Metabolic Accelerator Shows Promise for Weight Loss Side of Obesity-HFpEF Equation

The novel investigational weight loss agent HU6 had mixed results specifically targeting obesity-related heart failure with preserved ejection fraction (HFpEF), based on the small HuMain-HFpEF trial.

After 19 weeks on daily oral HU6 treatment, people shed on average 2.9 kg (~6.3 lb) or 2.7% of their starting body weight relative to placebo, both significant changes supporting some efficacy of the controlled metabolic accelerator (CMA), according to Ambarish Pandey, MD, of UT Southwestern Medical Center in Dallas.

HU6 also met expectations for significantly reducing adipose tissue (by 6.9% compared with placebo) while preserving lean muscle mass — though it did not improve peak exercise oxygen uptake from maximal cardiopulmonary exercise stress testing, nor did it have effects on functional parameters and cardiovascular and inflammatory biomarkers, Pandey reported during a late-breaking trial session held virtually by the Heart Failure Society of America (HFSA).

One secondary finding of note was HU6’s modest improvement of left ventricular ejection fraction (LVEF; +1.40% vs -2.36% with placebo).

“Future larger trials with longer-term follow-up are needed to evaluate whether HU6 can improve functional status and clinical outcomes in the growing population of patients with obesity related HFpEF,” Pandey concluded.

Drugmaker Rivus Pharmaceuticals had previously announced plans to proceed to a phase III trial for HU6 in obesity HFpEF next year. Meanwhile, a treatment specifically indicated for obesity-related HFpEF remains absent.

HFSA session moderator and discussant Amanda Vest, MBBS, MPH, of the Cleveland Clinic, suggested that HU6’s null results for most secondary endpoints may be a consequence of the present study’s small sample and relatively short duration.

She remarked on the “modest” extent of body weight reduction in HuMain-HFpEF. She acknowledged that it remains unknown how much weight loss is really needed to yield improvements in heart failure, however.

In any case, “we do anticipate that beyond weight loss, significant improvements in functional capacity endpoints would be necessary for adoption of a new anti-obesity medication specifically [in] heart failure clinical practice. And therefore we look forward to the next phase of investigation of HU6 in patients with obesity HFpEF,” Vest commented.

Pandey noted that another drug, semaglutide (Wegovy), has been shown to reduce body weight and improve quality of life and exercise capacity in older people with HFpEF. However, GLP-1 receptor agonists like semaglutide may cause loss of muscle mass, so investigators reason that another weight loss therapy is needed for the obesity-related HFpEF population that tends to be older and frail with low muscle mass.

Enter CMA therapy, which is thought to promote weight loss by increasing mitochondrial energy utilization preferentially to induce fat loss. Indeed, HU6 was previously shown to reduce fat mass while preserving skeletal mass in people with metabolic dysfunction-associated steatohepatitis.

“The positive HuMain results support the potential differentiating profile of HU6 in HFpEF, which could be the first disease-modifying treatment for this debilitating syndrome. The findings also support advancing our HFpEF clinical program with HU6,” said Jayson Dallas, MD, CEO of Rivus, in a company press release.

HuMain-HFpEF was a phase IIa randomized double-blind trial. Participants were ambulatory patients at least age 30 with BMI at least 30 kg/m², LVEF at least 50%, New York Heart Association class II-III symptoms, and a diagnosis of chronic HFpEF.

The dose-escalating design of the study had 66 patients randomized to HU6 or placebo. In both groups, people started at a low dose (150 mg) for 3 weeks, an intermediate dose (300 mg) for 3 weeks, then a high dose (450 mg) for 3 months. Those who reached the high-dose phase were 26 and 30 people, respectively, in the HU6 and placebo arms.

Pandey said the enrolled cohort was typical of an obesity-related HFpEF population: mean age around 64 years, majority women, and BMI approximately 40 kg/m². Peak Vo₂ averaged just over 13 ml/kg/min and the mean Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) was around 60 points at baseline.

While Pandey reported “no clinically meaningful” differences in baseline characteristics between the HU6 and placebo arms, there was some numerical imbalance in baseline diabetes (42.5% vs 24.2%), NT-proBNP (359 vs 265 ng/L), and SGLT2 inhibitor use (49% vs 31%).

As for safety, out of the 33 people in the HU6 arm, seven discontinued treatment and six de-escalated their dose (primarily from mild dyspnea). Serious adverse events were reported in 12.1% and 3.1% of treatment and control groups, while adverse events leading to discontinuation reached 6.1% vs 0. The most common adverse events were diarrhea (18.2%), dyspnea (12.1%), and headache (6.1%).

Vest noted that metabolic accelerators have historically been associated with risk, and urged careful monitoring of adverse events in future trials.

Regarding functional outcomes, HU6 failed to confer significant improvement on exercise time, the 6-minute walk test, and the KCCQ score.

The biomarkers NT-proBNP, troponin, and C-reactive protein were left unchanged after CMA therapy.

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