10:43 AM
Dec 05, 2018
 |  BC Extra  |  Politics & Policy

FDA NASH guidance charts course for surrogate endpoints tied to biopsies

Four companies with products in Phase III testing to treat non-alcoholic steatohepatitis are well positioned to meet endpoints that could support accelerated approval, according to requirements outlined in new FDA draft guidance. However, the guidance doesn’t do much to address questions about how imaging endpoints and biomarkers could help reduce requirements for invasive biopsies in NASH trials.

The draft guidance, which was released Monday, addresses general considerations as well as specific issues for Phase II, Phase III and pediatric trials to treat non-cirrhotic NASH with liver fibrosis.

For Phase III studies and late Phase II studies, the guidance asks sponsors to show evidence of efficacy on histological endpoints, which would require biopsies to confirm. It recommends trial durations of at least 12 months to allow histological changes to occur, unless sponsors can scientifically justify a shorter duration.

The guidance proposes three potential endpoints for accelerated approval: resolution of steatohepatitis and no worsening of fibrosis; at least one stage improvement in liver fibrosis and no worsening of steatohepatitis; or simultaneous resolution of steatohepatitis and at least one stage improvement in liver fibrosis.

All four products in Phase III testing to treat non-cirrhotic NASH are testing endpoints consistent with those requirements. They are Ocaliva obeticholic acid from Intercept Pharmaceuticals Inc. (NASDAQ:ICPT), selonsertib from Gilead Sciences Inc. (NASDAQ:GILD), cenicriviroc from Allergan plc (NYSE:AGN) and elafibranor from Genfit S.A. (Euronext:GNFT).

Ocaliva is an FXR agonist approved to treat primary biliary cirrhosis (PBC); selonsertib is an apoptosis signal-regulating kinase 1 (ASK1; MAP3K5) inhibitor; cenicriviroc is a dual CC chemokine receptor 5 (CCR5; CD195) and CCR2 (CD192) antagonist; elafibranor is a dual PPARα and PPARδ agonist.

The guidance also says confirmatory trials should be underway at the time of submission. These may use a composite endpoint that assesses progression to cirrhosis, hepatic decompensation events, Model for End Stage Liver Disease score above 15, liver transplant and all cause mortality.

It left open what methods companies may use to show proof of concept in early Phase II studies, so long as sponsors can scientifically justify their choices. The agency listed liver enzyme measures and imaging to assess liver stiffness or hepatic fat content as options.

The guidance also encourages companies to identify and validate biomarkers that could replace biopsies to diagnose and stage NASH and fibrosis. It encourages sponsors to test both histological and biochemical markers in early Phase II trials to help characterize non-invasive measures (see "New Endpoints in NASH").

Comments are due Feb. 4, 2019.

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