Antifibrotic therapies in liver disease: Ready for primetime?

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Abbreviations

AASLD

American Association for the Study of Liver Diseases

ECM

extracellular matrix

ESLD

end‐stage liver disease

FDA

Food and Drug Administration

HBV

hepatitis B virus

HCV

hepatitis C virus

HSC

hepatic stellate cell

NAFLD

nonalcoholic fatty liver disease

PBC

primary biliary cholangitis

UDCA

ursodeoxycholic acid

1.

The potential for therapies that specifically target liver fibrosis (i.e., inhibitors of fibrogenesis or inducers of fibrinolysis that are independent of underlying disease etiology) to be integrated into management of human chronic liver diseases has received increased attention over the last 5 to 10 years. For example, review of PubMed citation data shows that the number of publications on this subject from 2011 to 2016 is comparable with that in the entire preceding history of the PubMed database. Those recent works include several excellent reviews published in 2015 and 2016 to which interested readers are referred for additional information.1, 2, 3, 4, 5, 6 Rising interest in this subject is also demonstrated by recent American Association for the Study of Liver Diseases (AASLD)‐sponsored events, including the 2016 Pediatric Liver Disorders and Liver Fibrosis SIG Program, where the report summarized in this review was presented, and a 2014 conference focused on antifibrotic therapy clinical trial design.7 Several factors have likely contributed to this growing interest in antifibrotic therapies for liver diseases: (1) improving noninvasive biomarkers of liver fibrosis (which were also the subject of several presentations in this 2016 AASLD SIG program); (2) the emergence of nonalcoholic fatty liver disease (NAFLD) as one of the most common etiologies for which patients are being listed for liver transplantation; and (3) elucidation of the pathogenesis of liver fibrosis using various in vitro and in vivo experimental paradigms (reviewed by Delire et al.8 and Weiskirchen and Tacke9).

Preclinical research conducted over the last several decades has established that effective treatment of the underlying cause of chronic liver injury can reverse liver fibrosis in experimental models. That possibility was first suggested more than 30 years ago after the discovery of extracellular matrix (ECM)‐degrading enzymes in animal models of liver fibrosis.10 The reversibility of human liver fibrosis has subsequently been described in anecdotal reports of fibrotic regression in subjects with various liver diseases, and more recently, it has been demonstrated by prospective studies of subjects with chronic viral hepatitis B (HBV) or hepatitis C virus (HCV) infection, treated with effective antiviral therapies.11, 12 These data, together with recent Food and Drug Administration (FDA) approval of newer therapies for HBV and HCV, raise the exciting possibility that end‐stage liver disease (ESLD) caused by these conditions may be reversible with medical management, at least in some circumstances. Thus far, HCV and HBV have been the targets of the majority of FDA‐approved drugs for the treatment of human liver diseases introduced over the past 20 years. Recently, obeticholic acid received accelerated approval for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with inadequate response to or intolerance of UDCA treatment.13 Such approval was based on obeticholic acid–induced reduction in serum levels of alkaline phosphatase in PBC study subjects. Thus, whether such therapy delays, prevents, or reverses PBC‐induced cirrhosis has not been established.

The broader potential for antifibrotic medical management of ESLDs that result from primary disease etiologies that currently lack effective, disease‐specific pharmacological interventions, including NAFLD, remains an exciting but still uncertain possibility. Recent experimental research has begun to elucidate the mechanisms that are induced by chronic hepatic injury and also promote liver fibrosis. Those studies are defining new molecular targets for development of novel antifibrotic therapies to test in preclinical models, with the longer‐term goal of evaluating the most promising interventions for their abilities to suppress fibrogenesis and/or promote fibrinolysis, and thereby improve outcomes in patients with chronic liver diseases. This paradigm has already supported a number of clinical intervention trials testing drugs that target molecular mechanisms of hepatic fibrogenesis and fibrinolysis. Our recent review of Clinicaltrials.gov for adult liver disease drug intervention trials that included liver fibrosis as an outcomes measure identified 193 total studies, including 50 that are currently open and 40 that are actively recruiting, with 84 of 193 total trials, 44 of 50 open trials, and 35 of 40 recruiting studies initiated in the past 5 years. These studies include those testing interventions intended to suppress hepatic stellate cell (HSC) activation (e.g., transforming growth factor β, connective tissue growth factor, chemokine receptor CCR‐2/5, galectin‐3, tumor necrosis factor α), promote HSC inactivation (e.g., peroxisome proliferator‐activated receptor γ, heat shock protein 47), and reverse ECM crosslinking (e.g., lysyl‐oxidase‐like‐protein‐2), and others in adult patients with nonalcoholic steatohepatitis, chronic viral hepatitis, and other fibrotic liver disease. A similar review of Clinicaltrials.gov for trials involving pediatric subjects identified only 16 total studies and 3 active studies. One active trial (NCT01379469) is testing the efficacy of carbamazepine in pediatric and adult subjects with alpha‐1‐antitrypsin deficiency liver disease and portal hypertension, again based on preclinical data demonstrating the efficacy of this drug in a mouse model of that disease.14

Taken together, these considerations illustrate the substantial impact that basic research studies of liver fibrosis are having on efforts to develop novel medical approaches to chronic ESLD. However, there are not yet any fibrosis‐specific liver disease therapies that have been shown to be effective or approved for clinical use in chronic human liver disease. Thus, further research will be necessary before such antifibrotic therapies are ready for “primetime” in adult or pediatric human liver diseases. Such research should take advantage of the recommendations that emerged from a 2014 AASLD‐sponsored conference on anti‐fibrotic therapy clinical trial design,7 which included: (1) the importance of clarifying at‐risk study populations with respect to patient demographics, disease etiologies, and clinical status; (2) the need to standardize preclinical and clinical trial methodologies, including trials investigating liver fibrosis biomarkers; (3) the potential value of efforts to accelerate development and validation of reliable noninvasive biomarkers; and (4) the importance of considering the possibility of off‐target toxicities of antifibrogenic or profibrinolytic therapies. Indeed, the assessment of potential unintended consequences or adverse outcomes of such therapies administered in adult or pediatric subjects whose underlying cause of liver injury persists should be an essential component of those future intervention trials.