Understanding HU6 and Its Emerging Role in MASH, With Mazen Noureddin, MD, MHSc

The therapeutic landscape for metabolic dysfunction-associated steatohepatitis (MASH) continues to evolve rapidly, with multiple trials exploring new mechanisms to address the complex metabolic and inflammatory pathways driving disease progression. Among the emerging agents drawing attention is HU6, a novel, oral, first-in-class controlled metabolic accelerator in development for the treatment of obesity and associated cardiometabolic diseases, including MASH.

At the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025, Mazen Noureddin, MD, MHSc, a professor of medicine at Houston Methodist Hospital and co-chairman of Summit Clinical Research’s Board of Directors, presented phase 2 data highlighting the efficacy of HU6 in reducing liver fat and improving metabolic parameters in adults with MASH.

In the study, 273 patients with MASH with a VCTE score of 7.0–15.0 kPa and an MRI-proton density fat fraction (PDFF) ≥8% were randomly assigned to receive placebo or HU6 at 150, 300, or 450 mg/d for 26 weeks in a ratio of 2:1:2:2. The primary endpoint was percent change from baseline in liver fat content by MRI-PDFF. Secondary endpoints included categorical liver fat reduction, changes in body weight, body composition, and exploratory markers of metabolic health.

At week 26, the primary endpoint was met where HU6 reduced liver fat in patients across all doses (least-squares mean difference: −29.4%, −31.2%, −27.0% for HU6 doses of 150, 300, 450 mg, respectively, vs –6.7% for placebo; P <.005 vs placebo for each). Additionally, a ≥30% liver fat reduction occurred in the majority of patients, 57%, 58%, and 50% for HU6 doses of 150, 300, 450 mg, respectively, versus 22% with placebo (P <.005 vs placebo for each).

Investigators noted HU6 doses of 300 and 450 mg reduced body weight versus placebo (P <.05). Body fat mass was reduced with ~2:1 selectivity for visceral over subcutaneous fat at the 450-mg dose, with no change in lean or skeletal muscle mass. HU6 was generally safe and well tolerated, consistent with results of 2 prior phase 2 trials.

For additional insight into the data and HU6’s potential in MASH, the editorial team of HCPLive Hepatology spoke with Noureddin in the following Q&A:

HCPLive: Can you explain a bit about HU6 and its potential utility in MASH?

Noureddin: HU6 is a novel, oral controlled metabolic accelerator, and it works on the mitochondria. What you have in the mitochondria, usually in the interspace in the mitochondria, is an abundance of protons, which create what's called hyperpolarization, which leads to oxidative stress and inefficient oxidation of fat and sugar. With HU6, it opens the channels, improves this protein gradient and leads to decrease in this hyperpolarization immediately to decrease oxidative stress and improve the oxidation of blood and sugar. So it works in a selective, precise way in decreasing fat, particularly in the liver in this patient population.

HCPLive: How do the phase 2 data presented at AASLD add to our understanding of HU6 for MASH? What were some of the key findings?

Noureddin: There was a previous trial that was done on a milder patient population, MASLD, and there also was another trial in an obese HFPEF population. They were both positive, so we extended this trial into the MASH and F2 F3 population that had transient elastography stiffness between 7 and 15. They had to have enough fat on MRIPDFF, and then we randomized them into either placebo, 150 mg, 300 mg, or 450 mg. We saw a nice drop in the MRIPDFF, the 30% drop reduction was achieved between 50 and 58% of the patient population, all statistically significant, which was really nice to see. There was also weight loss in this patient population, about 2.6 kilograms, and most of it came from the fat after we measured it. In addition, there was a differential loss of fat in the adipose tissue, visceral adipose tissue compared to subcutaneous ratio, 2 to 1, and this is usually the opposite. So we preserve the muscle and got rid of the fat from the bad places that it is not supposed to be. It's also very well tolerated in comparison to the GLP-1s.

HCPLive: Did any new safety signals emerge?

Noureddin: No. It had very low GI side effects. People ask about this class of drug and if there was any flushing. There was transient and gradient, no issues and no one discontinued from it. People also ask about fevers. There was no fever in this patient population, and there was no increase in heart rate or no tachycardia.

HCPLive: Is there anything else you would like to add or highlight?

Noureddin: The drug is moving forward. I think it's a very promising oral drug as a standalone for the MASH population, especially with controlled weight loss and a low discontinuation rate. It also can be added on to many other oral medications.

Editors’ note: Noureddin reports relevant disclosures with Gilead, GlaxoSmithKline, Madrigal, Novo Nordisk, Takeda, 89BIO, Altimmune, Boehringer Ingelheim, and others.

References

1. Noureddin M, Khan S, Schott R, et al. HU6 Oral Investigational Therapy Reduces Liver Fat and Improves Adiposity Markers in Adults with MASH: Topline Results from a Phase 2 Randomized Placebo-Controlled Trial (M-ACCEL). Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

2. Rivus Pharmaceuticals; Rivus Pharmaceuticals Announces New Data from Phase 2 M-ACCEL Trial of HU6 in MASH in Late-Breaker Oral Presentation at AASLD The Liver Meeting® 2025. November 7, 2025. Accessed November 19, 2025. https://www.rivuspharma.com/news/press-releases/110725/