Several potential therapies for NASH are being investigated in phase 3 clinical trials and were discussed during this year’s The Liver Meeting, including resmetirom and aramchol, in addition to the glucagon-like peptide-1 analogue semaglutide (NCT04822181). Resmetirom is an orally active thyroid hormone beta receptor agonist designed to increase hepatic fat metabolism and reduce lipotoxicity (abstract LP19). Aramchol is designed to downregulate the fatty acid synthetic enzyme stearoyl-CoA desaturase 1 in hepatocytes (abstract LP23). 

Fibroblast growth factors (FGFs) are known for their potential effects on the repair and regeneration of tissue, and FGF analogues that are in development for the treatment of NASH include FGF19 molecules (abstract 8) and several FGF21 molecules (abstract LO5). In abstract 139, we presented data on BIO89-100, a glycoPEGylated FGF21 analogue. We also discussed TERN-101, a farnesoid X receptor (FXR) analogue, in abstract 143; the FXR is a crucial molecular actor in hepatic homeostasis. Additionally, information on TVB-2640, an oral, small-molecule fatty acid synthase (FASN) inhibitor, was presented at the meeting in abstract 141.

The use of noninvasive tests to measure improvements in liver disease is a feature of many of the trials in progress. With regard to the FGF21 analogue BIO89-100 (abstract 139), we had previously shown that this treatment leads to reductions in magnetic resonance imaging–derived proton density fat fraction and alanine transaminase (ALT). In presenting this abstract, I noted that there was a reduction in spleen volume, even in those with early disease. We typically see splenomegaly with cirrhosis, but, in this trial, we noticed that the spleen volume decreased as the liver volume decreased with the declining fat fraction. It is possible that when the liver fat increases with fatty liver disease, blood flow to the liver also increases to maintain that excess liver mass. And so, perfusion might be increasing in the liver at a subclinical level (ie, without portal hypertension). Likewise, there may be a subclinical increase in the spleen volume to maintain the liver perfusion that resolves with the resolving liver disease. We might be able to replicate these findings in studies of other therapies, so there will likely be more to come on that in the next year. 

FXR agonists hold promise for NASH, and we presented data on TERN-101, a synthetic nonsteroidal FXR agonist, where 5-, 10-, and 15-mg doses were evaluated in a phase 2a study (abstract 143). We reported an improvement in ALT and a numerical improvement in aspartate transaminase with the drug vs placebo. Liver fat content improvements were numerically higher but not statistically significant; however, we did see significant dose-dependent decreases in iron-corrected T1 mapping with TERN-101. The treatment was associated with an increase in low-density lipoprotein cholesterol, especially early on, but then it stabilized and it was not significant vs placebo at 12 weeks. Pruritus rates were not particularly high, and all incidents of pruritus that we observed were mild and there were no pruritus-related drug discontinuations. This was an important finding, since pruritus can be a limitation with FXR agonists.

I also presented data on TVB-2640 during the meeting (abstract 141). The inhibition of FASN decreases de novo lipogenesis and potentiates beta oxidation. Our study had 2 different cohorts: 1 from the United States and 1 from China. Despite differences in baseline characteristics between the cohorts, TVB-2640 reduced liver fat and decreased ALT in both populations. We saw a robust reduction in liver fat by magnetic resonance imaging–derived proton density fat fraction with the 50-mg dose relative to placebo, and there was a dose response with the 25-mg dose. We reported that aspartate transaminase and low-density lipoprotein cholesterol also improved, without an elevation of triglycerides—whereas an elevation of triglycerides has been observed with acetyl-CoA carboxylase inhibition. Other features of FASN inhibition included increased adiponectin, with the potential for increased insulin sensitivity, and increased FGF21. We also noticed an improvement in the NASH biomarker PRO-C3. We determined the optimal dose to be 50 mg, and a phase 2b trial in patients with biopsy-confirmed NASH is currently underway. In moving to phase 3, our goal would be to look at the liver histology to see improvements in NASH activity and NASH resolution, relative to placebo, with a 50-mg dose.

In conclusion, several promising agents for NASH are in development, and the respective clinical trials increasingly utilize noninvasive tests to measure improvements. We will need to see sustained efficacy in these clinical trials, so long-term data will be important.