HERALD: ALG-055009 Demonstrates Liver Fat Reduction in Phase 2a MASH Study

Rohit Loomba, MD, MHSc

Credit: UC San Diego Health

Aligos Therapeutics has announced positive topline results from the phase 2a HERALD study of ALG-055009, a thyroid hormone receptor beta (THR-β) agonist, in patients with metabolic-dysfunction associated steatohepatitis (MASH).¹

According to a release from Aligos, 0.5 to 0.9 mg ALG-055009 doses demonstrated statistically significant reductions in liver fat at week 12, with placebo-adjusted median relative reductions up to 46.2% as measured by Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF). Of note, as many as 70% of subjects achieved ≥30% relative reduction in liver fat compared to baseline.¹

“The robust improvements in liver fat and other clinically relevant biomarkers, such as lipoprotein (a), demonstrate why potency and PK are pertinent when designing molecules aimed at improving patient outcomes,” Rohit Loomba, MD, MHSc, chief of the division of gastroenterology and hepatology at the University of California, San Diego, said in a press release.¹ “This has been an exciting year for the MASH space, which continues with this excellent data from Aligos’ ALG-055009, which has the potential for not only improvement in resolution of MASH, but also fibrosis improvement. In addition, it has potential to improve cardiovascular risk if the non-invasive tests (NIT) data are confirmed in future trials.”

Described by Aligos as a potential best-in-class THR-β agonist, ALG-055009 was well tolerated, had dose-proportional pharmacokinetics and low variability, and demonstrated expected thyromimetic effects in a phase 1 first-in-human study, supporting its advancement to the phase 2a HERALD study.^1,2

A randomized, double-blind, placebo-controlled trial, HERALD enrolled 102 patients with presumed MASH and stage 1-3 liver fibrosis (F1-F3). Participants were randomly assigned to receive 1 of 4 doses (0.3, 0.5, 0.7, or 0.9 mg) of ALG-055009 or placebo given orally once daily for 12 weeks. Participants weighing >85 kg (>187.4 lbs) were enrolled in the 0.9 mg dose group, with no body weight restrictions implemented in the other dose groups.¹

Key endpoints assessed were safety, tolerability, pharmacokinetics, relative change in liver fat content by MRI-PDFF, and other non-invasive biomarkers/tests.¹

In total, 18 participants were assigned to the 0.3 mg group, 21 to the 0.5 mg group, 20 to the 0.7 mg group, and 17 to the 0.9 mg group. According to a release from Aligos, doses of 0.5 to 0.9 mg of ALG-055009 demonstrated statistically significant reductions in liver fat at week 12:

• 0.5 mg: -24.1 placebo adjusted % change (P = .0124 vs placebo)
• 0.7 mg: -46.2 placebo adjusted % change (P = .0004 vs placebo)
• 0.9 mg: -43.6 placebo adjusted % change (P = .0003 vs placebo)

Additionally, results showed treatment with ALG-055009 resulted in significant reductions in atherogenic lipids, including LDL-C, lipoprotein (a) (LpA), and apolipoprotein B. Dose-dependent increases in sex hormone binding globulin, a marker of THR-β target engagement in the liver, were also observed.¹

ALG-055009 demonstrated a favorable tolerability profile with no serious adverse events, or clinical hyper/hypothyroidism. The majority of treatment-emergent adverse events were mild to moderate, with a single discontinuation due to worsening insomnia in a subject with pre-existing insomnia.¹

According to the release, no clinically meaningful findings in laboratory tests, electrocardiograms, vital signs, or physical examinations were observed. The incidence of gastrointestinal-related TEAEs was similar in ALG-055009 dose groups compared to placebo, and a non-dose-related, lower incidence of diarrhea was observed in ALG-055009 dose groups compared to placebo.¹

“When designing ALG-055009, our goal was to create a potential best-in-class THR-β agonist through enhanced potency and a superior PK profile,” Lawrence Blatt, PhD, MBA, Chairman, President, and Chief Executive Officer at Aligos Therapeutics, said in a press release.¹ “Today’s data demonstrates that these enhanced pharmacologic properties did indeed translate into robust improvements in liver fat reduction. In addition, ALG-055009 demonstrated a favorable tolerability profile, which is important given that MASH medications will likely be administered for prolonged periods of time. We believe ALG-055009 has the potential to help patients better adhere to MASH treatment. These results indicate that ALG-055009 warrants further development.”

Aligos is in “early discussions” with potential partners and is evaluating options to fund the continued development of ALG-055009, with plans to complete the activities required for a phase 2b study by the middle of 2025.¹

References

1. ^{Aligos Therapeutics. Aligos Therapeutics Announces Positive Topline Results from the Phase 2a HERALD Study of ALG-055009 for the Treatment of MASH. September 19, 2024. Accessed September 19, 2024. https://investor.aligos.com/news-releases/news-release-details/aligos-therapeutics-announces-positive-topline-results-phase-2a}
2. ^{Aligos Therapeutics. Aligos Therapeutics Announces the Completion of Enrollment in the ALG-055009 Phase 2a HERALD Study for the Treatment of MASH. May 21, 2024. Accessed September 19, 2024. https://investor.aligos.com/news-releases/news-release-details/aligos-therapeutics-announces-completion-enrollment-alg-055009}