Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: Findings and recommendations from an American Association for the Study of Liver Diseases–U.S. Food and Drug Administration Joint Workshop

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in North America. It is a growing contributor to the burden of chronic liver disease requiring liver transplantation. Cirrhosis is also associated with an increased risk of hepatocellular cancer which may occur even in the absence of cirrhosis in subjects with nonalcoholic steatohepatitis (NASH) the histological form of NAFLD associated with increased liver-related mortality. The diagnosis of NASH currently requires a liver biopsy. There are also no FDA-approved therapies for NASH. There is therefore a need to develop better diagnostic and therapeutic strategies for patients with NASH targeting both those with early stage disease as well as those with advanced liver fibrosis. There are unique challenges in the design of studies for these target populations. The long relatively asymptomatic time interval in the progression of NAFLD and NASH to cirrhosis and ultimately liver failure, along with gaps in knowledge regarding disease modifiers combine to present significant challenges in trial design. There is therefore an urgent need to develop methods to identify the populations at particular risk of disease progression and to validate endpoints that reflect meaningful changes in health status in this population. This manuscript summarizes the discussion at a joint workshop held September 5th and 6th, 2013, in Silver Spring, Maryland, sponsored by the FDA and the AASLD to develop guidance on diagnostic and therapeutic modalities for NASH.

Serum endotrophin identifies optimal responders to PPARγ agonists in type 2 diabetes

“…Participants in the upper two tertiles who responded to treatment with a reduction in FPG and HbA 1c levels were at a reduced risk of developing lower leg oedema, a major AE associated with glitazone treatment. These efficacy and safety data are highly relevant for predicting benefit-to-risk ratios for patients treated with glitazones; this should also apply when the medications are considered for other indications, such as liver disease [32][33][34].…”

“…The ECM and its products, especially procollagen type VI and endotrophin, may be of particular relevance in fatty liver, including in the severe form of the disease, non-alcoholic steatohepatitis (NASH). NASH is a metabolic-fibrotic disorder of the liver that shows at least a partial overlap with type 2 diabetes [32][33][34]. Accordingly, we expect that this novel biomarker should assist in the diagnosis and management of NASH patients where insulin sensitisers may be beneficial for subpopulations, both for the treatment of insulin resistance and liver fibrosis.…”

EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease

“…Rationale: Drug therapy should be indicated for progressive NASH (bridging fibrosis and cirrhosis) but also for early-stage NASH with increased risk of fibrosis progression (age > 50 years; diabetes, MetS, increased ALT [122] ) or active NASH with high necroinflammatory activity [123] . No drug has currently been tested in phase III trials and is approved for NASH by regulatory agencies.…”

EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease

“…Rationale Drug therapy should be indicated for progressive NASH (bridging fibrosis and cirrhosis) but also for early-stage NASH with increased risk of fibrosis progression (age >50 years; diabetes, MetS, increased ALT [122]) or active NASH with high necroinflammatory activity [123]. No drug has currently been tested in phase III trials and is approved for NASH by regulatory agencies.…”