Rohit Loomba, MD: Promising Phase 2a HERALD Data for ALG-055009 in MASH

Findings from the phase 2a HERALD study of ALG-055009 in patients with metabolic dysfunction-associated steatohepatitis (MASH) and F1-F3 fibrosis suggest the thyroid hormone receptor-beta agonist is well-tolerated and significantly reduces liver fat after 12 weeks of treatment, supporting its advancement to a phase 2b trial.

HERALD data were presented in a late-breaking abstract at The Liver Meeting 2024 from the American Association for the Study of Liver Diseases (AASLD) in San Diego, California, by Rohit Loomba, MD, a professor of medicine, director of hepatology, and chief of the division of gastroenterology at the University of California at San Diego.

Results support the efficacy and safety as well as the pharmacokinetic and pharmacodynamic effects of ALG-055009 in noncirrhotic adults with presumed MASH and F1-F3 fibrosis, with the study meeting its primary endpoint for relative change from baseline in liver fat measured by MRI-PDFF at week 12.

For additional insight into ALG-055009 and what key data from HERALD suggest about its utility in MASH, the editorial team of HCPLive Hepatology spoke with Loomba in the following Q&A:

HCPLive Hepatology: Can you explain a little bit about the study drug and its potential significance in MASH based on what is currently known about its mechanism of action?

Loomba: ALG-055009 is a novel second-generation thyroid hormone receptor beta agonist. It's highly selective for the beta receptor, and it also has a favorable PK and once daily dosing. The role of thyroid hormone beta receptor agonism in the treatment of NASH has been shown in previous studies, both in preclinical models showing that you can reverse steatohepatitis and in animal models showing you can reverse fibrosis.

In humans, the only drug that is FDA-approved for NASH-related fibrosis is resmetirom, which is also a thyroid hormone beta receptor agonist. In terms of clinical efficacy and proof of concept, we have excellent data that thyroid hormone beta receptor agonism has a favorable safety profile and is also efficacious in reversing steatohepatitis and improving fibrosis in patients with stage 2/3 fibrosis.

The other thing about this particular entity is we have markers of target engagement, which include SHBG, steroid hormone binding globulin, or sex hormone binding globulin, which is a dose-dependent response that we see, and this helps us decide optimal dosing, as we did in a phase 2a trial.

The other thing that's also important, based upon a totality of data and evidence over the last 15 years, is that our group has developed MRI Proton Density Fat Fraction as a marker of treatment response, and this is a particularly effective way of assessing efficacy, particularly for thyroid hormone beta receptor agonists. With resmetirom as well as other thyroid hormone beta receptor agonists, we've seen a PDFF reduction, which has been significant compared to placebo. It’s also dose-dependent, so it can give us an idea of which dose should move forward into a biopsy-based trial from a phase 2a to a phase 2b to a phase 3.

HCPLive Hepatology: Looking at the HERALD study and the data that you're presenting at AASLD, what were, some of the key findings how did they build upon our understanding of this drug for MASH?

Loomba: In this particular trial, we had approximately 100 patients who were randomized to 4 different treatment doses for ALG055009 versus placebo. We had patients with a pretty significant body weight and a significant number of individuals also had type 2 diabetes. Baseline MRI PDFF ranged from 18 to 20%, so these patients had significant steatohepatitis assessed noninvasively. They had to have a liver stiffness on FibroScan of 7 to 20 kilopascals, so we excluded those who had features suggesting cirrhosis.

This was a typical population for a phase 2a trial, and they were randomized to 4 doses and 1 group to placebo. This led to a pretty efficient design in terms of understanding how the drug works, and what we found was there was a significant and robust reduction in MRI PDFF compared to placebo.

We saw up to 46.2% of MRI PDFF placebo corrective response with the 0.7 mg dose, and the 0.9 mg dose also showed about 43.6% MRI PDFF reduction. Based upon a series of studies in the past and a meta-analysis, we've established that if you achieve a 30% reduction in MRI PDFF, you start seeing features of histologic response at the 1-year time point, so a 12-week PDFF reduction of 30% predicts 1-year histologic response for NASH resolution, but also for fibrosis improvement with a thyroid hormone receptor beta agonist.

Here, we see that up to 70% of patients with the 0.7 mg dose achieve the 30% MRI PDFF response, which is excellent, and this tells me that the odds of histologic response with this therapy are likely going to be higher compared to placebo if we were to move to a phase 2b study, and it's well powered to assess that.

HCPLive Hepatology: Are there any other data from the study you want to highlight?

Loomba: Some patients were on a background GLP-1 therapy, and we looked at response in our patients who were on this therapy versus those who were not. The response to the drug was pretty robust, irrespective of whether they were on GLP-1 therapy or not. Even in those patients who have been receiving GLP-1 therapy, we saw you can still achieve further benefits with the addition of this thyroid hormone beta receptor agonist.

We also noticed that this drug not only lowers LDL cholesterol, but leads to a dose-dependent, robust reduction in lipoprotein (a), which is important because statins are not able to reduce this. With ALG-055009, we're seeing a robust dose-dependent reduction up to 26.8%, which is important because lipoprotein (a) is an independent risk factor for cardiovascular disease and cardiovascular events. Therefore, this drug may not only potentially improve liver disease if shown to improve histology in future studies, but it may also reduce cardiovascular risk in our patients with NASH who are at increased risk for cardiovascular disease.

HCPLive Hepatology: Were there any safety concerns based on the data from this trial?

Loomba: Excellent question. This is something that we pay close attention to, particularly in the setting of a phase 2a trial.

As we move on to a phase 2b trial, since it's a thyroid hormone beta receptor agonist, the first question is, do we see any thyroid alpha activity? We looked at patients’ heart rate, blood pressure, and other features, and did not see any difference in those clinical features in patients treated with the drug versus placebo, so that was reassuring.

We also looked at previous thyroid hormone beta receptor agonists and any side effects noted. Thyroid hormone beta receptor agonism oral therapy is associated with GI side effects, diarrhea in particular. In this setting, we did not see any significant difference in diarrhea in patients treated with the drug versus placebo, so that was also reassuring.

There were no severe adverse events related to the drug that led to discontinuation. There was one patient who discontinued because of worsening insomnia, but the patient had pre-existing insomnia. So, overall a very good safety profile, and we feel that this seems to be a good efficacy-to-tolerability ratio that we are seeing to move forward to a phase 2b trial.

Editors’ note: Loomba has relevant disclosures with Terns Pharmaceuticals; 89bio; Sagimet Biosciences; Arrowhead Pharmaceuticals; AstraZeneca; Pfizer; Novo Nordisk; Madrigal Pharmaceuticals; Janssen; Intercept; Eli Lilly; Bristol Myers Squibb; Boehringer Ingelheim; Amgen; Gilead; and others.

Reference

^{Loomba R, Desai D, Lucas KJ, et al. 5013 - ALG-055009, a Novel Thyroid Hormone Receptor Beta (THR-β) Agonist, was Well-tolerated with Significant Reductions in Liver Fat at Week 12 in Non-cirrhotic MASH Patients in the Ongoing Randomized, Double-Blind, Placebo-controlled Phase 2a HERALD Study. Paper presented at: AASLD’s The Liver Meeting 2024. San Diego, California. November 15-19, 2024.}