In a phase 2a study, the THR-β agonist ALG-055009, currently in clinical development, reduced liver fat in patients with metabolic dysfunction-associated steatohepatitis (MASH).
As lifestyle choices, the first-line therapy recommended for MASH, are often not enough on their own to adequately manage the disease, pharmacological treatment is recommended for those patients with non-cirrhotic MASH with advanced fibrosis. ALG-055009 is a THR-β agonist that has shown greater potency and selectivity for THR-β than resmetirom, the first-generation THR-β agonist currently approved for patients with non-cirrhotic MASH and moderate or advanced liver fibrosis. In this phase 2a study, conducted by Rohit Loomba, MASLD Research Center at the University of California, San Diego, and colleagues, the study evaluated the efficacy, safety, pharmacokinetics, and pharmacodynamics of ALG-055009, compared with placebo, among patients with non-cirrhotic MASH.
In the double-blind phase 2a HERALD trial, patients with presumed MASH with F1 to F3 liver fibrosis and a BMI of at least 25 kg/m2 were randomly assigned to receive 0.3 mg (n =20), 0.5 mg (n = 22), 0.7 mg (n = 20), 0.9 mg of ALG-055009 (n = 18; restricted to patients with a bodyweight greater than 85 kg), or placebo (n = 22) once daily for 12 weeks. The primary end point was the percentage of relative change from baseline in liver fat, as determined by MRI proton density fat fraction (MRI-PDFF) at week 12.
Of the 102 patients randomly assigned, five were excluded from the primary analysis (two from the 0.3 mg arm, one from the 0.5 mg arm, one from the 0.9 mg arm, and one from the placebo arm) due to missing baseline and week 12 MRI-PDFF data. There was a statistically significant change in relative percentage from baseline liver fat content by MRI-PDFF at week 12, with 0.5 mg, 0.7 mg, and 0.9 mg of ALG-055009, with the highest relative change observed in the 0.7 mg arm. The least-squares mean relative change was –6.9% for the 0.3 mg arm, –11.2% for the 0.5 mg arm, –25.9% for the 0.7 mg arm, –24.3% for the 0.9 mg arm, and 7.3% for the placebo arm. The placebo-adjusted least-squares mean relative changes in liver fat at week 12 were, respectively, –14.3% (P=0.067), –18.5% (P=0.014), –33.2% (P<0.001), –31.6% (P=0.001).
The odds ratio for the proportion of patients who achieved a relative reduction of at least 30% in liver fat content by MRI-PDFF at week 12 was 3.7 for the 0.3 mg arm (P=0.16), 4.7 for the 0.5 mg arm (P=0.084), 28.2 for the in 0.7 arm (P=0.004), and 11.2 for the 0.9 mg arm (P=0.007). For patients receiving ALG-05509, there were statistically significant reductions in LDL cholesterol, lipoprotein(a), and apolipoprotein B.
The study authors also noted that of the 14 patients on stable GLP-1 receptor agonist therapy who were randomized to any ALG-055009 treatment arm, 11 had decreases in liver fat. The four patients on GLP-1 treatment who were randomly assigned to the placebo arm had increases in liver fat.
Treatment-emergent events were mostly mild or moderate (grade 1/2 = 97%), and occurred in 13 patients in the 0.3 mg arm, 10 in the 0.5 mg arm, 13 in the 0.7 mg arm, 11 in the 0.9 mg arm, and 16 in the placebo arm. The most common adverse events were diarrhea (6% of patients treated with ALG-055009 vs 23% treated with placebo), fatigue (7.5% vs 0%), and constipation (6% vs 0%). This study observed no clinically meaningful changes in laboratory tests, electrocardiogram, vital signs, physical examinations, or clinical evidence of hypo/hyperthyroidism. There was one serious adverse event of unrelated hemangioma of bone in the placebo arm. No deaths occurred.
Dr. Loomba and colleagues concluded, “ALG-055009 could offer a promising treatment approach for patients with MASH” and added that these results support further studies evaluating “longer durations of ALG-055009 and its effect on liver histology.”