Nonalcoholic steatohepatitis: the next global epidemic?

Reviewed by Professor Brent A Tetri, Professor of Internal Medicine, St Louis University, USA.

Nonalcoholic steatohepatitis (NASH) is the progressive form of non-alcoholic fatty liver disease (NAFLD), and is the most common cause of liver disease in North America. It has become a serious concern given an increasingly obese population. The major feature of NASH is fatty infiltration of the liver, along with inflammation and damage. Even with severe disease NASH may be asymptomatic, and patients may be unaware of its existence.  Initial damage with associated scarring and fibrosis will progress to cirrhosis in 20% of patients, impairing liver function. It is estimated that NASH currently affects 5% (approximately 16 million) of the US population, while other developed countries have a similar or higher incidence. It also seems that there is variation in susceptibility to the disease between different populations. For example, in Japan the prevalence of NASH is rising although the population is not typically overweight.

End stage liver failure secondary to NASH is projected to become the most common indication for liver transplant by 2025. With limited options for drug treatment and an increasing burden of disease, this has rapidly become a key target for research and development of new therapies.

Conventional management

Initial management is focused on lifestyle modification and treating or reversing conditions associated with NAFLD. At this stage weight reduction and exercise are effective, particularly with a reduction in alcohol consumption and a healthy diet. Bariatric surgery also appears to have an impact. One small study revealed that after undergoing laparoscopic adjustable gastric banding, NASH resolved in 82% of patients who lost around 34 kilograms.¹ Patients with metabolic syndrome showed an improvement in liver histology with weight loss. Alongside additional studies, this suggests a positive impact of bariatric surgery.

Drug therapies

Vitamin E, omega 3 fatty acids, statins, metformin and others have been investigated for efficacy, with vitamin E showing some benefit. Glitazones (pioglitazone in particular) have been the focus of several studies for NASH treatment. Some have shown their use can lead to improvements in steatosis, fibrosis and hepatocellular ballooning (damage to liver cells), at the cost of significant weight gain.² Current guidelines suggest that pioglitazone can be used for the treatment of steatohepatitis in patients with biopsy-proven NASH.³ However, evidence of increased risk of bladder cancer, hepatitis, and cardiovascular events has led to pioglitazone and rosiglitazone being withdrawn from use in diabetes in France and Germany.

Currently the most advanced NASH treatments are a handful of drugs in Phase III trials. The first is the semi-synthetic bile acid analogue and selective farnesoid X receptor (FXR) agonist Ocaliva (obeticholic acid), developed by Intercept Pharmaceuticals and Dainippon Sumitomo. This is an oral medication with anti-inflammatory, immunomodulatory and antifibrotic properties. In 2014, the phase II FLINT trial was halted early after the drug met its primary endpoint, with 45% of Ocaliva-treated patients showing an improvement in disease versus 21% on placebo. Fibrosis was improved in 35% of the Ocaliva arm versus 19% for placebo. There was however, no significant difference in resolution of NASH between treated and placebo groups. At the same time pruritus and increased levels of LDL cholesterol were evident in treated patients.  As a result, Intercept is conducting a trial examining the effects of statin use on the cholesterol elevations seen with Ocaliva.

Based on these results, the FDA has given Ocaliva breakthrough therapy designation and a global phase III REGENERATE trial is currently underway, with dual endpoints of fibrosis and NASH. This is due to report in early 2018. Meanwhile Ocaliva has been given FDA advisory committee recommendation for treating the liver disease primary biliary cirrhosis.

GFT 505 (elafibranor) from Genfit, is an oral, dual peroxisome proliferator-activated receptor (PPAR) agonist (alpha and delta) which to date has completed eight clinical trials. In the GOLDEN-505 study, GFT 505 failed to show an improvement in NASH. Genfit claim that this was related to the patient group used in the study, with some exhibiting milder disease, and suggest that when this group is excluded the results were positive for NASH. A recent post-hoc analysis⁴ appears to support this view, showing that elafibranor can resolve NASH without the worsening of fibrosis, as well as reducing cardiometabolic risk. Further data will come from a global phase III trial started in November 2015. A different PPAR agonist that targets PPAR alpha and gamma, Lipaglyn (saroglitazar) from Zydus Cadila, is in phase III trials. Development of other drugs (aleglitazar, muraglitazar, tesaglitazar) in this class has been halted due to safety concerns.

On the horizon

There are more than a dozen treatments in Phase II trials, including PPAR and FXR agonists. TAK 652 (cenicriviroc) from Tobira Therapeutics, is an oral immunomodulatory drug that blocks two chemokine receptors (CCR2 and CCR5) with a role in the inflammatory and fibrogenic pathways in NASH. The drug has been granted FDA fast track status and is currently being evaluated in the phase IIb CENTAUR study. Global phase III trials are planned.

Shire has SHP 626 (volixibat) in development, an apical sodium-dependant bile acid transporter (ASBT) inhibitor, and early studies suggest that this class of drug may provide benefits in patients with NASH. In contrast, Novo Nordisk has decided to test diabetes drug Victoza (liraglutide), or longer-acting version semaglutide, in fatty liver disease in the phase II LEAN study, after a small study in NASH patients suggested Victoza could deliver improvements. Overweight NASH patients in the LEAN trial showed improvements in liver histology and little worsening of fibrosis. Commentators have said larger trials are needed to determine that it is the medication and not simply reduction in obesity that causes improvement in NASH.

Gilead Sciences has shown plenty of interest in the area, obtaining FXR agonists PX 102 / 104 from Phenex Pharmaceuticals and an acetyl-CoA carboxylase (ACC) inhibitor from Nimbus Therapeutics. Gilead’s GS 9674, and injectable anti-LOXL2 monoclonal antibody GS 6624 (simtuzumab) are now in phase II trials, although the latter has failed in both pancreatic cancer and idiopathic pulmonary fibrosis trials. Also entering phase II trials is the anti-inflammatory MN 001 (tipelukast) from Medici Nova.

Finally drug combinations are also under investigation: for example, Dong-A launched its DPP-4 Type 2 diabetes drug Suganon (evogliptin) in the Republic of Korea and has signed a deal with Tobira to test its drug in combination with the company’s NASH treatment cenicriviroc in phase III trials.

Over the horizon

Another dozen or so drugs are in early stage trials. Most notably, VBL Therapeutics is testing lecinoxoids VB 201 and VB 703. These are antagonists for Toll-like receptors 2 and 4 (TLR-2 and TLR-4), which play a role in NAFLD. In an exploratory trial, VB 201 demonstrated significant reduction of vascular inflammation, suggesting that lecinoxoids can restrict liver inflammation and ameliorate liver fibrosis. VBL Therapeutics has also developed related compounds which could offer greater efficacy than VB 201: VB 703 has demonstrated promising preclinical results in NASH and renal fibrosis models.

Finally, detecting the disease is also a key challenge. Blood tests do not always spot the signs, and for now the only means of proving a firm diagnosis of NASH is a liver biopsy, which only a small percentage of patients undergo. However new tests for the disease are in development. These include a biomarker test from Genfit and the BreathID diagnostic test from Exalenz BioScience.

References

1. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Lassailly G, Caiazzo R, Buob D, Pigeyre M, Verkindt H, Labreuche J, et al. Gastroenterology 2015;149:379-388.
2. Pharmacological agents for NASH. Ratziu V.Nat Rev Gastroenterol Hepatol. 10, 676-685 (November 2013)
3. The diagnosis and management of non-alcoholic fatty liver disease:Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. Hepatology 2012;55:2005-2023.
4. Elafibranor, an Agonist of the Peroxisome Proliferator−Activated Receptor−α and −δ,Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, et al. Gastroenterology May 2016 Volume 150, Issue 5, Pages 1147–1159.e5