CE / CME
Physician Assistants/Physician Associates: 0.50 AAPA Category 1 CME credit
Nurses: 0.50 Nursing contact hour
Physicians: maximum of 0.50 AMA PRA Category 1 Credit™
Released: March 13, 2024
Expiration: March 12, 2025
The Future of MASH Therapeutics: Ongoing Phase III Trials
This slide outlines the most common medications being studied in phase III trials. FDA approval for resmetirom is expected in early 2024. Obeticholic acid already has been stopped. The phase III ESSENCE trial of semaglutide in patients with MASH is ongoing. Lanifibranor is being studied in a 2-part trial. The trial for efruxifermin currently is enrolling, and pegozafermin is waiting at the starting line. I want to reemphasize the outcomes of MASH trials, so we need to read the next slides through the lens of a regulator.15
Adult MASLD Spectrum and Target Population
The disease spectrum starts at steatosis, then early MASH, then fibrotic MASH in F2 and F3, and then MASH cirrhosis (F4). It is noteworthy to mention that most phase III trials now focus on 2 populations: MASH in F2 and F3, and MASH cirrhosis. Studies focus on MASH in F2 and F3 because these patients have increased morbidity and mortality and the highest likelihood of positive outcomes from treatment. Patients with MASH cirrhosis are evaluated in separate trials because they are harder to treat, and it is harder to achieve outcomes. The MASLD activity score, or MASH score, represents the histologic outcomes currently in phase III trial; it is divided by steatosis, inflammation, and ballooning with a score from 0-8. If a patient has a score of 4 or higher, he or she is considered to have MASH and is enrolled on a trial. Researchers also look at fibrosis, and patients have to be F2 or higher to be enrolled. Before and after the trial, there are multiple assessments of histologic outcomes.16
FDA Efficacy Endpoints for Phase III Trials: Liver Histologic Improvement
FDA approval of a drug after a phase III trial requires 2 histologic endpoints: MASH resolution and fibrosis improvement. MASH resolution, on the left, must be achieved without worsening of fibrosis. Essentially, it is improvement of the MASH score to 0 or 1 with resolution of ballooning. At the same time, the patient’s steatohepatitis must be stable or improved. If either of these efficacy endpoints is reached, the drug gets Subpart H approval.17 If both conditions are met, that is even better.
Mechanisms of Action of Hepatic Drugs
This is a complex figure demonstrating the different mechanisms of action of hepatic drugs. There are multiple mechanisms that target de novo lipogenesis with FXR agonists, which are less popular nowadays. FGF-21s are mitochondrial-directed drugs. There are drugs that target genetic components, such as the peroxisome proliferator–activated receptors (PPARs) and THRs. In addition, there are drugs that are systemic or target the liver at the same time, such as GLP-1 RAs, and others that affect inflammation or fibrosis.15,18
Resmetirom (MGL-3196): Decreases Hepatic Fat at Week 12 MRI-PDFF, Associated With MASH Resolution at Week 36 Biopsy
The medical community is hoping for and anticipating FDA approval of the THR-β resmetirom in early 2024. This phase II study of resmetirom evaluated hepatic fat at 12 and 36 weeks via MRI, with baseline and 36-week biopsies. MRI-PDFF was improved in this study either by relative change or more than a 30% reduction. This study met its secondary endpoint of MASH resolution at 36 weeks but did not meet fibrosis improvement, even though it was not powered to meet histology.19
Resmetirom (MGL-3196): Biopsy Results in Responders
The histologic outcomes are shown in this table and demonstrate that the study did not meet the endpoint of fibrosis improvement.19
MAESTRO-NASH: Phase III Trial With Resmetirom Liver Biopsy (ITT) at Week 52
The phase III MAESTRO-NASH study of resmetirom met both endpoints: MASH resolution, reported in 30% of patients receiving resmetirom 100 mg vs 10% of patients receiving placebo, and fibrosis improvement, reported in 26% vs 14% of patients, respectively. This study demonstrated a favorable safety profile, and it is expected that resmetirom will be approved by the FDA in early 2024 (NCT03900429).20
Lanifibranor (Pan-PPAR Agonist): Improvements in Resolution of MASH and Regression of Fibrosis
Lanifibranor is a pan-PPAR agonist. In 2021, Francque and colleagues21 demonstrated MASH resolution in 45% of patients receiving lanifibranor 1200 mg vs 19% of patients receiving placebo. These patients also experienced fibrosis improvement (42% vs 24%); 31% of patients in the experimental group vs 7% in the placebo group achieved MASH resolution and fibrosis improvement. Although this is a 6-month study, the results were very promising, and this agent is expected to continue to perform. An ongoing phase III study is currently enrolling (NCT02704403).
Lanifibranor (Pan-PPAR Agonist): Safety Set (N = 247)
The adverse event profile of lanifibranor was favorable. As expected, some patients had increased weight, peripheral edema, and increased liver enzymes. Anemia also was reported in the cohort of patients receiving lanifibranor 1200 mg.21
Once-Daily SC Semaglutide (GLP-1 RA): Efficacy and Safety
A very popular mechanism for weight loss is the use of GLP-1 RAs such as semaglutide, which has been approved for T2D, weight loss, and improvement of cardiovascular outcomes. In a phase II study published in 2021, various doses of semaglutide (0.4 mg vs 0.2 mg vs 0.1 mg daily) were evaluated vs placebo. This was a biopsy-proven study that enrolled patients with MASH and fibrosis F1 to F3.22
Semaglutide (GLP-1 RA): Resolution of Steatohepatitis and No Worsening in Liver Fibrosis
What was shown in this study was that nearly 59% of the 56 patients receiving semaglutide 0.4 mg achieved MASH resolution compared with 17.2% of patients receiving placebo. Of note, this is one of the highest-reported numbers of patients with MASH resolution.22
Semaglutide (GLP-1 RA): Improvement in Liver Fibrosis and No Worsening in Steatohepatitis
Unfortunately, patients receiving semaglutide did not have significant fibrosis improvement compared with placebo. Nevertheless, the medical community is waiting for the results from phase III studies, which are ongoing with a weekly dose of semaglutide or placebo.22
Semaglutide (GLP-1 RA): Changes in Body Weight and A1C
The adverse events were overall favorable and included change in weight and other metabolic parameters; nausea and vomiting continue to be prevalent.22
REGENERATE Study: Phase III Trial of Obeticholic Acid in MASH, Interim Efficacy Analysis at 18 Months
I want to mention that in the REGENERATE study, obeticholic acid, an FXR receptor agonist, met the primary endpoint of fibrosis improvement—23% here compared with 12% for placebo. Unfortunately, after analysis by the FDA, the company decided not to continue with this drug, as they were asked for additional requirements that the company or the sponsor felt would not meet their priorities.23
Galectin-3 Inhibitor: Effects of Belapectin in Patients With MASH With Cirrhosis and Portal Hypertension
I also want to mention 2 ongoing studies that target patients with MASH and cirrhosis. The first one is investigating belapectin, which is a galectin-3 inhibitor that improves inflammation associated with fibrosis. A phase IIb study evaluated belapectin at 2 mg and 8 mg compared with placebo in patients with MASH, cirrhosis, and portal hypertension. It did not meet its primary endpoint of improvement in reduction in fibrosis or hepatic venous pressure gradient. However, in the subpopulation of patients without esophageal varices, belapectin prevented further progression. This study is ongoing and is in phase IIb/III with an adaptive design. The second study is ongoing and is investigating resmetirom in patients with MASH cirrhosis. It is very encouraging that the MASH drugs also are targeting the harder-to-treat populations, such as patients with cirrhosis.24
FGF-21: Phase IIb HARMONY Trial of Efruxifermin
In a randomized, double-blind, placebo-controlled phase IIb trial, the FGF-21 analogue efruxifermin showed fibrosis improvement in 41% of patients compared with 20% of patients receiving placebo. On the right, we see that efruxifermin also led to MASH resolution in a high proportion of patients—76% compared with 15% receiving placebo.25
Both Efruxifermin Doses Achieved Statistical Significance on Composite Endpoint (Fibrosis Improvement and MASH Resolution)
Patients in both treatment groups showed fibrosis improvement and MASH resolution. This study demonstrated statistical significance, and therefore this drug is being evaluated further in phase IIIstudies.25
Statistically Significant Reductions in Noninvasive Markers Reflect Histologic Improvement in Fibrosis
This slide shows that the fibrosis biomarkers (serologic or imaging) Pro-C3, Enhanced Liver Fibrosis (ELF) score, and liver stiffness improved significantly with both efruxifermin 28 mg and efruxifermin 50 mg compared with placebo.
Randomized, Controlled Trial of FGF-21 Analogue Pegozafermin in MASH
Pegozafermin is another FGF-21 analogue. In this biopsy study, patients with MASH treated with pegozafermin at 15 mg, 30 mg, and 44 mg weekly demonstrated MASH resolution and fibrosis improvement. It is worth noting that the placebo rate was quite low, so phase III study results are anticipated.26 Hopefully, researchers will replicate these results and overcome the phenomena of the placebo being lower than what has been seen in many other studies.
Pegozafermin
Noninvasive biomarkers such as alanine aminotransferase, liver fat content (MRI-PDFF), ELF score, and Pro-C3 were evaluated and compared between each subgroup. All were all improved in this study.26
Combination Therapy
Combination therapy is very important in the field of MASH. It is believed that combination therapy in this setting will be standard, just like in T2D, where medications can be added to the regimen to improve outcomes.
Ideal Combination
An ideal combination likely would be oral and well-tolerated, and it would have a synergistic effect on the body with histologic improvement in the liver, weight loss, or other cardiovascular benefits.27
Semaglutide + Firsocostat + Cilofexor: Study Design
I was involved in this open-label study, where semaglutide alone was compared with a combination of semaglutide with or without an acetyl-CoA carboxylase inhibitor and/or an FXR inhibitor.28
MRI-PDFF: Greater Improvements with Combinations
The triple combination of semaglutide plus firsocostat plus cilofexor led to more improvement in MRI-PDFF. Nearly all patients achieved at least a 30% MRI-PDFF reduction at Week 24, with a significant number of patients achieving an MRI-PDFF reduction of 50% or 70%, in addition to a reduction in liver stiffness.28
Reductions in Liver Stiffness by VCTE in All Groups
In addition, similar reductions in liver stiffness by vibration-controlled transient elastography (VCTE) were observed between treatment groups.28
FAST Score: Greater Improvements with Combinations
This approach is very attractive with such a drug. Here, one of the scores—called the FibroScan‒aspartate aminotransferase (FAST) score—also improved in all patients, with all combinations except cilofexor plus firsocostat resulting in significantly greater improvement.28
DUET: Selective THR-β Agonist (TERN-501) Plus Nonsteroidal FXR Agonist (TERN-101)
The DUET study also evaluated the combination of a THR-β drug plus an FXR agonist in MASLD/MASH.29 This was the first randomized, placebo-controlled trial where the combination therapy achieved statistical significance in the primary endpoint with the THR-β agonist, TERN-501 (6 mg), showing ≥30% liver fat reduction. The secondary endpoint of cT1 (a composite of liver inflammation and fibrosis) also was reached with statistical significance. With a very low adverse events profile, the results of this study are very promising, and the next step is a histologic study.
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