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.