OR WAIT null SECS
Oral HU6 Shows Fat-Selective Weight Loss in MASH, With Mazen Noureddin, MD
Noureddin discusses HU6’s mitochondrial uncoupling mechanism and why muscle preservation may become increasingly important in MASH care.
A novel oral therapy designed to increase energy expenditure through mitochondrial uncoupling is advancing in clinical development for metabolic dysfunction-associated steatohepatitis (MASH), with investigators emphasizing its potential to reduce liver and visceral fat while preserving skeletal muscle mass.
On April 14, 2026, Rivus Pharmaceuticals announced the first patients had been dosed in the phase 2 AMPLIFY trial evaluating HU6 in patients with F2/F3 MASH. The randomized, double-blind, placebo-controlled study is expected to enroll up to 180 patients and assess the safety and efficacy of 2 HU6 dosing regimens (450 mg daily or 300 mg twice daily) over 6 months.
In an interview with HCPLive, Mazen Noureddin, MD, MHSc, FAASLD, professor of medicine and transplant hepatologist at Houston Methodist Hospital, discussed the physiologic mechanism underlying HU6, the rationale for targeting energy expenditure in MASH, and why preservation of muscle mass may become an increasingly important consideration as the therapeutic landscape evolves.
HU6’s mechanism, mitochondrial uncoupling, is a physiologic process involved in daily caloric expenditure. Noureddin explained that the mechanism may offer a distinct approach compared with therapies that primarily focus on appetite suppression or downstream metabolic signaling.
According to Rivus Pharmaceuticals, prior phase 2 data from the M-ACCEL trial demonstrated significant reductions in liver fat alongside fat-selective weight loss and preservation of skeletal muscle mass. The company reported that most treated patients achieved > 30% liver fat reduction at 6 months, an MRI-PDFF threshold previously associated with MASH resolution and fibrosis improvement.
The primary endpoints of the ongoing AMPLIFY trial include percent change in liver fat measured by MRI-PDFF and the proportion of patients achieving > 30% liver fat reduction after 6 months. Secondary endpoints include changes in body composition, liver fibrosis markers, metabolic and inflammatory parameters, and pharmacodynamics.
Noureddin said clinicians should pay close attention not only to reductions in liver fat but also to the distribution of weight loss observed during treatment.
“You want to look at the muscles and make sure they're preserved, especially in older patients,” he said.
Muscle preservation has become an area of growing clinical interest in MASH, particularly among patients with advanced fibrosis who may already be at increased risk for sarcopenia. Noureddin noted that many patients with MASH are older than 50 years and may experience progressive muscle loss alongside worsening metabolic disease.
The broader MASH treatment landscape continues to expand, with therapies targeting fibrosis, inflammation, and metabolic dysfunction entering clinical practice and late-stage development. Although Noureddin cautioned against direct cross-trial comparisons, he described HU6’s oral administration, liver-centric activity, and muscle-preserving profile as encouraging differentiators.
Rivus reported that more than 500 patients have received HU6 across clinical studies to date, with a favorable safety and tolerability profile observed thus far. Top-line data from the AMPLIFY trial are anticipated in mid-2027 and expected to inform dosing selection ahead of planned late-stage clinical development. Noureddin said future studies will help determine how HU6 may ultimately be positioned, including whether it could serve as a standalone therapy or part of combination treatment strategies in MASH.
“We already have drugs that are effective,” Noureddin said. “We need to raise the bar… [and] increase the efficacy. Everyone knows that we need to consider other factors, such as burning fats from the right places while preserving the muscles, and we’re doing that here.”
Editor’s note: Disclosures for Noureddin include Madrigal Pharmaceuticals, Novo Nordisk AS, Boehringer Ingelheim Pharmaceuticals, PFIZER, Eli Lilly and Company, GlaxoSmithKline, Merck Sharp & Dohme, AstraZeneca UK Limited, Echosens North America, and more.
References
