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Lancet. 2018 Mar 24;391(10126):1174-1185. doi: 10.1016/S0140-6736(18)30474-4. Epub 2018 Mar 5.

NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

Author information

1
Radcliffe Department of Medicine, University of Oxford, Oxford, UK. Electronic address: sharrison@pinnacleresearch.com.
2
Division of Gastroenterology and Hepatology, Northwestern University, Chicago, IL, USA.
3
Duke University, Durham, NC, USA.
4
Clinical Research and Education, Texas Digestive Disease Consultants, Dallas, TX, USA.
5
Division of Gastroenterology and Hepatology, Brooke Army Medical Center, San Antonio, TX, USA.
6
Gastroenterology Consultants of San Antonio, Live Oak, TX, USA.
7
Hepatology, South Denver Gastroenterology, Englewood, CO, USA.
8
Department of Radiology, Duke University Medical Center, Durham, NC, USA.
9
Summit Analytical, Denver, CO, USA.
10
NGM Biopharmaceuticals, Inc, San Francisco, CA, USA.
11
Non-Alcoholic Fatty Liver Disease Research Center, Division of Gastroenterology and Epidemiology, University of California San Diego, San Diego, CA, USA.

Erratum in

Abstract

BACKGROUND:

Non-alcoholic steatohepatitis is a chronic liver disease characterised by the presence of hepatic steatosis, inflammation, and hepatocellular injury, for which no Food and Drug Administration (FDA)-approved treatment exists. FGF19 is a hormone that regulates bile acid synthesis and glucose homoeostasis. We aimed to assess the safety and efficacy of NGM282, an engineered FGF19 analogue, for the treatment of non-alcoholic steatohepatitis.

METHODS:

In this randomised, double-blind, placebo-controlled, phase 2 study, we recruited patients aged 18-75 years with biopsy-confirmed non-alcoholic steatohepatitis as defined by the non-alcoholic steatohepatitis clinical research network histological scoring system, from hospitals and gastroenterology and liver clinics in Australia and the USA. Key eligibility criteria included a non-alcoholic fatty liver disease activity score of 4 or higher, stage 1-3 fibrosis, and at least 8% liver fat content. Patients were randomly assigned (1:1:1) via a web-based system and stratified by diabetic status to receive either 3 mg or 6 mg subcutaneous NGM282 or placebo. The primary endpoint was the absolute change from baseline to week 12 in liver fat content. Responders were patients who achieved a 5% or larger reduction in absolute liver fat content as measured by MRI-proton density fat fraction. Efficacy analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02443116.

FINDINGS:

Between July 14, 2015, and Aug 30, 2016, 166 patients were screened across 18 sites in Australia and the USA. 82 patients were randomly assigned to receive 3 mg NGM282 (n=27), 6 mg NGM282 (n=28), or placebo (n=27). At 12 weeks, 20 (74%) patients in the 3 mg dose group and 22 (79%) in the 6 mg dose group achieved at least a 5% reduction in absolute liver fat content from baseline (relative risk 10·0 [95% CI 2·6-38·7] vs 11·4 [3·0-43·8], respectively; p<0·0001 for both comparisons) versus two (7%) in the placebo group. Overall, 76 (93%) of 82 patients experienced at least one adverse event, most of which were grade 1 (55 [67%]), and only five (6%) were grade 3 or worse. The most commonly (≥10%) reported adverse events were injection site reactions (28 [34%]), diarrhoea (27 [33%]), abdominal pain (15 [18%]), and nausea (14 [17%]). These adverse events were reported more frequently in the NGM282 groups compared with the placebo group. No life-threatening events or patient deaths occurred during the study.

INTERPRETATION:

NGM282 produced rapid and significant reductions in liver fat content with an acceptable safety profile in patients with non-alcoholic steatohepatitis. Further study of NGM282 is warranted in this patient population.

FUNDING:

NGM Biopharmaceuticals.

PMID:
29519502
DOI:
10.1016/S0140-6736(18)30474-4
[Indexed for MEDLINE]

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