TOPLINE

ALG-055009, a selective thyroid hormone receptor beta (THR-β) agonist, produced statistically significant, dose-dependent reductions in liver fat vs placebo at 12 weeks in non-cirrhotic adults with metabolic dysfunction-associated steatohepatitis (MASH), with a favorable safety profile.

METHODOLOGY

• Researchers conducted a randomized double-blind, placebo-controlled phase 2a trial (HERALD) evaluating ALG-055009, a selective and potent THR-beta agonist, in adults with MASH at multiple sites in the United States from February 2024 to September 2024.
• A total of 102 adults (mean age, 50.2 years; 38% men) with BMI ≥ 25 kg/m² (mean, 39.3 kg/m²) and stage 1-3 liver fibrosis were randomly assigned to receive oral ALG-055009 at doses of 0.3 mg (n = 20), 0.5 mg (n = 22), 0.7 mg (n = 20), or 0.9 mg (n = 18), or placebo (n = 22) once daily for 12 weeks.
• Enrollment in the 0.9 mg dose group was limited to participants with bodyweight exceeding 85 kg.
• The primary outcome was percentage relative change from baseline in liver fat measured by MRI-proton density fat fraction at week 12.
• Median exposure was 85 days across treatment groups.

TAKEAWAY

• ALG-055009 significantly reduced liver fat compared with placebo. The placebo-adjusted least-squares mean relative changes in liver fat were −18.5% (P = .014) for 0.5-mg dose, −33.2% (P < .0001) for 0.7-mg dose, and −31.6% (P = .0001) for 0.9-mg dose.
• A reduction of 30% or greater in liver fat occurred in 70.0% of participants who received 0.7-mg dose and 58.8% of those who received 0.9-mg dose vs 9.5% of patients in the placebo group.
• ALG-055009 at doses 0.7 and 0.9 mg significantly reduced LDL cholesterol, lipoprotein(a), and apolipoprotein B, and produced dose-dependent increases in sex-hormone binding
  globulin, a marker of THR-β target engagement.
• Treatment-emergent adverse event (TEAE) rates were 59% with ALG-055009 and 73% with placebo, most events were mild or moderate. Gastrointestinal
  related TEAEs were most frequent and no serious adverse events or deaths occurred in the ALG-055009 groups.

IN PRACTICE

"Significant reductions in liver fat and evidence of target engagement along with reductions in atherogenic lipid and lipoprotein levels and a safety profile similar to placebo, suggest that ALG-055009 could offer a promising treatment approach to patients with MASLD [metabolic dysfunction-associated steatotic liver disease] or MASH," the authors wrote.

SOURCE

The study was led by Rohit Loomba, MD, MASLD Research Center, Division of Gastroenterology and Hepatology, University of California, San Diego. It was published online on August 26 in The Lancet Gastroenterology & Hepatology.

LIMITATIONS

The limitations included short duration, small sample size, the absence of liver biopsy, and lack of data on long-term outcomes.

DISCLOSURES

The study was funded by Aligos Therapeutics. Loomba reported receiving grants and consulting fees from multiple pharmaceutical companies, holding stock in Sagimet Biosciences, and being cofounder of LipoNexus. Several authors reported being employees and shareholders of Aligos Therapeutics. Additional author disclosures are reported in the original article. 

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.