Leveraging the Powerhouse of the Cell to Induce Sustained, Fat-Selective, Muscle-Preserving Weight Loss

By harnessing the natural metabolic process of mitochondrial uncoupling, Rivus’ oral, investigational CMAs are designed to treat obesity and the resulting cardiometabolic diseases.

Increase Metabolic Rate With Precision Control

CMAs are oral, investigational small molecule therapies designed to improve cellular metabolism. CMAs safely harness a natural metabolic process in mitochondria, the powerhouse of cells, to increase the breakdown of fats and sugars and increase the resting metabolic rate (energy expenditure).

Reduce Fat, Preserve Muscle, Sustain Weight Loss

By increasing the metabolic rate (energy expenditure) in a controlled manner, CMAs decrease fat throughout the body while maintaining muscle mass. Muscle preservation is critical for sustained weight loss and improved metabolic health.

Advance A New Class Of Medicines For Obesity

In three Phase 2 clinical trials, Rivus’ lead candidate HU6 has demonstrated positive results with a favorable tolerability and safety profile. HU6 has been evaluated in individuals living with MASLD/MASH and HFpEF.

Clinical Data and Scientific Publications

Safety and Efficacy of Once-Daily HU6 Versus Placebo in People with Non-Alcoholic Fatty Liver Disease and High BMI: a Randomised, Double-Blind, Placebo-Controlled, Phase 2a Trial
The Lancet Gastroenterology & Hepatology 2023
Noureddin, Mazen, et al.

A Novel Controlled Metabolic Accelerator for the Treatment of Obesity-Related HFpEF: Rationale and Design of the Phase 2a HuMAIN Trial
European Journal of Heart Failure 2024
Kitzman, W., Dalane, et al.

Novel Controlled Metabolic Accelerator for Obesity-Related HFpEF: The HuMAIN-HFpEF Randomized Clinical Trial
JAMA Cardiology 2025
Pandey, Ambarish, et al.

HuMAIN HU6 Phase 2a Obesity-Related HFpEF Clinical Trial
Pandey, Ambarish, et al.
Presented by Rivus CMO Rob Schott

Relevant Literature

Oxidative Capacity in Failing Hearts
American Journal of Physiology 2003
Gong, Guangrong, et al.

Mitochondrial Function and Longevity

Further Support to the Uncoupling-to-Survive Theory: The Genetic Variation of Human UCP Genes Is Associated with Longevity
PLOS One 2011
Giuseppina, Rose, et al.

Cellular Energetics and Mitochondrial Uncoupling in Canine Aging
GeroScience 2019
Nicholatos, Justin W., et al.

Mild Mitochondrial Uncoupling in Mice Affects Energy Metabolism, Redox Balance and Longevity
Aging Cell 2008
Caldeira da Silva, Camille C., et al.

Mitochondrial Mechanics and Energy Metabolism

Use the Protonmotive Force: Mitochondrial Uncoupling and Reactive Oxygen Species
Journal of Molecular Biology 2018
Berry, Brandon J., et al.

Mitochondrial Uncouplers Induce Proton Leak by Activating AAC and UCP1
Nature 2022
Bertholet, Ambre M., et al.

Increased Substrate Oxidation and Mitochondrial Uncoupling in Skeletal Muscle of Endurance-Trained Individuals
Proceedings of the National Academy of Sciences of the United States of America 2008
Befroy, Douglas E., et al.

The Obesity Phenotype of HFpEF

Evidence Supporting the Existence of a Distinct Obese Phenotype of Heart Failure With Preserved Ejection Fraction
Circulation 2017
Obokata, Masaru, et al.

The HFpEF Obesity Phenotype: The Elephant in the Room
Journal of the American College of Cardiology 2016
Kitzman, Dalane W., et al.

References

¹Gleason et al. 2024 and Rodriguez et al. 2025

²Blundell 2017 doi:10.1111/dom.12932; McCrimmon 2020 doi:10.1007/s00125-019-05065-8; Wilding 2021 doi:10.1056/NEJMoa2032183; Yajima 2018 doi:10.1016/j.jdiacomp.2018.05.018; Jendle 2009 doi:10.1111/j.1463-1326.2009.01158.x; Bradley 2012 doi:10.1139/h2012-068

³Wilding et al; STEP 1 Study Group. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab. 2022 Aug;24(8):1553-1564. doi: 10.1111/dom.14725

⁴Jensen SBK, Sørensen V, Sandsdal RM, et al. Bone Health After Exercise Alone, GLP-1 Receptor Agonist Treatment, or Combination Treatment: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2024;7(6):e2416775. doi:10.1001/jamanetworkopen.2024.16775

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