Data from Penny Staton - Curated by Marshall Pearce - Last updated 29 September 2017

An intense race is going on right now in non-alcoholic steatohepatitis (NASH) research. A number of significant players within the pharmaceutical and biotechnology sectors are competing to develop the first major therapeutic advance in treatment for this neglected condition. But should we consider it more of a relay race? Could improved diagnosis, disease assessment and even combination therapy be the key to victory over this increasingly prevalent disease?

The spectrum of non-alcoholic fatty liver disease (NAFLD) extends from simple steatosis (fatty degeneration) to steatosis combined with hepatic inflammation, hepatocyte injury and fibrogenesis (hallmarks of NASH), cirrhosis and hepatocellular carcinoma (HCC) (Figure 1). With NAFLD being the hepatic component of metabolic syndrome, and associated with obesity and diabetes, it represents a significant health burden in the developed world. In fact, an estimated 33% of people in the US have NAFLD and an estimated 5% have NASH (over 16 million patients). Worryingly, growing numbers of NAFLD patients have resulted in a 170% increase in the number of liver transplants needed in the last 10 years. Liver transplants are expensive and reliant on suitable donors being available. However, it is especially challenging for patients with NASH as they are typically not suitable for split liver and living-donor transplantation as the graft is likely to be too small due to comorbid obesity. With the costs and challenges associated with liver transplantation in these patients, there is a clear need for new therapeutic approaches that can halt disease progression and hopefully promote liver recovery.

Horizons_Improving non alcoholic_Fig 1

Figure 1. Spectrum of non-alcoholic fatty liver disease including prevalence and incidence.

 

Diagnosis of NASH – getting off to a good start 

Physicians face two major challenges when attempting to diagnose NASH: spotting at-risk patients and confirming the diagnosis. Patients with NASH are largely asymptomatic or present with non-specific symptoms such as fatigue or an ache in the upper right abdomen. Unfortunately, for many patients, NASH is not discovered until they already have cirrhosis restricting their treatment options and putting them at risk of HCC. It is clear that we need to improve diagnosis and identify patients as early as possible to prevent this. So, how is NASH currently diagnosed?

If liver function tests show elevated levels of serum ALT (alanine aminotransferase) and/or serum AST (aspartate aminotransferase) and there are other signs of liver disease or risk factors, then a liver biopsy is recommended. Liver biopsies are painful, subject to sampling variability and occasionally associated with serious complications. Despite these limitations, biopsy is currently the only reliable way to diagnose NASH. Excitingly, progress is being made in the development of non-invasive diagnostics that allow for the identification and differentiation of NAFLD and NASH. 

Does my liver look fat in this scan?

Ultrasound and CT imaging can identify some NASH-related hepatic changes but unfortunately not all. Ultrasound elastography (Fibroscan®) and magnetic resonance elastography (MRE) are both able to measure liver ‘stiffness’, which is reflective of fibrosis, however, their use in assessing NASH disease severity remains unclear. Magnetic resonance imaging of estimated proton density fat fraction (PDFF), on the other hand, has recently been shown to correlate with histologic measures of steatosis including disease scores, lobular inflammation and relevant serum markers. In combination with measuring total liver volume, PDFF has been suggested as a dynamic and more responsive measure of NASH than histology. Widespread use of PDFF may be limited by the availability of specialist MRI scanners and trained technicians but there is hope that it can be replaced by cheaper ultrasound techniques. 

A breath of diagnostic fresh air?

Breath tests are already used in liver disease to predict cirrhosis severity (13C-galactose) and monitor liver regeneration (13C-phenylalanine). The 13C-methacetin breath test (13C-MBT) is used to quantitate liver function and has been shown to differentiate NASH from healthy controls and patients with steatosis. While the 13C-MBT test is not currently reliable enough for NASH diagnosis, research is ongoing with Exalenz (manufacturers of the BreathID 13C-MBT NASH diagnostic test) entering a collaboration with Conatus Pharmaceuticals to monitor patients in a planned Phase IIb NASH clinical trial. 

Time will tell if these exciting advances can finally replace liver biopsy as the standard of NASH diagnosis.

Chasing biomarkers 

Biomarkers are being eagerly sought in a number of conditions and NASH is no different. Given the amount of research looking for NASH biomarkers, it is clear that many agree with the potential benefits they could offer. With NASH being a multifactorial disease, it is unlikely that a single biomarker will be able to identify patients with NASH, predict disease progression and measure treatment effects. However, genetic analysis has identified disease modifiers for NAFLD and shown that epigenetic factors, such as DNA methylation and micro-RNA (miRNA) signatures correlate with NASH severity. Academia and industry are tackling this problem together with the recent ‘2nd International Workshop on NASH Biomarkers’ highlighting the ongoing collaborative biobank and registry efforts. These include the Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) programme in the EU and Non-Invasive BioMarkers of MetaBolic Liver DiseasE (NIMBLE) programme in the US. 

Excitingly, Genfit, a French biopharmaceutical company, recently completed a NASH biomarker programme feasibility phase. They announced the positive performance of a miRNA-based signature using patient data from the Phase III RESOLVE-IT trial. Their goal is to use the test to identify patients who may benefit from their NASH treatment currently in Phase III trials suggesting the era of personalised care may not be far away for patients with NASH.

Treating NASH – new contenders reach the final straight

If patients with NASH are to be diagnosed sooner, how will they be treated? NAFLD and NASH are considered reversible ‘lifestyle’ diseases as the majority of patients are overweight or obese with comorbidities such as diabetes, insulin resistance and hyperlipidaemia. Weight loss is the most obvious option and is typically the first-line treatment. A reduction in body weight of around 10% is enough to see significant health benefits including improvements in insulin sensitivity, liver biochemistry, histochemistry, steatosis and liver inflammation. However, as anybody who has ever tried to lose weight knows, committing to long-term changes in eating and exercise patterns is a huge, and often unsuccessful, challenge.

Surgery: a last resort?

To support patients in their weight loss, bariatric surgery can be provided to severely or morbidly obese patients. The majority of these patients will also have NAFLD, but bariatric procedures are not currently recommended for management of NAFLD or NASH. Despite this, bariatric surgery has shown improvements in liver steatosis, biochemistry, inflammation, insulin sensitivity and degree of fibrosis. Amazingly, these surgical procedures are being performed in combination with liver transplant to try and prevent NAFLD recurrence. Such measures are resource intensive and put patients under a lot of strain. Given that NASH is projected to overtake hepatitis C as the leading cause of liver transplants in the US, it is not an attractive, long-term therapeutic option for patients or healthcare systems. 

Pharmacological treatment: options on the horizon

Despite the significant burden of NASH, there are currently no drugs approved for its treatment. However, it looks like that is all about to change. While some older therapies for related conditions, such as lipase inhibitors, statins and insulin-sensitising agents have been tested in NASH without real success, there are a number of new options currently under investigation (Table 1).

Table 1: Potential treatments under investigation for NASH.

Insulin-sensitising agents and those affecting glucose metabolism
Drug
Company
Mechanism of action

Liraglutide (Victoza®, type II diabetes)

Novo Nordisk

Human glucagon-like peptide1 (GLP-1) analogue that improves pancreatic beta cell function and reduces appetite and delays gastric emptying

Semaglutide

Novo Nordisk

GLP-1 receptor agonist

Remogliflozin etabonate

Avolynt

Sodium glucose co-transporter 2 (SGLT2) inhibitor

Elafibrinor

Genfit

PPARα/δ agonist

IVA337

Inventiva

Next generation pan-PPAR agonist

Regulators of liver and metabolic homeostasis
Drug
Company
Mechanism of action

Obeticholic acid (Ocaliva®, primary biliary cholangitis)

Intercept

Modified bile acid which is a farnesoid receptor (FXR) agonist that increases glucose-stimulated insulin secretion and inhibits hepatic lipid synthesis and lipid uptake by adipocytes

GS-9674

Gilead

FXR agonist

LJN452

Novartis

FXR agonist

Aramchol

Galmed

First-in-class member of a novel family of synthetic fatty-acid/bile-acid conjugates (FABACs) initially intended as a treatment of cholesterol gallstones

GS-0976

Gilead

Investigational inhibitor of Acetyl-CoA carboxylase (ACC)

Regulators of inflammation and apoptosis that have anti-fibrotic effects
Drug
Company
Mechanism of action

Cenicriviroc

Allergan

Small-molecule CCR2 and CCR5 co-receptor antagonist originally studied for the treatment of HIV infection

Tipelukast (MN-001)

MediciNova

Numerous actions that promote down-regulation of genes that promote fibrosis (such as LOXL2, collagen type 1 and TIMP-1) and inflammation (such as CCR2 and MCP-1)

Emricasan

Conatus and Novartis

Pan-caspase inhibitor

Selonsertib

Gilead

Apoptosis signal-regulating kinase 1 (ASK1) inhibitor

GR-MD-02

Galectin Therapeutics

Complex carbohydrate drug that targets galectin-3, a member of the beta-galactoside-binding protein family with widespread biological effects

Potential treatment options reflect the multifactorial nature of NASH and target a wide range of processes affecting the liver (Figure 2). 

Horizons_Improving no alcoholic_Fig 2

Figure 2. Potential pharmacological treatment options for NASH grouped by underlying mechanism of action (adapted from Lazaridis & Tsochatzis, 2017).

Given the metabolic, inflammatory and fibrotic components of NASH, it has been suggested that targeting a single process may be unsuccessful. The logical next step is to combine drugs acting on the different aspects of the disease. While Gilead’s trial of the ASK1 inhibitor selonsertib combined with the human lysyl oxidase-like 2 (LOXL2) inhibitor simtuzumab failed to show increased efficacy over selonsertib alone, there is hope for other combinations currently being tested including concomitant treatment with FXR agonists and cenicriviroc (Novartis and Allergan). 

The race to develop a treatment for NASH has seen a number of new entrants in recent years. With competition to lead the initial pack nearing an end, continued focus on improved diagnosis and treatment strategies will be important to maintain the pace of progress.

 

References and further reading

European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) and European Association for the Study of Obesity (EASO). EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64:1388–1402.

Lazaridis N & Tsochatzis E. Current and future treatment options in non-alcoholic steatohepatitis (NASH). Expert Rev Gastroent 2017;11:357–69. 

Sanyal AJ, Friedman SL, McCullough AJ, Dimick L; AASLD, FDA. Challenges and opportunities in drug biomarker development for non-alcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases (AASLD) – Food and Drug Administration (FDA) joint workshop. Hepatology 2015;61:13

Nonalcoholic steatohepatitis: the next global epidemic? epgonline.org news trend, May 2016.

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