New Treatments for Fatty Liver Disease and Alcohol-Related Liver Disease: A Patient's Guide to the Science Behind the Clinical Trials

Table of Contents

• Key Points
• Understanding NAFLD and ALD: Two Diseases, Many Similarities
• Why Is There So Much Interest in NASH?
• Why the Heightened Focus on Alcohol-Related Liver Disease?
• What Have Researchers Learned From Clinical Trials So Far?
• Emerging Treatments: An Overview of Therapeutic Targets
• PPAR-Targeting Drugs
• Thyroid Hormone Receptor-Beta Agonists
• Bile Acid Pathways as a Treatment Target
• Clinical Implications: What This Means for Patients
• Study Limitations: What This Review Could Not Prove
• Recommendations for Patients
• Frequently Asked Questions
• Source Information

Key Points

• NAFLD and ALD are now the most common reasons for liver transplantation in the United States.
• Over 100 clinical trials for NASH are underway, testing drugs that target fat, inflammation, and fibrosis.
• In a meta-analysis of 39 trials, 25% of placebo patients improved NASH activity, making drug efficacy harder to prove.
• Thyroid hormone receptor-beta agonists like MGL-3196 and VK2809 reduced liver fat substantially in 12–36 week trials.
• Alcohol abstinence is the most effective therapy to reverse alcohol-related liver disease; only corticosteroids and transplantation are approved for alcoholic hepatitis.

Understanding NAFLD and ALD: Two Diseases, Many Similarities

Non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD) are very common forms of chronic liver disease around the world. Both are linked to a rising number of deaths from all causes — not just liver-related deaths. While they are distinct diseases with different triggers, NAFLD and ALD share striking similarities. Both can lead to fatty liver, inflammation of the liver (steatohepatitis), and the development of scar tissue (fibrosis). Over time, both can progress to cirrhosis and its complications, including liver cancer (hepatocellular carcinoma, or HCC).

When a patient has both conditions at the same time, the disease progresses even faster. Together, NAFLD and ALD are now the most common reasons for liver transplantation in the United States. They share several underlying biological pathways, including the buildup of fat in liver cells (hepatic steatosis), inflammation, and the activation of cells that produce scar tissue.

Why Is There So Much Interest in NASH?

Two epidemics are driving the urgency: obesity and NAFLD. In the United States, NAFLD — which includes both simple fatty liver (non-alcoholic fatty liver, or NAFL) and the more aggressive form, non-alcoholic steatohepatitis (NASH) — affects an estimated 65 to 90 million adults. That represents roughly 20–30% of the entire U.S. population.

NASH is the progressive form of the disease. It is defined by the presence of inflammation and damage to liver cells (hepatocytes), and it is typically accompanied by fibrosis and, eventually, cirrhosis. NASH has been recognized as a leading cause of liver cancer (HCC), and experts believe it is likely to become the most common reason for liver transplantation in the coming years.

Some key numbers help explain the scale of the problem:

• NASH accounts for about 20–30% of the NAFLD population.
• Of those with NASH, 4–6% can progress to cirrhosis — though this is likely an underestimate because the disease is not easily diagnosed.
• NASH is typically asymptomatic (producing no symptoms), and up to 30% of affected patients have completely normal liver enzymes on routine blood tests.
• The prevalence of NASH in the United States is projected to grow from 20% to 27% between 2015 and 2030.
• By that time, 20% of NASH cases are expected to have advanced fibrosis or cirrhosis (stage F3/F4), which is associated with accelerated disease, a higher risk of both liver-related and non-liver-related death, and a growing economic burden.

Why the sudden flood of interest from drug companies? A major reason is the success of hepatitis C treatments. Direct-acting antiviral agents now cure more than 95% of chronic hepatitis C infections, and aggressive global efforts aim to eliminate hepatitis C by 2030. This success has freed up pharmaceutical and biotechnology companies to redirect their drug development efforts toward NASH and its associated fibrosis.

The article notes that there are now over 100 registered clinical trials for NASH in various phases of development. Companies with successful track records in viral hepatitis have pivoted toward NASH, and companies with programs in cardiometabolic disease are leveraging the strong connections between NASH, obesity, and type 2 diabetes (T2DM). Because the stage of liver fibrosis is strongly associated with both liver-related and all-cause death, anti-fibrotic drugs — regardless of the underlying cause of liver disease — are also emerging rapidly as a treatment strategy.

Why the Heightened Focus on Alcohol-Related Liver Disease?

Alcohol-related liver disease covers a spectrum of conditions, from alcoholic steatosis (fatty liver) to alcoholic steatohepatitis (ASH) and advanced ALD characterized by alcoholic hepatitis (AH), cirrhosis, and complications such as hepatic encephalopathy, jaundice, portal hypertension-related problems, and liver cancer.

The true burden of ALD is almost certainly underreported. Patients often hide their alcohol use because of social stigma, and ALD frequently goes undiagnosed when it occurs alongside other chronic liver diseases. The article highlights these sobering statistics:

• ALD accounts for up to 48% of cirrhosis-related deaths in the United States.
• Alcohol-related mortality remains the fourth leading preventable cause of death in the U.S.
• In a 2016 report, ALD was the leading indication for liver transplantation in the United States.
• A 2018 U.S. population-based study demonstrated increasing alcoholic cirrhosis-related deaths in people aged 25 to 34 years.

An analysis of the National Health and Nutrition Examination Survey (NHANES) database from 2001 to 2016 found that the overall prevalence of ALD remained stable at 4.3% (95% CI, 3.5–5.0%) to 4.7% (95% CI, 4.2–5.1%) (P=0.69). However, the severity of disease is worsening:

• The prevalence of stage 2 fibrosis increased from 0.6% (95% CI, 0.5–0.8%) to 1.5% (95% CI, 1.3–1.8%) (P<0.001).
• The prevalence of stage 3 fibrosis or higher increased from 0.1% (95% CI, 0.02–0.10%) to 0.2% (95% CI, 0.2–0.4%) (P=0.045).

These trends point to a growing burden of advanced ALD in the near future. Yet despite the fact that ALD has been recognized for centuries, treatments remain outdated and inadequate. Current recommendations are largely based on studies performed decades ago. Alcohol abstinence remains the most effective therapy to reverse ALD. Early liver transplantation has been effective in selected patients with acute alcoholic hepatitis, offering both short-term and long-term survival benefits — but transplantation is not feasible for the vast majority of ALD patients.

What Have Researchers Learned From Clinical Trials So Far?

NASH has a highly variable clinical course. Some patients improve on their own (spontaneous regression), while others progress relentlessly to advanced fibrosis. This variability makes designing clinical trials genuinely difficult.

One of the major obstacles researchers have encountered is the high placebo response rate in NASH trials. Patients receiving a placebo (an inactive pill) often show improvement, which can make it hard to prove that an experimental drug is actually working. In a recent meta-analysis of 39 clinical trials, placebo was associated with a 2-point or greater improvement in the NAFLD Activity Score (NAS) in 25% of patients (95% CI, 21–29%) — with similar results even when the analysis was restricted to patients with no worsening in fibrosis.

Likewise:

• 30% of placebo-treated patients had at least a 1-point improvement in individual components of the NAS score.
• 21% of placebo-treated patients showed improvement in fibrosis stage.

This high placebo response likely reflects, in part, inadvertent lifestyle changes that patients make when they join a clinical trial. The authors stress that clinical trials should account for this by enrolling patients with more advanced disease, using evolving non-invasive surrogate markers.

Another challenge: proving a drug changes the course of the disease takes time. Detecting a 1-stage change in fibrosis may require up to 7 years of follow-up. Even if a drug is approved based on improvements seen on liver biopsy, long-term success — and therefore long-term drug approval — will depend on demonstrating that patients actually feel, function, and survive better. The U.S. Food and Drug Administration (FDA) has recently issued guidance on NASH clinical trial design that reflects this evolving landscape.

The gold standard for diagnosing NASH remains the liver biopsy, despite its limitations: it is invasive, carries risks, and can miss unevenly distributed disease (sampling variability). Researchers are increasingly using surrogate markers and imaging to identify patients and measure improvement, including:

• FIB-4 and the NAFLD fibrosis score — non-invasive blood test-based calculations;
• Vibration controlled transient elastography (VCTE) — an ultrasound-based technique that measures liver stiffness and fat;
• MRI proton density fat fraction (MRI-PDFF) — a precise imaging method to measure liver fat;
• Multiparametric MRI — to detect changes related to inflammation and fibrosis;
• Blood-based biomarkers such as cytokeratin-18 (CK-18) and the European Fibrosis Panel (ELF).

However, these non-invasive tools have not yet been validated enough to replace biopsy in late-stage (Phase 2b and Phase 3) trials, which still rely on biopsy-based histological endpoints. Early "proof-of-concept" (Phase 2a) studies are typically short — 12 to 16 weeks — making it difficult to show meaningful biopsy improvement. As a result, improvement predicted by non-invasive tests does not always translate into biopsy-confirmed improvement in longer trials.

Clinical trial design for ALD is even more challenging. The presentation of the disease varies greatly, there are few reliable non-invasive or serological tests for diagnosing and staging it, and patient follow-up is often uneven. Most clinical trials and approved therapies focus on alcoholic hepatitis, the most severe subset. Currently, the only approved treatments are corticosteroids and liver transplantation. The endpoints achieved with corticosteroid therapy are typically short-term — 28-day and 6-month mortality — with variable long-term survival benefits.

The article also raises an important ethical point: because corticosteroids are a known effective therapy for alcoholic hepatitis, it is difficult and potentially unethical to design placebo-controlled trials for these patients. Most new therapies for alcoholic hepatitis must therefore be compared against corticosteroids rather than against a placebo, which makes proving a drug's benefit more rigorous and more difficult. Unlike in NASH, where placebo-controlled trials are standard, researchers in ALD use prognostic scoring systems such as the Model for End-Stage Liver Disease (MELD), the age-bilirubin-INR-creatinine (ABIC) score, the Glasgow score, or the Lille score to help evaluate treatment effects. Liver biopsy in alcoholic hepatitis trials is highly controversial — it can help rule out conditions that mimic alcoholic hepatitis (like sepsis), but it carries high risk in very ill or unstable patients.

Emerging Treatments: An Overview of Therapeutic Targets

NASH and ALD are driven by different causes, but they share many clinical, pathological, and histological features. Both involve altered fat metabolism, the death of liver cells (hepatocyte apoptosis), activation of the innate immune system, and activation of hepatic stellate cells (the cells responsible for scar formation). They also each engage unique molecular signaling pathways and dysregulated microRNAs.

Based on the underlying biology of NASH, therapeutic targets fall into three categories:

1. Anti-inflammatory drugs — aimed at reducing liver inflammation;
2. Anti-steatotic drugs — aimed at reducing fat accumulation in the liver;
3. Anti-fibrotic drugs — aimed at preventing or reversing scar tissue.

Several drugs in clinical trials display more than one of these activities. There is also growing interest in using anti-diabetic medications for NASH, because type 2 diabetes and NASH frequently coexist and diabetes likely contributes to NASH progression. Because even effective drugs only improve NASH in a minority of patients, combination therapies that target multiple disease drivers are increasingly being explored. And given the overlap between NASH and alcoholic steatohepatitis, researchers are also investigating whether drugs developed for NASH could be repurposed for ALD. In practical terms, most agents are being tested first in NASH patients, with the expectation that promising drugs will subsequently be evaluated in ALD.

Here is a closer look at several drug targets that are already in late-stage development (Phase 2 and Phase 3 trials).

PPAR-Targeting Drugs

Peroxisome proliferator-activated receptors (PPARs) are proteins inside cells that act as "switches" to turn genes on and off. They are part of a family called nuclear hormone receptors, and they come in three subtypes: PPARα, PPARγ, and PPARβ/δ. Each plays a crucial role in metabolism:

• PPARα reduces triglycerides (blood fats) and regulates energy balance;
• PPARγ increases insulin sensitivity and promotes glucose metabolism;
• PPARβ/δ has a primary role in fatty acid metabolism.

Thiazolidinediones (TZDs), which act on PPARγ, are already widely used to treat type 2 diabetes. Studies show they also improve steatosis (fat in the liver), steatohepatitis (inflammation), and hepatic fibrosis. Interestingly, PPARγ drugs appear to work better in patients who have both NASH and type 2 diabetes than in those with NASH alone — a difference that needs further study. However, TZDs have significant side effects that limit their appeal: weight gain, osteopenia (weakening of bones), peripheral edema (swelling in the legs), and fluid retention.

Elafibranor is a selective "dual" PPAR-α/δ agonist — meaning it activates both PPARα and PPARβ/δ, but not PPARγ. It is liver-targeted, with little or no activity in skeletal muscle. The PPARα component improves insulin sensitivity and lipid balance by increasing fatty acid oxidation, while the PPARδ component exerts an anti-inflammatory effect. In a post-hoc (secondary) analysis of a Phase 2b trial, elafibranor improved the metabolic features of NASH and showed a favorable cardiometabolic profile. It is currently being tested in a Phase 3 trial called RESOLVE-IT (NCT02704403).

Thyroid Hormone Receptor-Beta Agonists

Thyroid hormone receptors (THRs) regulate organ development, growth, differentiation, energy metabolism, and lipid and glucose balance. The THRα subunit is mainly found in the brain, skeletal muscle, and cardiac muscle, and is responsible for many of the classic symptoms of thyroid hormone excess (thyrotoxicosis). The THRβ subunit is found predominantly in the liver, brain, and kidneys, and is mainly responsible for metabolic regulation.

Both subclinical hypothyroidism (mild underactive thyroid) and overt hypothyroidism are more common in patients with NAFLD. Because THRβ is so heavily expressed in the liver, drugs that selectively activate THRβ are attractive candidates for treating metabolic syndrome, NAFLD, and even liver cancer. Human studies have shown that activating THRβ can help break down fatty acids and improve mitochondrial function, reducing "lipotoxicity" (injury caused by fats) and significantly lowering LDL ("bad") cholesterol, triglycerides, and liver fat.

Two selective THRβ agonists stand out in the article:

MGL-3196 (resmetirom). This drug was studied in a 36-week, randomized, double-blind, placebo-controlled Phase 2 trial in patients with NASH. The primary endpoint was reduction in liver fat measured by MRI-PDFF; secondary endpoints included effects on NASH, liver enzymes, indirect fibrosis biomarkers, and blood lipids at weeks 12 and 36. The results were striking:

• Liver fat was reduced by 36% at 12 weeks and 37% at 36 weeks with the lower dose of MGL-3196;
• With the higher dose, liver fat fell by 42% and 49% at the same time points;
• Patients on placebo had only 8% and 10% reductions.

Patients taking MGL-3196 also achieved significant improvements in lipid profile, liver enzymes, and NASH histological (biopsy-based) endpoints compared with placebo. The greatest benefit on NASH endpoints was seen in patients who achieved a ≥30% fat reduction on MRI-PDFF: 37% of "MRI responders" improved versus only 4% of "MRI non-responders" (P=0.001). MGL-3196 is now moving forward into a Phase 3 clinical trial (NCT03900429).

VK2809. This is another selective THRβ agonist being evaluated in NASH. In a 16-week Phase 2 randomized placebo-controlled trial, patients with NAFLD were identified by MRI-PDFF showing more than 8% liver fat and LDL cholesterol higher than 110 mg/dL. The primary endpoint was change in LDL cholesterol, with secondary endpoints including change in liver fat (MRI-PDFF) and effects on other atherogenic lipoproteins (particles that promote artery-clogging plaque). The trial found:

• A significant placebo-adjusted reduction in LDL cholesterol of −23.6% in the every-other-day dosing arm and −20.2% in the daily arm;
• A dramatic relative reduction in liver fat of 56.5% (every other day) and 59.7% (daily) at week 12, compared with only 8.9% for placebo;
• Significant reductions in lipoprotein(a) and apolipoprotein B in both VK2809 arms versus placebo.

VK2809 is planned for a Phase 2B study.

Bile Acid Pathways as a Treatment Target

Bile acids are synthesized (produced) from cholesterol in liver cells, then secreted into the bile canaliculi along with other components of bile, including water, cholesterol, bilirubin, phospholipids, and inorganic salts. For decades, bile acids were known primarily for their role in cholesterol balance and fat digestion — they act like a natural detergent, emulsifying fats in the small intestine so they can be absorbed.

In more recent years, scientists have discovered that bile acids also function as powerful signaling molecules. They activate two major types of receptors: a nuclear receptor called the farnesoid X receptor (FXR), and a transmembrane (cell-surface) receptor called the Takeda G-protein-coupled receptor (TGR5). These receptors regulate a wide range of metabolic processes, including glucose and lipid metabolism, energy expenditure, and inflammation. This has made bile acid pathways a fertile area for drug development in fatty liver disease, with several FXR agonists advancing through clinical trials for NASH. (The original article's discussion of this section was truncated, but the key concept is that bile acid signaling — particularly through FXR — has become a major focus of NASH drug development.)

Clinical Implications: What This Means for Patients

This review carries several important messages for patients living with — or at risk for — NAFLD and ALD.

First, the placebo response in NASH trials is real and substantial. In a meta-analysis of 39 trials, a quarter of patients receiving placebo improved their NAS score by 2 points or more, and 21% improved their fibrosis stage. What does this mean for you? Lifestyle changes — even accidental ones — can genuinely improve liver health. The act of joining a trial and receiving regular medical attention appears to motivate diet and exercise changes that have measurable biological effects.

Second, the treatment landscape for NASH is about to change dramatically. With more than 100 registered clinical trials under way, multiple drug candidates are now in Phase 2 and Phase 3 testing. Drugs that selectively activate thyroid hormone receptor beta (MGL-3196, VK2809), dual PPAR agonists (elafibranor), FXR agonists (obeticholic acid), and anti-fibrotic agents are showing meaningful reductions in liver fat — in some cases 40–60% within 12 to 36 weeks — compared with single-digit reductions on placebo. While fat reduction is not the same as curing the disease, it is a strong early signal of efficacy.

Third, the field is shifting toward treating fibrosis, not just fat. Because fibrosis stage is the strongest predictor of death in NAFLD, anti-fibrotic drugs are being developed independently of the underlying cause. This means that patients with advanced fibrosis (F3/F4) may eventually have treatment options even if the fat and inflammation components of their disease have not fully resolved.

Fourth, ALD remains a neglected disease with urgent unmet needs. Only two treatments are approved for alcoholic hepatitis (corticosteroids and liver transplantation), and both are limited in their long-term effectiveness. The rising rates of advanced fibrosis in younger age groups (25–34 years) signal a coming wave of alcohol-related cirrhosis. The article calls for regulatory agencies, industry, and clinicians to work together to develop effective pharmacotherapies for ALD, combined with community-based approaches to reduce alcohol dependency.

Study Limitations: What This Review Could Not Prove

Because this is a review article, it does not present new patient data. Instead, it summarizes the state of the science at the time of publication (January 2021). Several important limitations should be kept in mind:

• The review cannot establish whether any of the drugs discussed will ultimately be approved. Early trial results — even positive Phase 2 data — frequently fail to be confirmed in larger Phase 3 trials. The authors themselves note that "unexpected negative results from potential therapies that showed promise in earlier stages of drug development" have already occurred in this field.
• The prevalence estimates for NAFLD, NASH, and ALD are based on population studies that carry their own uncertainties. ALD in particular is underreported because of social stigma, and NASH is underdiagnosed because it is often silent and up to 30% of affected patients have normal liver enzymes.
• The article's discussion of bile acid pathways is incomplete in the source text, so some details of that section could not be fully translated.
• Most of the clinical trial data presented come from relatively short-term studies (12 to 36 weeks). Because detecting a 1-stage change in fibrosis can take up to 7 years, long-term efficacy and safety remain unknown for all of these agents.
• Finally, the review was written before the full impact of the COVID-19 pandemic on clinical trials, alcohol consumption patterns, and liver disease progression could be assessed.

Recommendations for Patients

Based on the information in this review, patients and their families may wish to consider the following steps:

1. Ask about a liver fibrosis assessment. If you have been told you have fatty liver, ask your doctor about non-invasive tests such as FIB-4, NAFLD fibrosis score, or vibration controlled transient elastography (VCTE) to estimate your fibrosis stage. Advanced fibrosis (stage F3/F4) is the strongest predictor of liver-related and all-cause death, so knowing your stage matters for monitoring and treatment decisions.
2. Do not ignore NAFLD just because your liver enzymes are normal. Up to 30% of patients with NASH have normal liver enzymes. If you have risk factors such as obesity, type 2 diabetes, or metabolic syndrome, speak with your doctor about whether additional evaluation is warranted.
3. Consider clinical trials cautiously but optimistically. With over 100 registered NASH trials, there are more opportunities than ever to participate in research. However, the high placebo response rate documented in this review means that early enthusiasm for a new drug should be tempered until larger, late-stage results are available.
4. For alcohol-related liver disease, abstinence remains the most effective treatment. The review states this directly: "Alcohol abstinence remains the most effective therapy to reverse ALD." If you have ALD or are at risk for it, talk to a healthcare provider about alcohol reduction or cessation support programs.
5. Watch for combination therapies. Because even effective drugs improve NASH in only a minority of patients, the future likely belongs to combination treatments that target inflammation, fat accumulation, and fibrosis simultaneously. Patients should ask their doctors about whether any of the emerging drugs discussed in this article — or similar agents — might be appropriate for their specific situation.
6. Pay attention to the cardiovascular connection. NAFLD and ALD both increase the risk of cardiovascular disease, and the thyroid receptor beta agonists discussed here significantly improved lipid profiles (LDL, triglycerides, lipoprotein(a), and apolipoprotein B). Patients with fatty liver should have their cardiovascular risk factors assessed and managed aggressively, not just their liver enzymes.

Frequently Asked Questions

What is the difference between NAFLD and alcohol-related liver disease?

NAFLD is fatty liver not caused by alcohol; ALD is caused by alcohol. Both can cause fatty liver, inflammation, scarring, cirrhosis, and liver cancer. If you have both, progression is faster. Together they are the most common reasons for liver transplantation in the United States.

Why are there so many new clinical trials for NASH right now?

After hepatitis C became curable, drug companies turned to NASH. Currently over 100 clinical trials are registered. This is driven by rising obesity and NAFLD, plus strong links to type 2 diabetes. Researchers are testing many drugs that target fat, inflammation, and fibrosis.

What is the placebo response in NASH trials and why does it matter?

In a meta-analysis of 39 trials, 25% of patients taking placebo improved their NAFLD Activity Score by 2 or more points, and 21% showed improved fibrosis. This likely reflects lifestyle changes patients make when joining a trial. It makes proving that a drug truly works more difficult.

Should I worry about NASH if my liver enzymes are normal?

Yes, up to 30% of patients with NASH have completely normal liver enzymes on routine blood tests. If you have risk factors such as obesity, type 2 diabetes, or metabolic syndrome, ask your doctor whether additional evaluation, like a fibrosis assessment, is appropriate. Normal liver enzymes do not rule out NASH.

What should I ask my doctor if I have fatty liver?

Ask about a liver fibrosis assessment using non-invasive tests such as FIB-4, NAFLD fibrosis score, or vibration controlled transient elastography (VCTE). Advanced fibrosis (stage F3/F4) is the strongest predictor of liver-related and all-cause death, so knowing your stage helps guide monitoring and treatment decisions.

Source Information

Original article title: Basic science to clinical trials in non-alcoholic fatty liver disease

Authors: Amon Asgharpour, Amreen Dinani, Scott L. Friedman (all authors contributed equally to the conception and design; Asgharpour and Dinani share first authorship)

Affiliation: Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Journal: Translational Gastroenterology and Hepatology, 2021; Volume 6, Article 5

Publication details: Received August 27, 2019; Accepted January 17, 2020; Published January 5, 2021. DOI: 10.21037/tgh.2020.01.04

Note: This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and does not replace individualized medical advice from a qualified healthcare provider.