Outbreak of metabolic dysfunction-associated steatohepatitis pharmacotherapies in 2024: From resmetirom to tirzepatide

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly common chronic liver disease with a global prevalence among adults exceeding 30% and approximately 1.66 billion cases worldwide as of 2019.^[1] Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most aggressive subtypes of MASLD and is associated with an elevated risk of cardiovascular disease, advanced liver fibrosis, and increased liver-related and all-cause morbidity and mortality. The estimated global prevalence of MASH is >5% with approximately 39.9 million cases reported in 2019.^[1] The incidence of hepatic decompensation, hepatocellular carcinoma, and deaths linked to MASH cirrhosis is projected to rise twofold to threefold by 2030.^[2] Although weight loss leads to histological improvements, only 25% and 19% of patients achieve resolution of MASH and improvement in fibrosis, respectively. Additionally, achieving and sustaining weight loss is challenging and 20% of patients regain weight.^[3] Resmetirom, a thyroid hormone receptor-beta (THRβ) agonist, is the only drug approved by the US Food and Drug Administration (FDA) for MASH with significant liver fibrosis (stage ≥2); however, the conditional approval is local and no pharmacotherapy is currently recommended for MASH at the cirrhotic stage.^[4] Therefore, effective medications for MASH are urgently required.

MASH treatment should prevent progression to cirrhosis, hepatic decompensation, and all-cause mortality; however, observation of theses clinical outcomes requires long-term follow-up. Therefore, the FDA requires at least one of the following surrogate histologic endpoints for conditional approval: Resolution of MASH without worsening of fibrosis, or improvement in fibrosis by one stage or more and without worsening of MASH.^[5] The European Medicine Agency (EMA) requires both resolution of MASH and improvement in fibrosis. Drug candidates for MASH include farnesoid X receptor (FXR) agonist (e.g., obeticholic acid), glucagon-like peptide 1 (GLP-1) receptor agonist (e.g., semaglutide), THRβ agonist (e.g., resmetirom), fibroblast growth factor (FGF) 21 agonist (e.g., pegozafermin and efruxifermin), FGF19 agonist (e.g., aldafermin), and pan-peroxisome proliferator-activated receptor agonist (e.g., lanifibranor). The achievement of clinical endpoints requires long-term follow-up, and currently, no clinical trials for MASH drugs have reached the time to report clinical endpoints. Therefore, none of the drugs have achieved the clinical endpoints up to now. Before 2024, only lanifibranor, pegozafermin, and efruxifermin have been reported to achieve both MASH and fibrosis endpoints in phase 2 trials. However, the current drugs still have their own limitations. The trial of lanifibranor applied an easier-to-achieve endpoint for MASH improvement (i.e., ≥2-point decrease in the activity part of the Steatosis, Activity, Fibrosis [SAF] scoring system that incorporates the scores for hepatocellular ballooning and lobular inflammation [SAF-A] score without worsening of fibrosis), which cannot be directly equated with FDA’s definition of resolution of MASH. Pegozafermin had notable severe adverse events. Efruxifermin achieved improvement of fibrosis but without a dose-response effect. Besides, FGF19 agonists cause an increase in cholesterol, which is obviously unacceptable for MASH patients who already have a high cardiovascular risk due to metabolic abnormalities, thus becoming its inherent flaw. Therefore, no pharmacotherapies are widely accepted for MASH, and the treatment of MASH is a rough patch before 2024.

Three recent randomized controlled trials (RCTs) published in The New England Journal of Medicine brought hope to patients with MASH and fibrosis. First, as a result of the phase 3 MAESTRO-NASH trial, resmetirom (THRβ agonist) has received conditional FDA approval for non-cirrhotic MASH with significant fibrosis (stage ≥2). Resmetirom achieved both histological endpoints; 25.9% and 29.9% of participants achieved MASH resolution with no worsening of fibrosis in the 80 mg and 100 mg resmetirom groups, respectively, compared with 9.7% in the placebo group. Similarly, 24.2% and 25.9%, respectively, achieved fibrosis improvement by at least one stage with no worsening of the MASH score in the resmetirom groups vs. 14.2% in the placebo group.^[6] Later, in the SYNERGY-NASH trial, tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and GLP-1 receptors, also achieved both endpoints of resolution of MASH and improvement in fibrosis. MASH resolution rates were 44%, 56%, and 62% in the 5 mg, 10 mg, and 15 mg tirzepatide groups, respectively, vs. 10% in the placebo group. Fibrosis improvement rates were 55%, 51%, and 51% for the respective tirzepatide groups, compared with 30% in the placebo group.^[7] Sanyal et al^[8] reported a phase 2 trial of survodutide, targeting glucagon and GLP-1 receptors, showing significant improvement in MASH in 47%, 62%, and 43% of participants in the survodutide 2.4 mg, 4.8 mg, and 6.0 mg groups, respectively, compared with 14% in the placebo group. However, the effects of survodutide on fibrosis remain unclear. The remarkable effect of these three drugs on the histological improvement of MASH brought about a historic outbreak of treatment for MASH, offering an encouraging outlook for future MASH therapy.

Resolution of MASH is an easier-to-achieve endpoint, defined in the FDA and EMA guidelines as absent fatty liver disease or isolated or simple steatosis without steatohepatitis and an NAFLD activity (NAS) score of 0–1 for inflammation, 0 for ballooning, and any value for steatosis.^[5] Many drugs (e.g., semaglutide, lanifibranor, and efruxifermin) reached this endpoint, as did resmetirom and tirzepatide, with a large margin of improvement.^[9,10,11] Although survodutide also showed the potential to improve MASH, the criteria seemed to be easier to implement: a ≥2-point decrease in NAS score with a ≥1-point decrease in either lobular inflammation or hepatocellular ballooning. Therefore, the potential effect of survodutide on MASH resolution needs to be further confirmed.

Achieving a clinically significant improvement in fibrosis takes longer than resolving MASH. Before 2024, few drugs met the FDA endpoint of improvement in fibrosis and some had notable adverse events that prevented their approval. For example, obeticholic acid causes unbearable itching, and lanifibranor leads to significant weight gain.^[10,12] Resmetirom and tirzepatide showed the potential to improve fibrosis within only 52 weeks. Future studies with longer follow-up periods (>2 years) are required to confirm the effects on fibrosis reversal. The short trial duration might also explain why the rate of fibrosis improvement with resmetirom was only 10.2–11.8% higher than that with placebo, and why the fibrosis improvement rates (51–55%) were similar across the three doses of tirzepatide. A long-term effect of resmetirom on fibrosis improvement is expected based on the 54-month results. Additionally, Sanyal et al^[8] defined the endpoint of improvement in fibrosis as at least a one-stage decrease in fibrosis, regardless of MASH status, suggesting that the efficacy of fibrosis improvement was unclear with survodutide, likely due to insufficient trial duration, necessitating further evaluation.

Cirrhosis, which is a more severe stage of MASH, requires a much longer time to assess reversion. As fibrosis progression is slower in patients with MASH, with one stage of progression over approximately 7.1 years, only trials with sufficient follow-up can determine whether current fibrosis reversal therapies can fully prevent future cirrhosis. The MAESTRO-NASH trial will evaluate liver-related outcomes, including progression to cirrhosis at 54 months.^[6] Considering the significant effect of resmetirom on fibrosis improvement at 52 weeks, its effect on the prevention of cirrhosis is worth investigating in long-term follow-up studies. Two additional ongoing phase 3 trials are currently investigating the long-term effects of semaglutide (No. NCT04822181) and pegozafermin (No. NCT06318169). These 3–7-year trials aim to evaluate the impacts of these drugs on cirrhosis prevention.

Some MASH trials have specifically targeted participants with baseline cirrhosis to explore the possibility of reversing cirrhosis; however, few have used histological endpoints. Semaglutide failed to regress cirrhosis in a 48-week trial, whereas efruxifermin showed encouraging results.^[13,14] Of the 12 participants treated with efruxifermin, four (33%) showed at least one stage of fibrosis improvement without worsening of MASH, and three (25%) achieved resolution of MASH compared with none in the placebo group after 16 weeks. In addition, the remarkable efficacy of efruxifermin in MASH with F2-3 fibrosis suggests its strong potential to reverse cirrhosis. Ongoing studies, such as those on resmetirom (No. NCT05500222) and pegozafermin (No. NCT06419374), will provide further insights.

Cardiovascular disease, rather than liver-related mortality, is the leading cause of mortality among patients with MASH. Effective MASH pharmacotherapy should ideally reduce cardiovascular morbidity and mortality rates. However, current MASH trials mainly aim to improve both MASH and fibrosis outcomes, and no completed trials indicate whether improvements in histology translate into reduced cardiovascular risk. The MAESTRO-NASH trial will investigate the effect of resmetirom on certain cardiovascular assessments as exploratory endpoints at 54 months.^[6] Moreover, an ongoing phase 3 trial of semaglutide (No. NCT04822181) will include cardiovascular mortality as a secondary endpoint, providing insights into whether treatments targeting MASH can effectively reduce cardiovascular mortality after reversing MASH and fibrosis. Additionally, MASH is more common in individuals with obesity, and in the population of individuals with both MASH and obesity, cancer is also a significant disease burden that overwhelms the liver-related adverse events.^[15] Future MASH trials that include tumors as an endpoint as well as cardiovascular events will undoubtedly provide new evidence for the clinical benefits of MASH new drugs. Taking into account liver and metabolic endpoints together, including easily accessible cardiometabolic risk factors of MASLD (e.g., body mass index, glucose, blood pressure, triglycerides, and cholesterol), in endpoint settings could potentially hold greater clinical significance in future MASH trials.

Rowe and Parker^[16] found a more apparent reduction in fibrosis in patients with F3 fibrosis than in those with F2 fibrosis. The inclusion criteria for fibrosis stages varied: Some trials (e.g., tirzepatide, pegozafermin, and efruxifermin) typically included participants with F2–3 fibrosis, whereas others, such as phase 3 trials of obeticholic acid and resmetirom, and phase 2 trials of survodutide, semaglutide, lanifibranor, and icosabutate, also enrolled those with F1 fibrosis. The resmetirom and tirzepatide trials included more participants with F3 fibrosis (62% and 57%, respectively), demonstrating their advantages and yielding positive results. Although post hoc analyses have indicated that survodutide improves fibrosis in MASH with F2–3 fibrosis, definitive conclusions remain ambiguous because only 35% of the participants had F2–3 fibrosis.

Since 2024, three exciting RCTs have provided encouraging results regarding potentially effective pharmacotherapies for MASH. In the near future, the treatment of MASH will no longer be a clinical challenge, thereby benefiting 1.6 billion individuals.

Funding

This work was supported by the National Key Research & Development Program of China (No. 2022YFA1303804), Peking University People’s Hospital Scientific Research Development Funds (No. RDJ2022-21), and Peking University Hepatology Institute Qi-Min Project.

Conflicts of interest

HR received speaking fees from Bristol-Myers Squibb, Gilead, and AbbVie. Other authors declare no conflict of interest.