What drugs are in development for Nonalcoholic Steatohepatitis?

Introduction to Nonalcoholic Steatohepatitis (NASH)

Definition and Pathophysiology
Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that is characterized by hepatic steatosis (fat accumulation), inflammation, hepatocellular injury (ballooning), and various degrees of fibrosis. Over time, this inflammatory damage can lead to cirrhosis, increased risk of hepatocellular carcinoma, and liver-related death. The pathogenesis of NASH is multifactorial and involves a complex interplay of metabolic, immune, and cellular stress pathways. Insulin resistance, lipotoxicity (related to free fatty acid accumulation), oxidative stress, and the release of inflammatory cytokines are considered critical in the evolution from simple steatosis to steatohepatitis. Moreover, genetic predispositions (such as variants in PNPLA3), epigenetic modifications, and alterations in gut microbiota further contribute to disease progression. This complex pathophysiology means that multiple pathways are simultaneously active and dynamic, which in turn explains why clinicians and researchers believe that “one drug” is unlikely to fit all patients with NASH and why combination therapies or personalized treatment protocols may eventually be needed.

Current Treatment Landscape
Currently, in clinical practice, there is no approved pharmacologic therapy for NASH even though lifestyle intervention—with dietary modifications, weight loss, and exercise—remains the cornerstone of management. Several off‑label agents have been used with some benefit in selected patients. These include antidiabetic drugs like pioglitazone and even vitamin E, which have shown histological improvement in some populations, yet their use remains limited by side effects and the lack of long‑term outcome data. Such limitations underline the enormous unmet medical need and have driven the rapid expansion of the drug development pipeline, with over 55 different drugs in various phases of development according to several synapse references. In addition, the industry is also exploring combination therapies of different mechanisms in order to address both the inflammatory and fibrotic components of NASH.

Drug Development Pipeline for NASH

Drugs in Preclinical and Clinical Stages
The pipeline for NASH therapeutics is remarkably diverse. Investigational drugs span from early preclinical candidates to those in advanced phase III trials. A number of compounds have been evaluated in phase II and phase III settings, and many target distinct or overlapping pathways in the disease. For example:

• Obeticholic acid (OCA) is a farnesoid X receptor (FXR) agonist. It was the first drug with phase III data in NASH that demonstrated significant, though complex, effects on liver histology, particularly fibrosis improvement. However, its side‑effect profile (including pruritus and changes in lipid parameters) has raised concerns.

• Resmetirom (also known as MGL‑3196) is a selective thyroid hormone receptor beta (THR‑β) agonist that has shown promising results in reducing liver fat and improving histological markers in phase III studies. Resmetirom is being evaluated with endpoints such as NASH resolution and fibrosis improvement, and its clinical development timeline includes several upcoming milestone readouts.

• Aramchol, a modulator of stearoyl‑coenzyme A desaturase‑1 (SCD‑1), has been shown in phase II studies (such as the ARREST study) to reduce liver fat content and slow fibrosis progression, making its mechanism of targeting de novo lipogenesis particularly attractive.

• Cenicriviroc (CVC), an antagonist of the chemokine receptors CCR2/CCR5, targets inflammatory and fibrotic pathways simultaneously. Although its phase IIb data (from CENTAUR) showed some promise, results from subsequent phase III trials raised concerns regarding efficacy, leading to a premature halt of a study (AURORA trial).

• Belapectin is a galectin‑3 inhibitor that has been examined in the context of preventing portal hypertension and esophageal varices in patients with NASH‑related cirrhosis. Phase II data suggest that while it may not dramatically improve histology in all patients, it could reduce the hepatic venous pressure gradient in selected patients.

• Elafibranor, a dual peroxisome proliferator‑activated receptor (PPAR) α/δ agonist, has been developed to target dyslipidemia, insulin resistance, and inflammation. Although phase II data initially appeared promising by demonstrating histological improvements, its later-stage efficacy has been called into question with several studies not meeting primary endpoints.

• Other agents in clinical development include FXR agonists beyond OCA (such as tropifexor), synthetic agonists of the THR‑β receptor (like VK2809), and GLP‑1 receptor agonists (e.g., semaglutide). Semaglutide, while initially developed and approved for type 2 diabetes, is under investigation for its beneficial effects on weight loss, insulin resistance, and liver inflammation in NASH.

• Additionally, combination therapies are emerging in this pipeline. For example, the pairing of a potent FXR agonist (such as tropifexor) with agents that reduce insulin resistance or target chemokine pathways (like CVC) may produce additive or synergistic effects.

In the preclinical stages, a multitude of other molecules target metabolic pathways including inhibitors of fatty acid synthase (FASN), SCD‑1 modulators, and various agents modulating inflammatory pathways (such as inhibitors of TNF‑α signalling). These preclinical candidates are also exploring novel delivery systems, including nanoparticle encapsulation, which intends to improve bioavailability and reduce off‑target toxicity. The significant expansion in preclinical research is echoed by the number of phase I and II clinical studies that have been initiated within the past several years.

Mechanisms of Action
The drugs under development for NASH employ a variety of mechanisms to intervene either at the level of lipid metabolism, inflammation, cell injury, or fibrosis, and often more than one mechanism is targeted simultaneously. Key mechanisms include:

• FXR Agonism: Activation of the FXR receptor modulates bile acid metabolism and has downstream effects on lipid metabolism and inflammation. Obeticholic acid is the archetypal drug employing this mechanism, although other FXR agonists such as tropifexor are also in development.

• THR‑β Agonism: Drugs such as resmetirom and VK2809 selectively target the thyroid hormone receptor beta in the liver to regulate gene expression linked to lipid metabolism. By improving lipoprotein profiles, reducing steatosis, and enhancing β‑oxidation, these agents address key metabolic discrepancies in NASH.

• SCD‑1 Modulation: Aramchol reduces the synthesis of monounsaturated fatty acids by modulating the activity of SCD‑1. This results in decreased de novo lipogenesis, lower hepatic fat deposition, and a subsequent reduction in inflammation and fibrosis signals.

• CCR2/CCR5 Antagonism: Cenicriviroc blocks these chemokine receptors, thereby decreasing monocyte/macrophage recruitment to the liver, reducing inflammation and fibrogenesis. Although the mechanism is attractive, clinical efficacy remains under debate.

• PPAR Agonism: Targeting the PPAR family of nuclear receptors (which regulate glucose and lipid metabolism and have anti‑inflammatory effects) is another strategy. Elafibranor’s dual PPARα/δ activation was intended to improve multiple metabolic parameters concurrently, although its later clinical performance was less robust than hoped.

• Galectin‑3 Inhibition: By inhibiting galectin‑3, belapectin aims to reduce the activity of this lectin involved in fibrosis. Its potential ability to reduce portal pressure indicates that even if it does not change the histological score dramatically, it might improve clinical parameters in advanced disease.

• GLP‑1 Receptor Agonism: While originally approved for treating type‑2 diabetes by enhancing insulin secretion and reducing appetite and thus body weight, these agents (exemplified by semaglutide) are now in development for their pleiotropic effects on hepatic fat reduction and anti‑inflammatory actions.

• Combination Mechanisms: Many researchers and companies believe that the multifactorial nature of NASH will eventually require combination therapies. These can combine complementary mechanisms such as FXR or THR‑β activation with anti‑inflammatory agents or metabolic modulators. The goal is to simultaneously reduce steatosis, suppress inflammation, and promote fibrosis regression.

Clinical Trials and Efficacy

Key Clinical Trials and Results
Clinical trials in NASH have evolved considerably. Most phase II clinical studies, such as FLINT for obeticholic acid, ARREST for aramchol, and CENTAUR for cenicriviroc, have provided the groundwork for understanding how these agents impact not only biochemical markers (such as ALT and liver fat fraction by MRI‑PDFF) but also histological descriptors of NASH (improvements in the NAFLD activity score, resolution of ballooning, and fibrosis stages).

For instance, the FLINT study in patients with non‑cirrhotic NASH using obeticholic acid demonstrated significant improvements in these endpoints, but side effects (such as pruritus and lipid abnormalities) remain a concern for that drug. In the ARREST study, aramchol showed dose‑dependent decreases in liver fat content and some improvement in histology, supporting the idea that modulating de novo lipogenesis can affect the progression of NASH.

Resmetirom’s phase II and planned phase III results have been particularly encouraging, showing reductions in liver fat content as well as favorable trends in histological endpoints such as inflammation and fibrosis, giving hope that THR‑β agonism may prove both effective and well‑tolerated.

The CENTAUR study on cenicriviroc initially reported improvement in fibrosis without worsening NASH. However, subsequent larger scale studies raised concerns about its consistency in effect, highlighting the inherent variance when translating anti‑inflammatory mechanisms into clinical benefits.

Other ongoing studies include the use of GLP‑1 receptor agonists (such as semaglutide and liraglutide) in phase III or later‑phase investigations. Early studies have demonstrated improvements in body weight, glycemic control, and liver enzyme levels—with some histological benefits observed in smaller controlled trials—although definitive histological effects need confirmation in larger studies.

Combination trials are also emerging—for example, studies evaluating tropifexor in combination with CCR2/CCR5 inhibitors in order to determine if a “two‐hit” strategy can produce synergistic benefits in NASH patients. These trials compare monotherapy arms with combination therapy arms in randomized, controlled settings to establish any additive or synergistic effects on liver disease endpoints.

Comparative Efficacy and Safety
Comparing therapeutic candidates for NASH has proven difficult because the trials have often enrolled different patient populations, used different endpoints (biochemical versus histological), and incorporated various lengths of follow‑up. However, several patterns emerge from the literature based on synapse‑sourced findings:

• Obeticholic acid has clearly demonstrated efficacy in reducing liver fibrosis and improving the NAFLD activity score in clinical trials, but its safety profile concerning pruritus and dyslipidemia limits its broad applicability.

• Resmetirom, by contrast, has shown promising efficacy with fewer systemic side effects in the early reports. Its selective THR‑β activation provides a targeted approach that appears to improve hepatic lipid metabolism while minimizing adverse cardiovascular or dermatologic events.

• Aramchol’s efficacy in reducing liver fat content is significant, although its effect on histological endpoints may be less pronounced compared to obeticholic acid or resmetirom. Its tolerability appears acceptable, making it promising for patients with fewer advanced fibrosis changes.

• Cenicriviroc showed improvement on narrow histological metrics in some phase II studies, but later phase evaluations have raised questions about its reproducibility and safety signals in larger, more heterogeneous populations.

• Belapectin, as a galectin‑3 inhibitor, may be better suited for patients with advanced fibrotic or cirrhotic changes, as it shows beneficial effects on reducing portal hypertension; however, its overall efficacy in reversing histological fibrosis remains uncertain.

• Elafibranor’s initial promise with PPAR‑α/δ agonism has not translated into consistent efficacy across later‑phase studies, and its adverse effects profile has contributed to its unclear benefit‑risk balance for NASH.

• GLP‑1 receptor agonists, like semaglutide, show a dual promise by reducing body weight (a driver of NAFLD progression) and exerting direct anti‑inflammatory effects on the liver. Early studies suggest improved insulin sensitivity and a reduction in hepatic fat, but the comparative histological efficacy versus metabolic agents remains under study.

Comparative analyses underscore that while many agents improve certain biochemical or imaging markers of liver fat, the ultimate goal is histological improvement with features such as NASH resolution and at least one‑stage fibrosis improvement. Safety, tolerability, and long‑term outcomes are critical; a drug’s overall efficacy is measured not only by surrogate endpoints but by clinical outcomes such as reduced progression to cirrhosis, decreased portal hypertension, and fewer liver‑related complications.

Future Directions and Challenges

Emerging Therapies and Innovations
Looking forward, the therapeutic pipeline for NASH is expected to expand beyond the single‑agent therapies mentioned above. Important future directions include:

• Combination therapies: Given the multifactorial nature of NASH, combining agents with complementary mechanisms—for example, pairing metabolic modulators like THR‑β agonists with anti‑inflammatory agents or FXR agonists with CCR2/CCR5 inhibitors—may yield synergistic benefits. Early combination studies are being designed to test whether such an approach can enhance efficacy while reducing individual drug adverse effects.

• Gene therapies and precision medicine: As our understanding of the genetic risk factors for NASH (such as PNPLA3 mutations) improves, therapies tailored to individual genomic profiles may be developed. Some companies are already investigating gene therapy approaches that could provide chronic modulation of metabolic pathways or fibrosis-related gene expression.

• Novel targets and bio‑nanotechnology: New drug candidates are under investigation that target previously underexplored pathways such as apoptotic signalling (e.g., ASK‑1 inhibitors), lipid oxidation, and mitochondrial function. Nanoparticle delivery systems are also being optimized to enhance drug bioavailability and minimize systemic toxicity; however, clinical translation in this area remains challenging due to scalability and regulatory hurdles.

• Biomarker‑driven trials: A major innovation in this field is the increasing use of noninvasive biomarkers—such as MRI‑PDFF, elastography, and serum markers like ELF—to reduce reliance on invasive liver biopsy endpoints. These advances will help stratify patients better, identify subpopulations that could benefit most from a given therapy, and speed up clinical trial enrollment and evaluation.

Regulatory and Market Challenges
Despite the promising developments, there remain significant hurdles. The regulatory pathway for NASH drugs is complicated by the need for histological endpoints and long‑term outcome data. The Food and Drug Administration (FDA) and other regulatory agencies require demonstration of clinically meaningful benefits—such as NASH resolution or fibrosis improvement—rather than just surrogate outcomes. In addition:

• High placebo response rates, variability in biopsy sampling, and differences in endpoint definitions continue to be major barriers in clinical trial design.
• Inconsistent results across trials have led to cautious interpretations of efficacy data. This uncertainty hampers market adoption even when drugs show promise in early phase trials.
• Safety concerns, particularly for agents such as obeticholic acid (pruritus, dyslipidemia) or drugs that show marginal effects in large heterogeneous populations (e.g., cenicriviroc), highlight the need for more refined patient selection and better‐designed studies.
• Finally, the competitive landscape is crowded with many investigational products. Given the expected heterogeneity of NASH patients, it is likely that multiple drugs or combinations will eventually be approved, each targeting specific subgroups. This, in turn, increases the complexity of treatment algorithms and requires clear markers for response and stratification.

Conclusion
In summary, the pipeline of drugs in development for NASH is not only wide-ranging but also highly complex, reflecting the multifactorial nature of the disease itself. At the early stage of development, agents such as obeticholic acid, resmetirom, aramchol, cenicriviroc, belapectin, and elafibranor have advanced into various phases of clinical trials. These drugs target different aspects of NASH pathophysiology—from FXR and THR‑β agonism to SCD‑1 modulation, CCR2/CCR5 antagonism, galectin‑3 inhibition, and PPAR modulation. Their mechanisms of action are designed to improve liver fat metabolism, reduce the inflammatory cascade and oxidative stress, and ultimately reverse or halt the progression of fibrosis.

Clinical trials have provided early proof‑of‑concept data through improvements in surrogate endpoints (such as imaging‐based liver fat quantification and biochemical markers) and histological endpoints (improvement in NAFLD activity scores and fibrosis staging). However, challenges remain in terms of achieving consistent results across different trials, ensuring long‑term safety, and translating improvements on biopsy into meaningful clinical outcomes like reduced cirrhotic complications. In parallel, combination therapies and nanoparticle‑based drug delivery systems are emerging as promising strategies, but they too face scalability and regulatory challenges. Regulatory hurdles further complicate the process, as agencies demand long‑term clinical outcomes, and high placebo response rates can dilute the apparent efficacy in trials. Looking ahead, the integration of noninvasive biomarkers, genomics‑based patient selection, and a focus on combination therapies offers hope that personalized treatment protocols will be developed, ultimately bridging the gap between promising early data and widespread clinical application.

In conclusion, while the drug development pipeline for NASH is robust and diverse—with candidate drugs targeting multiple pathogenic mechanisms—the complexity of the disease and variability in patient response present substantial challenges. Continued innovation in clinical trial design, the development of reliable noninvasive biomarkers, and the adoption of personalized and combination therapy approaches appear to be the future directions for optimizing NASH management. These efforts, combined with rigorous regulatory scrutiny, will ultimately determine which therapies reach the market and how effectively they improve outcomes for patients with this increasingly prevalent liver disorder.