“From trials to treatment: resmetirom as the first approved drug for NASH”

Dear Editor, Non-alcoholic steatohepatitis (NASH) is an advanced stage of non-alcoholic fatty liver disease, with multiple causes of steatosis, including liver injury and inflammation1. The prevalence of NASH has been observed in patients with type 2 diabetes and obesity, as triggered by impaired adipose tissue function and insulin resistance2,3. Although the disease has been associated with life-threatening adverse effects, there have been no clinically approved treatments for NASH. However, in the recent MAESTRO-NASH phase III trial, resmetirom has been used as an intervention. As thyroid hormone receptor (THR)-β, which is involved in modulating biochemical pathways, is compromised in NASH, resmetirom is a targeted THR-β agonist that is administered orally once per day. In the recent trials, major findings reported no tolerability issues; although diarrhea and nausea were more recurrent in the intervention group when compared with placebo, they were more frequent in the first 12 weeks of resmetirom administration. Furthermore, the study concluded notable secondary outcomes, including a substantial decline in LDL-C and related lipoproteins levels, and ALT, AST, and GGT were also reported to be normalized4. Moreover, resmetirom is a THR-β agonist, but its actions did not influence the level of thyroid hormones, raising safety concerns, followed by its approval for the treatment of NASH in March 20245. Despite its approval, there remain key uncertainties regarding long-term efficacy and safety outcomes. The MAESTRO-NASH trial demonstrated histologic and biochemical improvements at 52 weeks; however, data on the durability of these effects beyond 1 year are lacking. This remains as a significant clinical gap, as NASH is a chronic, progressive condition requiring decades of management. The 52-week data serve only as a surrogate endpoint; until longer-term results are published, it remains unproven whether resmetirom therapy directly prevents hard clinical outcomes such as liver failure, hepatocellular carcinoma, or the need for transplantation. The management of such advanced liver disease complications often requires specialized pharmacological interventions to optimize patient care6. Moreover, patients with F0 and F1 fibrosis were excluded, thereby limiting the generalizability of findings to early-stage disease populations. Compared to previous candidates such as obeticholic acid (OCA; FXR agonist) and selonsertib (ASK1 inhibitor), which failed in late-phase trials due to adverse events and lack of histologic benefit, resmetirom’s selective THR-β agonism represents a more targeted approach, directly modulating hepatic lipid metabolism rather than fibrogenesis alone. This distinction is vital; for instance, OCA faced regulatory rejection in 2023 primarily due to a poor benefit–risk profile characterized by severe pruritus and a concerning increase in LDL-C levels – side effects that resmetirom appears to mitigate through its lipid-lowering THR-β mechanism. In the broader therapeutic context, THR-β agonists such as resmetirom differ mechanistically from other investigational classes. Although SGLT2 inhibitors have shown promise in modifying inflammatory profiles in other chronic metabolic conditions7, FXR agonists modulate bile acid metabolism and inflammation but have been limited by pruritus and lipid elevations; PPAR agonists target insulin resistance and fibrogenesis; and FGF analogues (FGF19/FGF21) improve metabolic and inflammatory pathways. In contrast, THR-β agonists directly enhance hepatic mitochondrial β-oxidation and reduce steatosis, producing both hepatic and systemic lipid benefits that may indirectly lower cardiovascular risk. Although other emerging classes, such as FGF21 analogs, have demonstrated more robust rates of fibrosis reversal in early data, they typically require subcutaneous injections. Resmetirom’s oral, once-daily administration provides a significant advantage in patient adherence and usability in primary care settings compared to these injectable alternatives. However, there are key limitations reported in the trial, including no long-term safety outcomes being recorded to ensure long-term use of resmetirom. One of the major causes of death in patients with NASH is cardiovascular disease, which has been linked to increased levels of lipoproteins observed in NASH8. Although the levels of these lipids have been significantly reduced in the treatment, these markers are not accurate measures for the management of cardiovascular diseases in these patients. Furthermore, the MAESTRO-NASH trial specifically targeted “at-risk” NASH (stages F2 and F3), while explicitly excluding patients with F0 and F1 fibrosis. This creates a clinical paradox – while the drug is approved for “NASH with liver fibrosis,” there is no trial-based evidence to support its use in patients with early-stage disease (F0–F1), who represent a vast portion of the asymptomatic population; hence, the results recorded may not be widely applicable to patients with severe liver disease. While the approval of resmetirom marks a major therapeutic advance, global inequity in access remains a concern. The burden of NASH is disproportionately rising in low- and middle-income countries (LMICs), where access to diagnostic imaging, biopsy facilities, and advanced therapeutics is limited. A primary barrier in these settings is the dependence on histological confirmation via liver biopsy, as seen in the MAESTRO-NASH protocol. Without the widespread validation and implementation of non-invasive testing as an alternative to biopsy, the drug’s reach in LMICs will remain negligible due to a lack of pathology infrastructure. High treatment costs and regulatory delays may further restrict adoption outside high-income regions, underscoring the need for strategies that ensure equitable availability and affordability. Emphasizing the MAESTRO-NASH phase III trial, safety, and tolerability with mild adverse effects, and reduced inflammation demonstrated by resmetirom has highlighted the efficacy and potential of resmetirom in the treatment of NASH. However, due to major research gaps, the drug approval for the treatment of the disease globally has been challenging. Hence, there is a need for further clinical trials to be conducted for the authorization of resmetirom as the first approved drug for NASH globally. This manuscript is in compliant with the TITAN Guidelines, 2025, declaring no use of AI9.