Efruxifermin improves liver fat and fibrosis in people with NASH

15 Dec 2020 Keith Alcorn
Originally published on www.infohep.org

Efruxifermin reduced liver fat and improved liver inflammation and fibrosis in the majority of people with NASH who received it in a phase 2a trial but nausea and vomiting led 10% of people who received the drug to drop out of the trial, Professor Stephen Harrison of the University of Oxford reported at the online AASLD Liver Meeting last month.

Non-alcoholic steatohepatitis (NASH) refers to liver inflammation and fibrosis caused by non-alcoholic fatty liver disease (NAFLD). Left untreated, NASH may lead to the development of cirrhosis and hepatocellular carcinoma. NASH is often accompanied by obesity and other metabolic disorders such as type 2 diabetes and dyslipidemia.

A meta-analysis of studies carried out in Europe shows that around one in 20 people have advanced fibrosis due to NAFLD or NASH, and NASH is the fastest-growing reason for a liver transplant in the United States.

Although NAFLD can be treated by dietary and exercise interventions that may be effective for a minority of people for as long as they are adhered to, there is no approved form of treatment for NASH. Numerous pharmaceutical companies are working to develop treatments targeting a variety of metabolic pathways.

Efruxifermin is designed to treat NASH by regulating levels of FGF-21.

FGF-21 is involved in the regulation of numerous metabolic pathways governing glucose and lipid levels. Levels of FGF-21 are elevated in people with NAFLD, type 2 diabetes and obesity. Efruxifermin is an analog of FGF-21, designed to normalise FGF-21 levels.

Efruxifermin is dosed subcutaneously once a week.

The phase 2a study recruited patients with biopsy-confirmed NASH and F1-F3 fibrosis. All participants had an NAFLD activity score of at least 10%. The study population was evenly balanced between men and women, had an average age of between 50 and 53 according to study arm and high mean body weight (103-108kg). The NAFLD activity score ranged from 5.1 to 5.6. Approximately two-thirds of participants had F2 or F3 fibrosis.

The study randomised 80 participants in equal proportions to one of three doses of efruxifermin (28mg, 50mg or 70mg) or placebo for 16 weeks. Responders (those with a liver fat reduction of at least 30% at week 12) underwent liver biopsy after completion of treatment.

Seventy-nine people began treatment in the study and 68 remained on treatment at week 12 (seven withdrew due to adverse and four for administrative reasons). Fifty people on treatment at week 12 were classed as responders and 42 underwent post-treatment liver biopsies. Eight biopsies could not be carried out due to COVID-19.

Liver fat declined significantly at all doses compared to the placebo group. Liver fat reduced substantially in more patients in the 50mg and the 70mg groups compared to the 28mg group. In the 50mg group, all participants experienced a 50% reduction in liver fat content and 53% experienced a reduction of 70% or more. In the 70mg group, 93% experienced a reduction of 50% or more and 80% experienced a reduction of 70% or more.

Participants in the 70mg group were more likely to experience a normalisation in liver fat content (< 5%). Sixty-seven per cent in the 70mg group experienced normalisation of liver fat content compared to 53% in the 50mg group and 25% in the 28mg group.

At all doses of efruxifermin, biomarkers of liver fibrosis fell significantly by week 12 (p < 0.001). Participants in the efruxifermin study arms also achieved reductions of at least 30-40% in ALT and AST levels, signalling a reduction in liver inflammation.

Forty-eight per cent of responders in the efruxifermin arms achieved resolution of NASH (no ballooning of liver cells detectable and no or minimal lobular inflammation) by post-study biopsy. There was no difference between dosing groups in the proportion who achieved NASH resolution.

In people with F2 or F3 fibrosis at baseline who received efruxifermin (n = 22), 68% experienced a 1-stage or 2-stage improvement in fibrosis. Nine per cent experienced worsening of fibrosis and fibrosis remained the same in 23%.

Participants in the efruxifermin groups experienced significant reductions in triglyceride and non-HDL cholesterol levels, as well as increases in HDL cholesterol.

The most common adverse events were gastrointestinal (diarrhoea 36%, nausea 34%). Nausea and vomiting led to treatment discontinuation in six people in the efruxifermin groups (10%). No treatment-related discontinuations occurred in the 50mg group; four of the six discontinuations occurred in people receiving the highest dose of 70mg. Dr Harrison said that the gastrointestinal symptoms tended to improve as treatment went on.

A phase 2b/3 clinical trial of efruxifermin in NASH patients is due to begin recruiting in early 2021, drug developer Akero Therapeutics said in a press release. The study is expected to use doses of 28mg and 50mg.