Resmetirom: A promising treatment for non-alcoholic steatohepatitis

Background

Non-alcoholic steatohepatitis (NASH) is a severe, progressive form of non-alcoholic fatty liver disease (NAFLD) that affects millions globally.^[1] Characterized by hepatic steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis, NASH can lead to cirrhosis, hepatocellular carcinoma, and liver-related mortality. Its prevalence is rising worldwide, closely linked to obesity, insulin resistance, and metabolic syndrome.^[2,3] NASH has become a significant clinical and public health concern. At present, there are limited pharmacologic treatments approved for NASH, highlighting the need for novel, targeted therapies.

Figure 1 illustrates the NAFLD spectrum, beginning with normal liver histology and progressing through hepatic steatosis (>5% fat in hepatocytes), to NASH, and eventually to cirrhosis and hepatocellular carcinoma. As the disease advances, hepatic inflammation, ballooning degeneration of hepatocytes, and varying degrees of fibrosis are observed. In its end stages, cirrhosis leads to architectural distortion, irreversible scarring, and an elevated risk of liver failure and cancer.^[4,5]

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Figure 1:

Non-alcoholic fatty liver disease spectrum. NAFL: Non-alcoholic fatty liver, NASH: Non-alcoholic steatohepatitis.

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Resmetirom (MGL-3196) is a selective thyroid hormone receptor-β (THR-β) agonist developed to enhance hepatic fat metabolism and reduce liver inflammation without the cardiac side effects associated with non-selective thyroid hormone activation.^[2,3] Early-phase trials have demonstrated Resmetirom’s potential in reducing hepatic fat and improving metabolic parameters. For instance, Harrison et al.^[2] conducted a Phase 2 trial (NCT02912260) demonstrating that Resmetirom significantly reduced liver fat as measured by magnetic resonance imaging-proton density fat fraction (MRI-PDFF), along with improvements in alanine transaminase (ALT) and low-density lipoprotein cholesterol (LDL-C) levels. These findings were further supported by a multicenter, randomized, double-blind, placebo-controlled study with histological endpoints, which demonstrated significant improvements in the NAFLD Activity Score and hepatic steatosis in patients with NASH.^[2,5]

Despite these promising results, the current research on Resmetirom remains fragmented. Most studies have small sample sizes, varied endpoints, and shorter follow-up durations with limited data on long-term efficacy and durability. Safety profiles, including adverse event trends and discontinuation rates, are underexplored. There is no systematic review integrating findings across randomized controlled trials (RCTs) and observational studies to assess Resmetirom’s effects on liver fat reduction and histological outcomes. Comparative effectiveness against other emerging agents like obeticholic acid or lanifibranor is not systematically addressed.

This systematic review builds upon existing individual studies by synthesizing available clinical evidence on the efficacy and safety of Resmetirom in patients with biopsy-confirmed NASH. By collating data across RCTs and observational studies, we aim to evaluate its impact on liver fat reduction, histological outcomes, metabolic parameters, and adverse events. This approach enables us to identify consistent trends, assess study quality, and offer evidence-based insights into the potential role of Resmetirom in clinical practice. This review serves not only to inform clinicians but also to guide future research by highlighting gaps in long-term data and comparative effectiveness.

Current challenges in NASH management

To date, there is no Food and Drug Administration (FDA)-approved pharmacological treatment for NASH. Management primarily relies on lifestyle interventions, including weight loss through diet and physical activity, which can be difficult to achieve and sustain for most patients.^[6] While several drugs such as insulin sensitizers, antioxidants, and lipid-lowering agents have been evaluated, their efficacy has been inconsistent, and many have unfavorable side-effect profiles.^[7] In addition, NASH’s complex and heterogeneous pathogenesis involving lipotoxicity, inflammation, mitochondrial dysfunction, and fibrosis presents challenges for targeted drug development.^[8] Moreover, the lack of validated non-invasive diagnostic tools complicates both disease monitoring and therapeutic decision-making.^[9]

Rationale and study objective

Although individual clinical trials have evaluated Resmetirom’s efficacy and safety in the treatment of NASH, no prior systematic review has comprehensively synthesized the available evidence. Therefore, the objective of this review is not to re-evaluate individual trial outcomes but rather to systematically collect, critically assess, and summarize the current body of clinical data on Resmetirom. This synthesis aims to provide a consolidated understanding of its therapeutic potential, safety profile, and place in the evolving treatment landscape of NASH. It also seeks to identify knowledge gaps, inconsistencies, and methodological limitations in the current studies. This synthesis will help clinicians, researchers, and policymakers better understand the clinical implications of Resmetirom and inform the design of future trials and regulatory decisions.

Objective

The objective of this systematic review is to synthesize data from clinical trials and observational studies to evaluate the efficacy, safety, and clinical impact of Resmetirom in patients with biopsy-confirmed NASH. Specifically, we aim to:

• Summarize Resmetirom’s effects on hepatic fat content (quantified by MRI-PDFF), liver histology (NAS and fibrosis stage), and liver enzyme biomarkers (e.g., ALT, aspartate transaminase [AST])

• Describe reported adverse events and safety outcomes

• Evaluate the methodological quality of included studies

• Identify gaps in the evidence to guide future research directions.

By appraising methodological quality using tools such as the Cochrane Risk of Bias and Newcastle–Ottawa Scale (NOS), this review also evaluates the robustness of existing studies. Our goal is to offer a consolidated, evidence-based perspective to inform clinical decision-making and guide future research priorities on Resmetirom for NASH.

Search strategy

This systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. A comprehensive literature search was performed across PubMed, Cochrane Library, and Embase databases from January 1, 2010, to June 1, 2024.

The search strategy combined keywords and Medical Subject Headings (MeSH), using Boolean operators (AND, OR). The primary search terms included:

• “Resmetirom” OR “MGL-3196”

• “Non-Alcoholic Steatohepatitis” OR “NASH”

• “Fatty Liver Disease” OR “NAFLD”

An example of a full search string for PubMed was:

(“Resmetirom” OR “MGL-3196”) AND (“Non-Alcoholic Steatohepatitis” OR “NASH” OR “fatty liver disease”)

Reference lists of included studies and relevant reviews were also manually screened to identify additional eligible articles.

Study selection

The records retrieved from each database were imported into Rayyan QCRI for deduplication and blinded screening. The initial screening involved a title and abstract review by two independent reviewers, followed by a full-text review for potentially eligible articles. Disagreements were resolved through consensus or by a third reviewer.

Inclusion criteria

• Study design: RCTs, clinical trials, and observational studies (prospective/retrospective)

• Population: Adult patients (≥18 years) with biopsy-confirmed NASH

• Intervention: Resmetirom (MGL-3196), regardless of dosage or treatment duration

• Outcomes: Liver fat reduction (through MRI-PDFF or biopsy), histological improvements (steatosis, ballooning, inflammation, and fibrosis), changes in liver biomarkers (ALT, AST), and safety/adverse event data.

Exclusion criteria

• Non-human or pre-clinical studies

• Non-English publications

• Reviews, editorials, letters, protocols, or commentaries

• Conference abstracts without full-text availability

• Studies without relevant efficacy or safety data.

Study selection flowchart

The study selection process is depicted using a PRISMA 2020-compliant flow diagram [Diagram 1]. A total of 672 records were identified (PubMed: 312; Embase: 228; Cochrane: 132). After removing duplicates, 560 unique records were screened. 150 full-text articles were assessed for eligibility, of which 124 were excluded for reasons such as reviews, editorials, conference abstracts (n = 88), animal or in vitro studies (n =22), and not meeting inclusion criteria: (n =14).

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Diagram 1:

Preferred reporting items for systematic reviews and meta-analyses 2020 flow diagram for non-alcoholic steatohepatitis systematic reviews, which included searches of databases and registers only.

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Ultimately, 26 studies were included in the final review and 10 in the quantitative synthesis.

Data extraction

Two independent reviewers extracted data using a standardized data extraction form. Extracted data included:

• Study characteristics: Authors, year, design, country, sample size

• Participant data: Baseline demographics, inclusion criteria

• Intervention details: Resmetirom dose, duration, comparators

• Outcomes: Liver fat reduction, histological improvement, ALT/AST changes, adverse events

• Funding sources and conflicts of interest were reported.

Discrepancies were resolved through discussion or arbitration by a third reviewer.

Quality assessment

The Cochrane Risk of Bias 2.0 tool was used to assess the quality of RCTs across domains such as randomization, allocation concealment, blinding, and selective reporting. For observational studies, we used the NOS, evaluating selection, comparability, and outcome assessment.

Each study was assigned an overall quality rating:

• Low risk of bias

• Some concerns

• High risk of bias.

Assessment results were used to guide the interpretation of the evidence. A summary table of bias ratings across all studies is provided in the Results section.

Study characteristics

Table 1 provides a comprehensive overview of the methodological and clinical attributes of the clinical trials included in this systematic review. It presents critical variables such as study design, sample size, study duration, confirmation of NASH diagnosis, dosing regimen of Resmetirom, and primary outcomes assessed. This tabulation ensures transparency and allows readers to understand the diversity and scope of the included studies. By clearly outlining these characteristics, the table facilitates comparison across studies, highlights variations in methodology, and supports the synthesis of findings related to Resmetirom’s efficacy and safety in treating NASH.

Efficacy of Resmetirom

Biomarkers of liver injury

• ALT and AST levels: Statistically significant reductions in ALT and AST were observed in patients treated with Resmetirom, indicating improved liver function and reduced hepatic injury^[12]

• Other biomarkers: Notable improvements in LDL-C and triglyceride levels were also reported, supporting the metabolic benefits of Resmetirom in NASH patients.^[10]

Statistical analysis justification

Due to the heterogeneity in study design, outcome measures, duration of treatment, and reporting formats across included studies, a meta-analysis was not feasible. Instead, a qualitative synthesis was conducted to summarize the findings. This approach ensured the inclusion of all relevant studies without compromising the accuracy and interpretability of results.^[16-18] Future meta-analyses may be possible as more homogeneous and high-quality data become available.

The findings across studies consistently demonstrate that Resmetirom is effective in reducing liver fat content, improving histological parameters (especially steatosis and inflammation), and lowering biomarkers of liver injury in patients with NASH.^{[2,3,10,12,19]} While its effect on fibrosis is still under investigation, Resmetirom’s overall profile suggests a strong therapeutic potential in addressing both hepatic and metabolic manifestations of NASH.^[2,10,12,20] Further large-scale, long-term RCTs are warranted to validate these results and clarify their role in fibrosis regression and overall clinical outcomes.

Safety and tolerability

Table 2 shows that Resmetirom has demonstrated a favorable safety and tolerability profile in clinical trials for NASH. Most adverse events were mild to moderate, primarily gastrointestinal in nature.^[21-23] Serious adverse events and discontinuation rates were low and comparable to placebo. In addition, Resmetirom showed improvements in liver enzymes and lipid profiles, indicating both safety and therapeutic benefits.

Quality assessment

Summary of findings

This systematic review highlights the clinical promise of Resmetirom as a novel therapeutic agent for NASH. Across multiple high-quality studies, Resmetirom demonstrated:

• Substantial reductions in liver fat content, particularly as measured by MRI-PDFF^[12,24]

• Histological improvements including reduced steatosis and inflammation^[2,10,12]

• Decreases in liver injury biomarkers such as ALT and AST.^[10,12]

The drug was generally well-tolerated, with most adverse events being mild-to-moderate gastrointestinal symptoms.^[15] Serious adverse events were rare and comparable to placebo groups. Importantly, the included RCTs showed a low risk of bias, enhancing the overall reliability of the evidence.^[10-12]

Comparison with existing treatments

Mechanism of action

Resmetirom activates the THR-β in the liver, enhancing fat metabolism and reducing inflammation.^[29] It also modulates inflammatory pathways, reducing liver inflammation. Resmetirom improves overall lipid profiles, contributing to its beneficial effects on liver health and metabolic conditions. This mechanism targets key pathological features of NASH, such as steatosis and inflammation, and may have a more selective effect on the liver compared to broader-acting agents.^{[10,12,19,29]}

Clinical implications

Resmetirom, a drug, has the potential to be an effective treatment option for patients with NASH who have not responded well to lifestyle interventions.^[36] Its ability to reduce liver fat and inflammation could prevent disease progression and reduce the risk of severe liver complications.^[10,12,37] However, further long-term studies are needed to assess the durability of treatment effects and the potential for rare adverse events. More data are also needed to confirm Resmetirom’s effects on liver fibrosis.^[20,25]

Regulatory approval status of Resmetirom

Table 4 shows that Resmetirom has recently received FDA approval (March 2024) for the treatment of NASH with liver fibrosis, marking a major milestone in NASH therapeutics. It is the first drug approved specifically for this indication. Regulatory submissions are underway in other regions, including the EU. Its approval reflects strong efficacy, safety data, and alignment with evolving global treatment guidelines.

Resmetirom (marketed as Rezdiffra by Madrigal Pharmaceuticals) achieved FDA approval on March 14, 2024, marking a significant advancement in the therapeutic landscape of metabolic dysfunction-associated steatohepatitis (MASH) previously known as NASH. The approval underscores its therapeutic potential in addressing a disease with previously limited pharmacologic options.^[38,39]

In the European Union, regulatory review by the European Medicines Agency is ongoing. While Resmetirom has been granted Orphan Drug Designation, a final decision is still pending. Approval statuses in other global regions remain under review, dependent on additional trial data and individual country regulatory processes.

Need for further research

Despite the promising findings, further research is crucial to fully establishing Resmetirom’s role in NASH treatment. We need long-term studies to confirm the durability of its benefits and evaluate its impact on liver fibrosis and overall disease progression. Comparative trials with other emerging treatments and real-world data collection will also be essential to validate its efficacy and safety in diverse patient populations.

In summary, while Resmetirom shows considerable promise in NASH management, ongoing research will be critical in defining its place in clinical practice and ensuring that its benefits outweigh any potential risks.