What's the latest update on the ongoing clinical trials related to Nonalcoholic Steatohepatitis?

Overview of Nonalcoholic Steatohepatitis (NASH)

Nonalcoholic steatohepatitis (NASH) is widely recognized as an advanced, progressive form of nonalcoholic fatty liver disease (NAFLD) characterized by hepatic steatosis accompanied by inflammation, hepatocyte injury (ballooning) and various degrees of fibrosis. As a multi‐factorial disease, its pathogenesis involves metabolic dysregulation, oxidative stress, inflammatory cascades and fibrogenic processes. This backdrop of complex biology underpins the challenges of accurately diagnosing and treating NASH, and it subsequently has stimulated a broad research effort aimed at developing both noninvasive diagnostics and novel therapeutics.

Definition and Pathophysiology

NASH is defined by the presence of fat accumulation in the liver, accompanied by evidence of liver cell injury (typically ballooning) and lobular inflammation. In its more advanced stages, fibrosis may develop, eventually leading to cirrhosis and hepatocellular carcinoma. The underlying pathophysiological processes are complex, involving insulin resistance, lipotoxicity, mitochondrial dysfunction, endoplasmic reticulum stress, and dysregulation of inflammatory cytokines. In this condition, the excessive accumulation of free fatty acids within hepatocytes triggers oxidative stress and inflammatory signaling. This promotes immune cell activation and fibrogenesis through hepatic stellate cell activation. Additionally, emerging evidence suggests that gut dysbiosis and variations in the gut–liver axis also contribute to the pathogenesis of NASH. These multifaceted mechanisms have driven research to identify specific molecular targets that can disrupt these pathological pathways, prompting the development of compounds targeting nuclear receptor agonism (such as FXR agonists), peroxisome proliferator-activated receptor (PPAR) agonists, and various anti-inflammatory, anti-fibrotic as well as metabolic modulators.

Epidemiology and Risk Factors

Epidemiologically, NASH affects a substantial proportion of the global population. Estimates suggest that NASH affects between 1.5% and 6.5% of adults worldwide, although its prevalence is expected to rise as metabolic syndrome and obesity become increasingly common. Risk factors include obesity, type 2 diabetes mellitus, dyslipidemia, and components of the metabolic syndrome. Patients with insulin resistance are particularly predisposed due to the associated disturbances in lipid metabolism that lead to hepatic fat deposition and subsequent inflammation. In addition, genetic predisposition may also influence individual susceptibility to NASH, as research indicates that polymorphisms in genes related to lipid metabolism, inflammation and fibrosis can impact disease progression. The broad range of contributing factors illustrates that NASH is not a homogenous entity; rather, its presentation can vary considerably among patients, thereby influencing both the clinical course of the disease and the difficulty in achieving consistent therapeutic outcomes.

Current Treatment Landscape for NASH

The current treatment landscape for NASH is evolving. While lifestyle modifications—such as weight loss through dietary changes and increased physical activity—remain the cornerstone of management, there is an urgent need for pharmacological treatments that can reverse or halt disease progression. Despite the many molecules under investigation, there has been limited progress in establishing approved therapies, with many compounds showing mixed or modest efficacy in clinical trials.

Existing Therapies

At present, there are several treatment strategies that have been evaluated. For example, vitamin E has been studied in patients with NASH, and while it may yield some histologic improvement in select populations, particularly those without diabetes, concerns about its safety profile and the lack of robust long‐term data have prevented its widespread endorsement as a definitive therapy. Pioglitazone, a thiazolidinedione that improves insulin sensitivity, has also been examined and shown to improve features of NASH in some studies, but its association with weight gain and other adverse effects limits its broader use. Other agents, such as saroglitazar—an agent with PPAR-α and -γ activity—have been approved in some regions (for example, in India) for the treatment of NASH in non-cirrhotic patients. However, these treatments mainly target metabolic alterations rather than the fibrotic and inflammatory aspects of NASH, and their efficacy in altering long-term outcomes remains uncertain.

Unmet Medical Needs

Despite these advances, a significant unmet medical need persists. No single therapy is yet approved by global regulatory authorities specifically for NASH, largely because of the heterogeneous nature of the disease and the challenges inherent in demonstrating substantial histological improvement and clinical outcomes in a consistent manner. Many investigational agents have shown promise in early-phase studies, but the complexity of NASH—with its interrelated metabolic, inflammatory, and fibrotic processes—necessitates either combination therapies or personalized approaches tailored to individual pathogenic profiles. Moreover, the lack of reliable, noninvasive biomarkers for disease progression and treatment response further complicates the development and evaluation of therapeutics. In addition, the high placebo response rates observed in some phase 2 and 3 clinical trials, as well as variability in histological assessments via liver biopsies, have hampered the consistent demonstration of clinical benefit. These challenges have spurred the research community and industry to design more sophisticated clinical trials and adopt innovative endpoints that can more accurately capture the therapeutic effects on both NASH resolution and fibrosis regression.

Ongoing Clinical Trials for NASH

Ongoing clinical trials in NASH are at the forefront of efforts to address these unmet needs. There is a broad spectrum of interventional studies spanning various phases, with some trials designed to demonstrate histological improvements while others are incorporating noninvasive imaging and biomarker endpoints. These trials include both monotherapies and combination regimens, targeting an array of pathogenic mechanisms.

Major Trials and Their Objectives

Several major ongoing clinical trials have been designed with clear objectives to improve not only liver histology but also clinical outcomes for patients with NASH. For instance, the TANDEM study is a 48-week, phase 2b multicenter, randomized, double-blind study assessing the combination of the FXR agonist tropifexor (TXR) with the C-C chemokine receptor 2/5 inhibitor cenicriviroc (CVC) compared to their respective monotherapies in patients with noncirrhotic NASH. The rationale behind this combination is that the complementary mechanisms of action may lead to synergistic improvements in reducing inflammation, hepatocyte injury, and fibrosis. In preclinical studies, TNXR and CVC combination therapy demonstrated significant anti-inflammatory effects, and early phase trials with this combination are closely monitoring changes in liver enzymes, histological endpoints including improvement in fibrosis stage, and noninvasive biomarkers.

Another key trial is the ICONA Phase 2b study, which evaluates icosabutate—an ingeniously engineered fatty acid with potent anti-inflammatory, antifibrotic, and antioxidant properties—in patients with NASH. In this trial, patients are administered either 300 mg or 600 mg of icosabutate once daily over a 52-week period. The interim analysis based on the first 90 patients treated for 16 weeks has shown dose-dependent significant improvements in liver enzymes, notably a reduction in alanine aminotransferase (ALT) as well as reductions in gamma-glutamyl transferase (GGT) and plasma triglycerides. The study’s objectives are not only focused on biochemical improvements but also aim at documenting histological resolution of NASH and improvement in fibrosis scores on liver biopsy.

Resmetirom, a selective thyroid hormone receptor-β agonist, is another agent undergoing extensive clinical study in the NASH arena. The MAESTRO-NASH program, which comprises several phase 3 trials including MAESTRO-NASH, MAESTRO-NAFLD-1 and MAESTRO-NAFLD-OLE, aims to demonstrate the efficacy and long-term safety of resmetirom in biopsy-confirmed NASH patients with varying degrees of fibrosis. Interim analysis from a 52-week portion of MAESTRO-NASH has shown promising reductions in liver stiffness measured by vibration-controlled transient elastography, as well as improvements in noninvasive markers such as the Enhanced Liver Fibrosis (ELF) score and FIB-4. These endpoints are vital as they may serve as surrogates for histological improvements, and the ongoing trials are being closely followed by regulatory agencies as potential candidates for accelerated approval.

In addition to these landmark studies, several other trials are exploring various novel approaches. For instance, there is a trial evaluating low-dose thyroid hormone for NASH in veterans, which seeks to assess if modulating mitochondrial fatty acid oxidation can improve liver histology and biochemical parameters. Moreover, the TARGET-NASH registry is noteworthy, as it is a large, real-world observational study that has enrolled more than 7,000 patients with NAFLD and NASH, with over 500,000 patient-months of follow-up. This registry is providing critical insights into disease progression, risk stratification and the long-term safety profiles of potential therapeutics.

There are also global clinical trial analyses reported by ResearchAndMarkets.com, which provide a macro-level overview of the clinical trial landscape by country, phase, sponsor type and endpoints. These reports indicate that the majority of ongoing trials are in phase II and phase III, and they underscore the robust investment from industry in developing novel therapies for NASH. The global clinical trial data also reveal trends in enrollment numbers, geographic distribution and the increasing use of advanced imaging and digital pathology endpoints to reduce reliance on invasive liver biopsies.

Key Findings and Interim Results

The interim results emerging from these trials have provided several promising signals but have also highlighted the inherent challenges in NASH drug development. For example, the ICONA Phase 2b trial with icosabutate reported a highly significant reduction in ALT of approximately 25–36 U/L, along with significant improvements in GGT and plasma triglyceride levels, especially in the 600 mg dosing group. These biochemical improvements are encouraging because previous studies have correlated such reductions with histological improvement in NASH patients. However, the trial is still ongoing, and longer-term histological endpoints will be required to fully validate the therapeutic potential of icosabutate.

Similarly, interim data from the MAESTRO-NASH phase 3 program with resmetirom have shown statistically significant reductions in measures of liver stiffness and favorable trends in noninvasive biomarkers of fibrosis, with improvements noted at both 12 and 52 weeks. These findings are particularly compelling because they address the key transition from biochemical improvement to potential histological and clinical benefit. The fact that resmetirom has been evaluated in a large cohort of over 1,000 patients and continues to show promising results in reducing markers of liver injury and fibrosis adds to the growing evidence that selective THR-β agonism may be a viable therapeutic strategy for NASH.

The TANDEM study, which examines the combination of TXR and CVC, continues to explore the benefit of targeting complementary pathways in NASH. Although full results are pending, early assessments have indicated that the combination can achieve greater reductions in liver transaminases and improvements in liver inflammation compared to either compound alone. These data are being interpreted in the context of preclinical evidence where the dual inhibition of inflammatory cytokine synthesis and chemokine receptor signaling appeared to yield additive or synergistic effects.

Furthermore, real-world registries and observational studies such as TARGET-NASH are contributing valuable data regarding the natural history of NASH and the longitudinal effects of various interventions. With more than 7,000 patients enrolled and the capacity to track over half a million patient-months of follow-up, TARGET-NASH is providing insights into disease progression, treatment adherence, and safety profiles in routine clinical practice. This real-world evidence is likely to complement the data derived from randomized controlled trials and may help fine-tune treatment algorithms and patient selection criteria in the future.

Other ongoing clinical trials are exploring novel endpoints and surrogate biomarkers that could improve the efficiency of clinical trials. For example, several studies are incorporating advanced imaging techniques such as magnetic resonance imaging–proton density fat fraction (MRI-PDFF) and magnetic resonance elastography (MRE) to quantitatively assess changes in liver fat content and stiffness. These noninvasive modalities are attractive because they can reduce dependence on liver biopsy—the current gold standard but one that is fraught with sampling variability and procedural risk. These technological innovations in trial design and endpoint selection signal a broader trend toward precision medicine in NASH, where treatment efficacy can be monitored more reliably and in a less invasive manner.

Future Directions in NASH Research

Looking ahead, the future of NASH research is marked by a blend of innovative therapeutic candidates, advanced trial designs and the increasing incorporation of precision medicine techniques. The field is moving toward a paradigm where combination therapies may be more effective in addressing the multifaceted nature of NASH, and where patient subpopulations may be stratified based on underlying pathogenic mechanisms.

Emerging Therapies in Development

Emerging therapeutic agents span a wide range of targets and mechanisms of action. Aside from the traditionally studied metabolic agents, several new molecular entities are being investigated for their ability to modulate inflammation, inhibit fibrogenesis, or improve lipid metabolism. Agents such as lanifibranor, a pan-PPAR agonist with demonstrated efficacy in phase 2 trials, have recently garnered attention for their ability to improve insulin sensitivity and reduce fibrosis markers. Similarly, obeticholic acid, despite its mixed performance and regulatory challenges, continues to be explored in combination regimens and in refined dosing schedules to optimize the benefit:risk profile.

The use of experimental molecules like icosabutate, which not only target inflammation and oxidative stress but also exert antifibrotic effects, exemplifies the trend toward leveraging multi-mechanistic compounds. Additionally, the pipeline now includes drugs based on novel targets such as apoptosis signal-regulating kinase 1 (ASK1) inhibitors, FXR agonists with improved tolerability profiles and agents designed to modulate the gut–liver axis through microbiome manipulation. Gene therapies and technologies such as RNA interference (RNAi) are also on the horizon, with early-phase studies suggesting that these approaches could offer prolonged efficacy with minimal side effects, although most of these have thus far been limited to animal models.

From a trial design perspective, there is a notable movement toward platform and adaptive clinical trials that allow for the simultaneous assessment of multiple agents within a single trial structure. Such designs can allow for more efficient resource utilization, streamline patient recruitment and provide early signals of efficacy that can accelerate the development timeline. Furthermore, advancing digital pathology through artificial intelligence and machine learning has already shown promise in refining histological assessments, thereby reducing the variability inherent in liver biopsy interpretation. These technological advances, combined with improved noninvasive diagnostic tools such as blood-based biomarkers and advanced MRI techniques, are likely to improve both patient selection and treatment monitoring in future clinical trials.

Challenges and Opportunities

Despite the optimistic developments, several challenges remain. One of the chief obstacles is the heterogeneity within the NASH patient population. As NASH is a syndrome with multiple underlying pathogenic drivers—metabolic, inflammatory, and fibrotic—a one-size-fits-all therapy is unlikely to be effective. This creates an opportunity for personalized or combination therapy approaches where treatments are tailored according to patient-specific risk factors and molecular profiles. However, this also necessitates the identification and validation of reliable biomarkers that can guide both diagnosis and treatment response.

Another significant challenge in NASH clinical trials is the high placebo response rate, which can confound the evaluation of treatment efficacy. High placebo responses are partly attributable to the invasive nature of liver biopsies and the inherent variability in histological scoring systems. In response, researchers are increasingly adopting noninvasive imaging endpoints and redefining outcome measures to capture clinically meaningful improvements in fibrosis and inflammation rather than just improvements in liver enzyme levels. Furthermore, the regulatory landscape is evolving, with agencies beginning to accept surrogate markers and noninvasive endpoints as part of accelerated approval pathways, provided that these correlate strongly with long-term clinical outcomes.

Operational challenges, such as the lengthy trial durations, difficulties in patient enrollment and retention, and the financial costs associated with large-scale trials, also persist. Recent estimates suggest that hundreds of patients may be required across many sites to meet enrollment targets, driving overall trial costs upward. Adaptive trial designs and platform studies are seen as promising strategies to overcome these hurdles, allowing for more flexible patient allocation based on interim results and reducing the overall number of patients required in any single study.

There remains considerable opportunity in leveraging real-world evidence from registries like TARGET-NASH. Such registries provide comprehensive, longitudinal data on patient outcomes, treatment adherence, and the natural history of NASH. Integrating these data with randomized controlled trial (RCT) outputs can enrich our understanding of the disease and help identify subpopulations most likely to benefit from specific interventions. In doing so, the clinical trial landscape may become more streamlined and ultimately more predictive of long-term patient outcomes.

Moreover, the emergence of combination therapies stands as a promising frontier. Trials such as TANDEM, which combine agents with complementary mechanisms, are paving the way for future protocols that may use dual or even triple therapy regimens. By targeting different aspects of the disease simultaneously—such as combining a drug that improves lipid metabolism with one that mitigates inflammation and another that reverses fibrosis—clinicians hope to achieve more robust and sustained treatment responses. This combinatorial approach, however, requires meticulous trial design to identify appropriate dosing regimens, manage drug–drug interactions and establish synergistic endpoints.

The continuous technological progress in high-throughput sequencing techniques and digital pathology is also expected to refine patient stratification in NASH. Single-cell sequencing and spatial transcriptomics, for instance, may soon enable researchers to identify specific cell populations driving disease progression and therapeutic resistance. This translational research could inform the design of clinical trials and lead to more personalized treatment regimens that accurately address the underlying pathogenesis in individual patients.

Finally, regulatory agencies are beginning to recognize the unique challenges in NASH drug development and are open to innovative trial designs that use novel surrogate endpoints. The acceptance of noninvasive imaging modalities and blood-based biomarkers as part of the regulatory framework offers promising opportunities for faster, less invasive monitoring of treatment efficacy. With such advancements, the waiting time for an approved, effective therapy for NASH could be shortened, potentially changing the clinical management landscape for millions of patients worldwide.

Detailed Conclusion

In summary, the latest updates on ongoing clinical trials in NASH reflect an era of intense activity, innovation and adaptation in the face of a complex, multifactorial disease. The clinical research landscape includes several major trials with distinct objectives:

• The TANDEM study is investigating the combination of tropifexor (TXR) and cenicriviroc (CVC) to target both inflammatory and fibrotic pathways, with early data suggesting that combination therapy may yield additive benefits over monotherapy.
• The ICONA Phase 2b study is evaluating icosabutate, a next-generation fatty acid derivative, and has reported significant reductions in ALT, GGT and triglycerides in interim results, highlighting its potential anti-inflammatory and antifibrotic effects.
• Resmetirom, as part of the MAESTRO-NASH program, is being evaluated in large phase 3 trials, with interim analyses showing favorable reductions in liver stiffness and improvements in noninvasive fibrosis markers, positioning it as a strong candidate for future regulatory approval.
• Additional trials, including those exploring thyroid hormone modulation and innovative noninvasive biomarkers, are underway to better capture treatment effects and long-term outcomes.
• Large observational registries such as TARGET-NASH continue to provide invaluable real-world data that complement RCT findings and help refine patient selection, treatment response predictions, and overall disease management strategies.

From these developments, it is clear that the field is transitioning from a reliance on monotherapies to exploring combination treatments that simultaneously address multiple pathogenic pathways. The integration of novel endpoints—ranging from advanced imaging techniques like MRI-PDFF and MRE to refined serum biomarker panels—as well as adaptive and platform trial designs, means that future clinical studies are likely to be more efficient, less invasive and more reflective of real-world patient experiences.

The translational potential of these trials is further enhanced by insights from cutting-edge technologies such as artificial intelligence in digital pathology and single-cell transcriptomics, which are poised to revolutionize how we understand patient heterogeneity and disease progression at the molecular level. As these data accumulate, the opportunity for personalized, precision-based approaches in NASH treatment becomes increasingly tangible.

Despite promising interim results, significant challenges remain. The heterogeneity of the NASH population, high placebo response rates, and limitations in current noninvasive diagnostics all underscore the need for continued innovation in trial design and therapeutic development. Nevertheless, the cumulative evidence—supported by robust real-world data and rapidly evolving clinical trial methodologies—suggests that the next few years may witness the first regulatory approvals of targeted therapies for NASH, offering genuine hope to millions affected by this progressive liver disease.

In conclusion, the latest update on ongoing clinical trials in NASH highlights a dynamic and rapidly evolving research landscape. Multiple agents are in late-stage development, with promising interim results that show improvements in both biochemical parameters and noninvasive markers of liver pathology. These trials are not only addressing the unmet medical needs by introducing innovative therapeutic strategies but are also refining the methodologies used to assess disease progression and treatment response. While the path to an approved, effective treatment remains challenging due to the inherent complexity and heterogeneity of NASH, the advances seen in adaptive trial designs, combination therapies and state-of-the-art diagnostic approaches represent significant steps forward. Ultimately, these combined efforts are expected to translate into better, more personalized patient care and a potential paradigm shift in the management of NASH worldwide.