HU6 Reduces Liver Fat, Body Weight in Patients with NAFLD with High BMI


Compared to placebo, patients using once-daily oral HU6 100 mg, HU6 300 mg, and HU6 450 mg experienced significant changes in liver fat, volume, and whole-body adiposity after 61 days of treatment.

Results from a phase 2a dose-finding trial of HU6 are highlighting its effect on liver fat and body weight in patients with high body mass index (BMI) and nonalcoholic fatty liver disease (NAFLD).

Mazen Noureddin, MD, MHSc | Credit: Houston Methodist

Mazen Noureddin, MD, MHSc

Credit: Houston Methodist

Participants treated with HU6 150 mg, 300 mg, and 450 mg experienced –26.8%, –35.6%, and –33.0% mean change in liver fat content from baseline to day 61 compared with a 5.4% gain in liver fat content among those treated with placebo.1

“In addition to hepatic complications, NAFLD is a risk factor for atherosclerotic cardiovascular disease, which is associated with increased mortality. Thus, an urgent need exists for treatments for NAFLD and NASH that are effective for managing liver manifestations and systemic metabolic complications,” wrote investigators.1

A controlled metabolic accelerator, HU6 activates proton leak and mitochondrial uncoupling to increase the oxidation of sugars and fats while maintaining the same baseline production of adenosine triphosphate. This results in fat-specific weight loss due to preferential oxidation of pathogenic adipose tissue and preserves lean muscle mass while reducing inflammation. HU6 reduces adipose tissue where excess adipose tissue contributes to disease pathophysiology, including NAFLD or nonalcoholic steatosis (NASH), diabetes, and heart failure with preserved ejection fraction.1

HU6 has previously been evaluated in single-ascending and multiple-ascending dose studies in healthy volunteers and participants with high BMI. Results from both phase 1 trials showed a linear pharmacokinetic profile across the therapeutic range.2,3

The randomized, double-blind, placebo-controlled, phase 2a trial was led by Mazen Noureddin, MD, MHSc, medical director of the Houston Research Institute, and conducted at a single clinical community site in St Paul, Minnesota. Adults aged 28 to 65 years with a BMI of 28 to 45 kg/m2, a FibroScan controlled attenuation parameter score of > 270 decibels per meter, and at least 8% liver fat by MRI-proton density fat fraction (MRI-PDFF) were randomly assigned to either once-daily HU6 100 mg, HU6 300 mg, HU6 450 mg, or matching placebo by oral administration for 61 days.1

Between April 28, 2021, and November 29, 2021, 506 participants were assessed for eligibility and 80 were enrolled in the study. Randomization was blocked 1:1:1:1 and stratified by baseline glycated hemoglobin, with normal baseline defined as HbA1c <5.7% and high baseline defined as HbA1c ≥5.7%. In total, 20 patients were assigned to placebo, 20 to HU6 150 mg, 21 to HU6 300 mg, and 19 to HU6 450 mg. Investigators noted treatment groups were well matched for sex, age, ethnicity, and weight for all participants and the subgroup with high baseline HbA1c. All participants and study personnel involved with outcome assessments were masked to treatment assignment.1

The primary endpoint was the relative change in liver fat content from baseline to day 61 as assessed by MRI-PDFF. Investigators measured the primary outcome in the full analysis set of patients who were randomly assigned, received at least 1 dose of treatment, and had less than 4.5 kg of weight gain or weight loss from the time of screening to day 1 of treatment.1

In total, 74 (93%) participants completed the study. Among those treated with HU6, 2 treated with 150 mg and 1 treated with 300 mg discontinued treatment due to treatment-emergent adverse events, although investigators noted none of the events were considered serious. An additional 2 patients treated with placebo also discontinued due to treatment-emergent adverse events. Consent was withdrawn by 1 patient on placebo, leading to treatment discontinuation.1

Upon analysis, the relative mean change in liver fat content from baseline to day 61 was –26.8% (standard deviation [SD], 17.4) for the HU6 150 mg group, –35.6% (SD, 13.8) for the HU6 300 mg group, –33.0% (SD, 18.4) for the HU6 450 mg group, and 5.4% (SD, 19.8) for the placebo group.1

In the pooled HU6 dose group, 36 (61%) participants had at least a 30% reduction in liver fat from baseline to day 61, with investigators pointing out greater responder rates were associated with the 300 mg (71%) and 450 mg (72%) doses compared to the 150 mg dose (40%). Investigators also pointed out all 3 HU6 doses were significant compared to placebo, where 1 participant achieved a 30% reduction in liver fat (5%; all P < .0001).1

Further analysis revealed similar results in the high baseline HbA1c subgroup, showing increased responder rates were associated with the 300 mg (75%) and 450 mg (86%) doses versus the 150 mg dose (43%) and all were significant compared with placebo (0%; all P < .0001).1

As part of the MRI-PDFF measurements of liver fat, investigators also assessed changes in liver volume and noted the least squares mean change was –0.08 (95% confidence interval [CI], –0.15 to 0.01) for the HU6 150 mg group, –0.14 (95% CI, –0.21 to –0.07) for the HU6 300 mg group, –0.14 (95% CI, –0.21 to –0.08) for the HU6 450 mg group, and 0.00 (95% CI, –0.07 to 0.07) for the placebo groups.1

Investigators highlighted decreases in body weight from baseline were observed for each HU6 dose, whereas no change was observed with placebo. Compared with placebo, differences in least squares mean change of whole-body adiposity were –0·37% (95% CI, –1.26 to 0.51) in the HU6 150 mg group (P = .40), –1·03% (95% CI, –1.90 to –0.16) in the HU6 300 mg group (P = .021), and –1·49% (95% CI, –2.38 to –0.60) in the HU6 450 mg group (P = .0014).1

“The Phase 2a trial results showed that HU6, a first-in-class controlled metabolic accelerator, stands alone in its mechanism for fat selective weight loss, meeting the primary endpoint for reducing liver fat, as well as reducing body fat in the treated population,” said Shaharyar Khan, PhD, Chief Scientific Officer of Rivus Pharmaceuticals.4 “These results setup the next phase of HU6 clinical development in cardio-metabolic disease, including a Phase 2a trial in obese patients with heart failure with preserved ejection fraction, which is currently enrolling, and a Phase 2b trial in obesity that will begin enrollment in 2023.”


  1. Noureddin M, Khan S, Portell F, et al. 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. Lancet Gastroenterol Hepatol 2023.
  2. Ascending Dose Study of HU6 in Healthy Volunteers. May 4, 2021. Accessed October 5, 2023.
  3. Multiple Ascending Dose Study of HU6 in High BMI Volunteers. August 16, 2021. Accessed October 5, 2023.
  4. Rivus Pharmaceuticals. Rivus Pharmaceuticals to Present Results from a Phase 2a Trial Evaluating its Controlled Metabolic Accelerator, HU6, at the American Association for the Study of Liver Diseases (AASLD) 2022 Meeting. November 4, 2022. Accessed October 5, 2023.
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