HU6 Shows Promise in Treating Obesity-Related Heart Failure by Reducing Body Fat While Preserving Muscle Mass
Key Insights
Rivus Pharmaceuticals (search)' Phase 2a HuMAIN trial results published in JAMA Cardiology show HU6 significantly reduced body weight and fat mass while preserving muscle mass in patients with obesity (search)-related heart failure.
The novel oral therapy, classified as a Controlled Metabolic Accelerator (search) (CMA), demonstrated improvements in cardiac function including increased left ventricular ejection fraction and decreased blood pressure over the 19-week study period.
HU6 represents a potential breakthrough as the first disease-modifying treatment for heart failure with preserved ejection fraction (search) (HFpEF (search)), a condition with limited effective treatments and poor survival rates.
Rivus Pharmaceuticals (search) has announced the publication of promising results from its Phase 2a HuMAIN clinical trial evaluating HU6 in patients with obesity (search)-related heart failure with preserved ejection fraction (search) (HFpEF (search)). The findings, published in JAMA Cardiology, demonstrate that the novel once-daily oral therapy significantly reduced body weight and fat mass while preserving muscle mass in this difficult-to-treat patient population.
The multicenter, randomized, double-blind, placebo-controlled study met its primary endpoint, showing a significant reduction in body weight with HU6 compared to placebo over the 19-week treatment period. Patients receiving HU6 lost an average of 6.8 pounds compared to just 0.5 pounds in the placebo group (p=0.0026).
"I am excited to see the potential of HU6 in significantly reducing visceral adiposity and total body fat without affecting lean mass in patients with obesity (search) and HFpEF (search)," said Dr. Ambarish Pandey, a cardiologist, lead author of the publication, and member of the HuMAIN study Steering Committee. "As we know, visceral adiposity is causally implicated in the development and progression of HFpEF and having a therapy that can directly target this could be transformative in HFpEF treatment."
Novel Mechanism Targets Fat While Sparing Muscle
HU6 belongs to a new class of investigational therapies called Controlled Metabolic Accelerators (CMAs). Unlike weight loss approaches that decrease energy intake, such as GLP-1 agonists or bariatric surgery, CMAs increase resting metabolic rate by leveraging the natural metabolic process of mitochondrial uncoupling (search). This results in increased energy consumption primarily from fat tissue.
The trial results showed HU6 produced:
- A 7.4-pound reduction in total fat mass (vs. 0.88 pounds with placebo, p=0.0003)
- A 1.5% decrease in visceral fat (vs. 0.2% with placebo, p=0.0028)
- A 4.8% reduction in body fat percentage (vs. 0.45% with placebo, p=0.0002)
- No significant change in lean body mass or skeletal muscle mass
This selective fat reduction while preserving muscle mass is particularly important for HFpEF (search) patients, who are typically elderly, frail, and already have reduced muscle mass.
Improvements in Cardiac Function
Although the study was primarily designed to assess weight loss, several secondary endpoints showed promising improvements in cardiac function with HU6 treatment:
- Increased left ventricular ejection fraction (LVEF) of 3.76% compared to placebo
- Decreased left ventricular end-systolic volume of 5.64 ml compared to placebo
- Improved right ventricular function (right ventricular systolic velocity of 2.10 cm/s)
- Reduced resting systolic blood pressure (-8.7 mm Hg) and diastolic blood pressure (-4.9 mm Hg)
"Although HuMAIN was a small study of short duration powered only for a reduction in body weight, the significant improvements observed in body composition and cardiac and metabolic secondary endpoints are meaningful," said Dr. Jayson Dallas, Chief Executive Officer of Rivus Pharmaceuticals (search). "These positive study results, especially the improvements in cardiac structure and function, suggest that HU6 could be the first disease-modifying treatment for HFpEF (search), a debilitating disorder associated with poor quality of life and physical limitations."
Study Design and Patient Population
The Phase 2a HuMAIN trial enrolled 66 patients with chronic, stable obesity (search)-related HFpEF (search) in the intention-to-treat population. Participants were randomized to receive either HU6 (starting at 150 mg/day and potentially up-titrated to 450 mg/day based on safety and tolerability) or placebo.
The study population represented typical HFpEF (search) patients:
- Average age of 64.5 years (range: 38 to 87 years)
- Average BMI of 39.4 kg/m²
- Average body weight of 110.9 kg (245 pounds)
- Multiple comorbidities and taking an average of 15 concomitant medications
The primary efficacy endpoint was the change in body weight from baseline to Day 134 (19 weeks). Secondary endpoints included changes in body composition, peak oxygen uptake, 6-minute walk distance, and various cardiac and inflammatory markers.
Safety Profile
HU6 demonstrated a favorable safety profile consistent with previous studies. The therapy was well-tolerated in the study population despite their advanced age and multiple comorbidities. Overall rates of serious adverse events were low, with four patients taking HU6 and one patient taking placebo experiencing serious adverse events, all deemed unrelated to the study drug.
The Burden of HFpEF
Heart failure with preserved ejection fraction (search) is a chronic debilitating syndrome characterized by severely reduced exercise capacity and poor quality of life. Obesity (search) is a strong risk factor for HFpEF (search) and a key contributor to its increasing worldwide prevalence, with as many as 80% of HFpEF patients in Western countries being either overweight or obese.
The condition has a poor prognosis, with studies showing a five-year survival rate of just 24.3% for people hospitalized with HFpEF (search) in the United States. Current treatment options are limited, with few therapies specifically approved for HFpEF.
Future Development
In addition to the HuMAIN study in HFpEF (search), Rivus is evaluating HU6 in the Phase 2 M-ACCEL trial for patients with metabolic dysfunction-associated steatohepatitis (MASH (search)). The company expects to announce topline results from this trial in the second quarter of 2025.
To date, more than 400 patients have been treated with HU6 across various clinical trials. Previous studies have shown that HU6 significantly reduced liver fat content and body weight with no loss of lean muscle mass in patients with high BMI and metabolic dysfunction-associated steatotic liver disease (MASLD (search)).
The development of HU6 represents a potentially significant advance in the treatment of obesity (search)-related cardiometabolic diseases, offering a novel approach that addresses the underlying metabolic dysfunction while preserving the muscle mass essential for physical function and quality of life.