Beyond efficacy: Insights from the norursodeoxycholic acid phase III trial in metabolic dysfunction-associated steatotic liver disease

Abstract

The therapeutic landscape for metabolic dysfunction-associated steatotic liver disease (MASLD) is undergoing rapid transformation with recent drug approvals. This editorial contextualizes a recent phase III trial of norursodeoxycholic acid within this dynamic progress. Panuganti et al recently published a study in World Journal of Hepatology, while demonstrating significant alanine aminotransferase normalization and FibroScan-based liver stiffness improvement, the trial’s short duration (24 weeks), reliance on non-invasive endpoints, and absence of histological confirmation underscore persistent challenges in MASLD drug development.

Key Words: Clinical endpoints; Drug development; Liver fibrosis; Metabolic dysfunction-associated steatotic liver disease; Norursodeoxycholic acid; Pharmacotherapy; Clinical trial

Core Tip: The phase III trial of norursodeoxycholic acid (norUDCA) in metabolic dysfunction-associated steatotic liver disease reflects broader methodological challenges in the field: Short duration, reliance on non-invasive surrogate endpoints, and high placebo response rates. While norUDCA’s mechanism and safety profile differ from newly approved agents, its future role may be further evaluated.

This editorial refers to “Phase III, multicenter, randomized, double-blind, placebo-controlled study of norursodeoxycholic acid in metabolic dysfunction-associated steatotic liver disease patients” by Panuganti VK et al, 2025; https://doi.org/10.4254/wjh.v17.i12.113658.

---

INTRODUCTION

Nonalcoholic fatty liver disease (NAFLD) has cemented its position as the most prevalent chronic liver condition worldwide, with a global prevalence estimated at 30%-35% and projections pointing to a relentless rise in tandem with obesity and type 2 diabetes mellitus pandemics[1-3]. Although recent consensus redefined NAFLD as metabolic dysfunction-associated steatotic liver disease (MASLD) to better reflect metabolic drivers, population-level prevalence estimates remain comparable due to overlapping diagnostic criteria. Its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), is a leading cause of cirrhosis, hepatocellular carcinoma, and liver-related mortality, while also contributing significantly to cardiovascular disease burden[4-6]. For decades, the management of MASLD rested almost exclusively on the pillars of lifestyle modification-weight loss, dietary changes, and increased physical activity[7]. While effective, the long-term sustainability of these interventions is often poor, leaving a vast therapeutic void for a disease affecting billions.

The year 2024 marked a historic turning point with the United States Food and Drug Administration approval of resmetirom, the first drug specifically indicated for the treatment of MASH with moderate-to-advanced liver fibrosis[8,9]. This milestone was quickly followed by the accelerated approval of semaglutide for MASH in 2025[10,11]. These approvals have shattered the long-standing therapeutic nihilism in MASLD, validating key biological targets and catalyzing an explosive phase of drug development. The pipeline now includes agents targeting a diverse array of pathways: Nuclear receptors [farnesoid X receptor (FXR), peroxisome proliferator-activated receptor (PPAR)], metabolic hormones [glucagon-like peptide-1 (GLP-1), fibroblast growth factor 21 (FGF21)], fibrogenic processes, and the gut-liver axis[12-15].

It is within this newly energized and competitive landscape that the Phase III trial of norursodeoxycholic acid (norUDCA) must be evaluated. NorUDCA is not a newcomer; its distinct pharmacology and early clinical signals have been recognized for years[16]. In a recent issue of the World Journal of Hepatology, Panuganti et al[17] reported a prospective study. This recent large-scale, randomized, placebo-controlled study provides preliminary evidence for its efficacy and safety in a MASLD population. This editorial offers a dual perspective: A granular critique of the norUDCA phase III trial and a strategic analysis of where this agent might fit within an increasingly complex, multimodal MASLD treatment paradigm.

This editorial argues that the norUDCA trial functions less as a therapeutic breakthrough and more as a “stress test” for current clinical trial paradigms-particularly regarding endpoint selection, duration, placebo response, and global generalizability in an era where histology-based fibrosis regression is now the regulatory gold standard.

EXPANDING PHARMACOPEIA: A SNAPSHOT OF CURRENT MASLD DRUG DEVELOPMENT

To appreciate the significance of any single agent, one must understand the spectrum of approaches being pursued. The current MASLD drug development ecosystem can be categorized by primary mechanism of action:

Thyroid hormone receptor-beta agonists

Resmetirom’s approval is seminal. It acts selectively on hepatic thyroid hormone receptor-beta (TRβ), boosting mitochondrial function and lipid metabolism, leading to reductions in hepatic fat, inflammation, and, crucially, fibrosis[8]. Its success has validated hepatic metabolic reprogramming as a potent anti-MASH strategy.

GLP-1 receptor agonists

Semaglutide’s MASH resolution is likely driven predominantly by profound weight loss (approximately 13% in ESSENCE), though direct anti-inflammatory hepatic effects cannot be excluded[10]. Their cardiorenal benefits make them particularly attractive for the comorbid MASLD patient[18].

FXR agonists

FXR activation regulates bile acid homeostasis and exerts anti-inflammatory and anti-fibrotic effects directly in the liver[19]. While obeticholic acid (first-gen) showed antifibrotic efficacy at the cost of pruritus and low-density lipoprotein (LDL) elevation[14], next-generation FXR modulators (e.g., tropifexor, cilofexor) aim for improved tolerability through partial agonism or gut-restricted action.

PPAR agonists

This class, including pan-PPAR agonists like lanifibranor, targets multiple facets of MASLD: PPAR-α for lipid metabolism, PPAR-δ for fatty acid oxidation, and PPAR-γ for insulin sensitization and anti-inflammation[12]. They offer a broad-spectrum approach but require careful monitoring for side effects like weight gain.

FGF21 analogues

Pegbelfermin and other FGF21 mimetics mimic a metabolic hormone that improves insulin sensitivity, lipid metabolism, and energy expenditure. They have shown promise in reducing hepatic fat and biomarkers of cell stress in clinical trials[15].

Anti-fibrotic & anti-inflammatory agents

Directly targeting the fibrosis cascade (e.g., through LOXL2 inhibition) or key inflammatory pathways represents a complementary strategy, often envisioned for use in combination with metabolic agents[20].

Some of these drugs have undergone high-quality clinical trials, demonstrating their therapeutic efficacy against MASH and their ability to improve fibrosis (Table 1). This rich pipeline signifies a shift from seeking a single “magic bullet” to building a multi-pronged, often combinatorial, therapeutic toolkit tailored to disease stage and patient phenotype[21].

Table 1 Comparative overview of metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis pharmacotherapies.

Drug class/agent (example)	Sample size (total randomized)	Trial duration	Baseline fibrosis stage1	Primary regulatory endpoint(s) achieved	Placebo-subtracted effect size2	Key safety trade-offs
TRβ agonist resmetirom	966 (MAESTRO-NASH, phase III)	52 weeks	F1B-F3	√ MASH resolution with no worsening of fibrosis; √ fibrosis improvement with no worsening of MASH (≥ 1 stage)	MASH resolution with no worsening of fibrosis: 16.4%-20.7%; fibrosis improvement with no worsening of MASH: 10.2%-11.8%; liver fat: -26.7% to 37.9% (MRI-PDFF)	GI intolerance (diarrhea and nausea); generally well tolerated
GLP-1 RA semaglutide	1197 (ESSENCE, phase III)	72 weeks	F2-F3	√ MASH resolution with no worsening of liver fibrosis; √ fibrosis improvement with no worsening of MASH	MASH resolution with no worsening of liver fibrosis: 28.7%; fibrosis improvement with no worsening of MASH: 14.4%; Weight loss: -8.5%	GI intolerance (nausea/vomiting); contraindicated in medullary thyroid cancer risk; low hypoglycemia risk
FXR agonist obeticholic acid	1968 (REGENERATE, phase III)	18 months	F1-F3	× MASH resolution with no worsening of liver fibrosis; √ fibrosis improvement with no worsening of MASH	MASH resolution with no worsening of fibrosis: 3%-4% (NS); fibrosis improvement with no worsening of MASH: 6%-11%	Pruritus (28%-51%, often grade 1- grade 2); LDL-C ↑ (1.4-2.7 mg/dL); HDL ↓
Pan-PPAR agonist lanifibranor	247 (NATIVE, phase IIb)	24 weeks	F1-F3	√ A decrease of SAF-A score and no worsening of fibrosis	A decrease of SAF-A score and no worsening of fibrosis: 15%-22%; resolution of MASH without worsening of fibrosis: 17%-27%; fibrosis improvement with no worsening of MASH: 5%-17%	Weight gain (2.4-2.7 kg); mild edema; GI intolerance (diarrhea and nausea)

¹Baseline fibrosis stage: Based on central histology (nonalcoholic steato hepatitis clinical research network system) unless otherwise noted.

²Effect sizes: Approximate placebo-adjusted differences.

NS: Not significant; MAESTRO-NASH: Metabolic associated steatotic liver disease and metabolic associated steatohepatitis research network; MASH: Metabolic dysfunction-associated steatohepatitis; GI: Gastrointestinal; MRI-PDFF: Magnetic resonance imaging - proton density fat fraction; LDL-C: Low-density lipoprotein cholesterol; HDL: High-density lipoprotein; REGENERATE: Randomized global phase 3 study to evaluate the impact on NASH with fibrosis of obeticholic acid treatment; NATIVE: Name of a phase 2b/3 clinical trial evaluating the efficacy and safety of lanifibranor in adult patients with nonalcoholic steatohepatitis and liver fibrosis; SAF-A: Steatosis, activity, fibrosis - activity score; TRβ: Thyroid hormone receptor β; GLP-1 RA: Glucagon-like peptide-1 receptor agonist; FXR: Farnesoid X receptor; PPAR: Peroxisome proliferator-activated receptor.

NORUDCA: MECHANISM AND THE PHASE III TRIAL IN FOCUS

NorUDCA, a 23-carbon homologue of the familiar ursodeoxycholic acid (UDCA), possesses a unique pharmacological profile. Unlike UDCA-which primarily stabilizes hepatocyte membranes-and FXR agonists-which systemically modulate bile acid synthesis-norUDCA acts locally via cholehepatic shunting to exert direct antifibrotic and cytoprotective effects without significantly altering systemic bile acid pools. Its shortened side chain confers resistance to amidation, allowing it to undergo “cholehepatic shunting”. This means it is efficiently absorbed from the bile ducts back into hepatocytes, leading to high and sustained intrahepatic concentrations-a pharmacokinetic advantage over UDCA[16]. Mechanistically, it primarily downregulates key profibrogenic pathways, including transforming growth factor-beta signaling and collagen I expression, thereby directly countering the fibosis[22]. Also, it promotes a healthier bile acid profile by indirectly influencing FXR signaling and regulating bile acid transporter expression. This shifts the bile acid pool toward a more hydrophilic and less toxic composition, which supports metabolic homeostasis[4]. It further mitigates inflammation and provides direct protection to hepatocytes, shielding them from various injurious stimuli[22].

The phase III trial evaluated norUDCA (1500 mg/day) vs placebo over 24 weeks in 165 Indian patients with MASLD[17]. Its design and outcomes offer a concrete case study in modern MASLD trial execution. The co-primary endpoints were alanine transaminase (ALT) normalization and improvement in liver stiffness measured by FibroScan at week 12. Key efficacy results showed a significantly higher proportion of patients in the norUDCA group achieved ALT normalization at week 12 compared to the placebo group (89.8% vs 76.4%; P = 0.022). The regression in liver stiffness at week 12 was observed in 57.4% of the norUDCA group vs 40.0% in the placebo group (P = 0.035), with this antifibrotic signal strengthening to 83.3% vs 65.5% by week 24 (P = 0.009). The drug was well-tolerated with no serious adverse events reported; adverse events were mostly mild-to-moderate and gastrointestinal.

CROSS-CUTTING ANALYSIS: INTERROGATING THE NORUDCA TRIAL THROUGH THE LENS OF FIELD-WIDE CHALLENGES

The norUDCA trial, while a positive study, vividly illustrates several universal challenges in MASLD drug development.

Conundrum of trial duration and meaningful endpoints

The 24-week duration of the norUDCA trial is both a pragmatic strength and a scientific limitation-a tension common in the field[23]. While it efficiently demonstrates ALT normolization and transient elastography improvements, MASLD is a chronic, indolent disease. True “disease-modification” likely requires treatment durations of 72 weeks or more, as seen in the registration trials for resmetirom and semaglutide[8,10]. The choice of FibroScan as a primary endpoint, while ethically and practically justified over repeated liver biopsies, also sparks debate about its sensitivity for early fibrosis and its correlation with hard clinical outcomes[24]. This reflects a field-wide struggle to balance feasibility with regulatory and clinical rigor[25].

Pervasive and potent placebo effect

The norUDCA results demonstrate the powerful placebo effect in MASLD trials. The placebo group achieved a remarkable 76.4% ALT normalization rate at week 12. This phenomenon, observed across countless studies, is attributed to the “trial effect”: Intensive lifestyle counseling and heightened medical attention leading to behavioral changes[26]. The trial protocol reportedly included standard dietary advice, but adherence was not monitored-potentially contributing to the high placebo response. Also, the trial’s lack of a pre-randomization run-in period likely allowed this effect to inflate the placebo response, thereby potentially underestimating the true treatment effect size[23].

Decoupling biochemical from histological/structural response

An intriguing finding is the temporal discordance between ALT normalization (peak effect at week 12) and FibroScan improvement (progressive through week 24). This underscores a key principle: Improvement in liver enzymes is not a surrogate for antifibrotic efficacy[25]. The field is gradually moving towards accepting composite endpoints that include both resolution of steatohepatitis and improvement in fibrosis stage. In norUDCA trial, FibroScan improvement was implicitly treated as a surrogate for fibrosis regression, though its correlation with histologic change remains imperfect-especially over 12-24 weeks.

Limitations of ethnic and regional generalizability

South Asian populations display a unique metabolic phenotype, characterized by higher visceral adiposity and insulin resistance, which leads to a greater prevalence of MASLD even at lower body mass indices. Given norUDCA’s primary effect on bile acid metabolism, its efficacy may differ in populations with distinct genetic and physiological backgrounds-such as variations in bile acid pool composition or transporter expression (e.g., apical sodium-dependent bile acid transporter polymorphisms). Therefore, future clinical trials should move beyond simple replication in Western cohorts and instead incorporate region-stratified analyses or adaptive designs to better evaluate potential population-specific responses.

Safety in a metabolically vulnerable population

The safety profile of norUDCA appears favorable. However, the occurrence of metabolic adverse events (dyslipidemia, new-onset diabetes) in both arms highlights a crucial point: MASLD trial populations are, by definition, metabolically unstable. Disentangling drug-related metabolic effects from the natural progression of underlying cardiometabolic risk factors is exceptionally difficult, a challenge also faced by other drug classes like FXR agonists[14]. Given MASLD’s association with cardiovascular risk, 24-week safety data are inadequate to rule out long-term metabolic or bile acid-related adverse effects.

POSITIONING NORUDCA IN THE CURRENT AND FUTURE TREATMENT PARADIGM

Given its efficacy, safety data and its combined anti-inflammatory and direct anti-fibrotic action, norUDCA could be beneficial across MASLD stages[27]. Its bile acid-centric mechanism may offer particular utility in patients with overlapping MASLD and cholestatic features[22]. Its favorable safety and tolerability-notably the absence of pruritus or LDL elevation-contrasts with the known limitations of FXR agonists. Furthermore, its mechanism of action is independent of weight loss, offering a potential alternative for patients intolerant of or unresponsive to GLP-1 receptor agonists.

However, significant evidence gaps must be addressed for norUDCA to achieve broader clinical relevance. Critically, the absence of robust histologic data showing ≥ 1-stage fibrosis improvement after ≥ 72 weeks of treatment remains a major limitation; such proof of durable histological benefit is essential for competitiveness. Furthermore, there are no head-to-head or additive trials comparing norUDCA with approved agents like resmetirom or semaglutide, and a lack of long-term (> 1 year) efficacy and safety data places it at a disadvantage in a market where newer therapies are supported by multi-year trial results.

Combination therapy represents a promising frontier in MASLD treatment[4,28,29], with norUDCA positioned as a compelling candidate for rational pairing. Its unique, bile acid-focused mechanism supports two particularly viable strategies: First, with a GLP-1 receptor agonist such as semaglutide, to concurrently address systemic metabolic drivers-via improved glycemic control, weight loss, and reduced inflammation-while providing direct hepatic anti-fibrotic action, an approach especially compelling for patients with obesity, insulin resistance, and established fibrosis; and second, with a thyroid hormone receptor-beta agonist like resmetirom, creating a dual-pronged regimen that enhances hepatic metabolic function while modulating the bile acid pool. From a safety perspective, these combinations carry a low risk of pharmacokinetic interactions, as none are significant CYP450 substrates, though additive gastrointestinal side effects may require careful clinical management. The primary development challenge lies in the substantial evidence required for regulatory approval: Agencies will demand clear demonstration of an added histological benefit over monotherapy, necessitating large, long-term trials with strategic patient selection, which inherently increases both the cost and complexity of bringing such combinations to market.

SYNTHESIS AND FUTURE DIRECTIONS: LESSONS FROM NORUDCA FOR THE FIELD

The norUDCA trial represents more than a report on a single therapeutic agent; it serves as a microcosm of the contemporary endeavor to treat MASLD. The discussion of the trial reinforce several imperatives for future trial design, with the following three as top priorities: Extend pivotal trials to ≥ 72 weeks with histologic endpoints. Standardize and validate non-invasive tests across diverse populations. Launch early-phase combination trials with mechanistic synergy.

To mitigate the placebo effect, incorporating run-in periods is feasible strategy[23,26]. Also, Future research should seek to identify biomarkers that predict response to specific mechanisms, moving from a one-size-fits-all to a tailored approach. Baseline serum bile acid profiles or expression of bile acid transporters (e.g., apical sodium-dependent bile acid transporter) could serve as predictive biomarkers for norUDCA response[30].

CONCLUSION

The phase III trial of norUDCA demonstrates its capacity to safely improve key hepatic parameters, thereby expanding the available therapeutic arsenal for MASLD. However, its arrival underscores the evolving and increasingly rigorous standards of the field. In this context, the trial serves as a salient case study, exposing key systemic constraints in contemporary MASLD drug development: The limitations of trials with relatively short duration, a reliance on non-invasive surrogate endpoints, and the confounding impact of high placebo response rates. As effective therapies like resmetirom and semaglutide establish new benchmarks with multi-year histological data, the imperative for more definitive evidence grows. Consequently, the future path for novel agents must involve longer, histology-anchored trials enriched by validated biomarkers. This shift necessitates more exacting scrutiny from regulators, clinicians, and scientific journals alike to ensure that new additions to the therapeutic toolbox meet the heightened evidentiary threshold now demanded in the post-approval era.

ACKNOWLEDGEMENTS

We would like to acknowledge Dr. Ying-Feng Liu for his work in data verification.