COMMENTARY

New Studies Highlight Increasing Global Prevalence of NAFLD/NASH and Its Considerable Toll

William F. Balistreri, MD

Disclosures

January 18, 2017

In This Article

Novel Treatment Strategies

Cenicriviroc

The immunomodulator cenicriviroc (CVC) blocks two chemokine receptors—CCR2 and CCR5—involved in NASH-associated inflammation, and has been shown to exert potent anti-inflammatory and antifibrotic activity in animal models of liver disease.

Sanyal and colleagues[12] assessed the efficacy and safety of this oral compound as a treatment for NASH in adults at increased risk for progression to cirrhosis in a phase 2b, randomized, double-blind, placebo-controlled study. A total of 289 participants with histologically defined NASH, liver fibrosis, and diabetes or metabolic syndrome were randomly assigned to CVC 150 mg daily or placebo. The investigators documented that the compound blocked its target molecules. They noted a marked reduction in levels of four markers of systemic inflammation (fibrinogen, interleukin-1B, interleukin-6, and C-reactive protein) compared with placebo. Although CVC did not meet the projected primary endpoint of reducing the NAFLD activity score while not worsening fibrosis, this compound outperformed placebo in improving fibrosis scores. After 1 year of treatment, improvement in fibrosis by at least one stage and no worsening of steatohepatitis was achieved in significantly more CVC-treated persons than placebo recipients. CVC was well tolerated, and no treatment-related adverse events occurred.

Selonsertib

Apoptosis signal-regulating kinase (ASK1) is a serine/threonine kinase that promotes hepatic inflammation and fibrosis in the setting of oxidative stress. ASK1 stimulates apoptotic, fibrinogenic, and inflammatory pathways; therefore, activation of the ASK1 pathway, observed in NASH, correlates with fibrosis. It has been demonstrated that ASK1 inhibition is associated with improved steatosis, inflammation, and fibrosis in a rodent model of NASH.

Loomba and colleagues[13] described the preliminary study of the efficacy of selonsertib, a selective inhibitor of ASK1, in a randomized, open-label trial of 72 people with biopsy-confirmed NASH and advanced fibrosis. Participants received either selonsertib (6 mg or 18 mg orally per day) alone or in combination with simtuzumab (125 mg subcutaneously weekly) or simtuzumab alone. After 24 weeks, those treated with selonsertib were more likely to have a reduction in fibrosis stage and a ≥ 15% decline in hepatic stiffness, as assessed by magnetic resonance elastography, and were less likely to progress to cirrhosis versus patients who received simtuzumab monotherapy. The changes in fibrosis correlated with changes in hepatic collagen content by morphometry and steatosis grade. Furthermore, those treated with selonsertib (18 mg) were most likely to have a ≥ 30% decline in hepatic fat content compared with 10% of those who received simtuzumab alone. This decline correlated with changes in steatosis on biopsy; body weight; and serum ALT, AST, GGT, alkaline phosphatase, glucose, and CK18 levels.

Selonsertib's dose-dependent, antifibrotic, antisteatotic effects in patients with NASH and moderate to severe fibrosis provide optimism about its future as a therapeutic option.

Future Prospects

The increasing prevalence and projected impact of severe fatty liver disease, as well as the current lack of effective management strategies as underscored by these studies, were somewhat mollified by the presentations. They offered hope in the form of the application of genomic approaches to diagnosis, genetically tailored treatment recommendations, and the possibility of manipulating the gut microbiome via prebiotics or probiotics as a method to forestall obesity-related disease. Researchers discussed promising, personalized, precision medicine approaches to these disorders.

One novel approach—human adult liver-derived mesenchymal stem cell infusion—is a potentially promising candidate strategy for modulation of the proinflammatory and profibrogenic environment of fatty liver because of their immunomodulatory properties. Gellynck and colleagues[14] reported that one such preparation exerts anti-inflammatory, antifibrosis, and anti-NASH effects, both in vitro and in a preclinical model of NASH. This observation provides a basis for clinical studies in patients with NASH.

The importance of this and other futuristic projections was underscored by the striking data regarding the increasing prevalence and impact of NAFLD/NASH.

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