Twenty-four weeks of treatment with lanifibranor, a drug designed to treat NASH, improved liver
fibrosis in 42% of people treated in a phase 2b clinical trial, Professor Sven Francque of Antwerp University Hospital reported at the online AASLD Liver Meeting last
month. The drug also reduced liver inflammation and NASH activity in 55% of those treated with the higher dose.
NASH (non-alcoholic steatohepatitis) is a condition in which
liver tissue becomes inflamed and cells in the liver are damaged, leading to
liver fibrosis or scarring. NASH develops in people with non-alcoholic fatty
liver disease (NAFLD), after substantial fat accumulation in the liver. NASH is often accompanied
by metabolic disorders including type 2 diabetes, and obesity.
Lanifibranor is a PPAR agonist. It activates all three types
of PPAR and is dosed orally, once a day.
Improvement in a tumour. Also, a mathematical model that allows us to measure the degree to which one of more factors influence an outcome.
Abnormal fat deposits in the liver.
or pertaining to the internal organs.
PPARs regulate the expression of genes and are involved in
the regulation of numerous metabolic and inflammatory pathways.
The PPARs alpha, gamma and delta are expressed in adipose
tissue and the liver. When activated, PPARs have anti-inflammatory effects in
the liver, as well as playing a role in lipid, triglyceride and glucose
appear to play a role in the development of NAFLD and NASH and levels of PPARs
are reduced in people with NASH.
Various PPAR agonists are being tested in clinical trials.
Lanifibranor is the only PPAR agonist which activates all forms of PPAR. At
this point it is unclear if activation of all forms of PPAR results in superior
outcomes to activating one form of PPAR.
Product developer Inventiva has tested lanifibranor in phase
1 safety and phase 2a and 2b dosing and efficacy studies. The NATIVE phase 2b
study randomised people with biopsy-confirmed NASH to either 800mg or 1200mg of
lanifibranor or placebo for 24 weeks. Participants underwent liver biopsy four
weeks after completion of treatment.
The study used a new outcome measure, changes in
steatosis-activity-fibrosis (SAF) score, rather than NAFLD activity score. SAF
score is calculated differently from NAFLD Activity Score, using only liver
tissue inflammation and ballooning of hepatocytes to assess the severity of
disease. The study investigators say that as the severity of ballooning and
inflammation predict the presence and progression of fibrosis, SAF is an
The primary endpoint was a 2-point reduction in SAF activity
score. The secondary outcomes were resolution of NASH without worsening of
fibrosis and 1-stage regression in fibrosis without worsening of NASH.
Two hundred and forty-seven people were randomised and
received at least one dose of study drug; 194 completed treatment and had
paired baseline and follow-up biopsies to assess NASH status and fibrosis.
Fifty-eight per cent of participants were women, the mean age
of study participants was 53 years and 94% were white. Participants had a mean
body mass index of 32.9 kg/m2 (moderately obese), 42% had type 2 diabetes and
76% had F2/F3 fibrosis at baseline. The mean SAF score was 3.3 and 73% had an
NAFLD Activity Score of 6 or above (highly active NASH). There were no
significant differences in patient characteristics between arms.
After 24 weeks of treatment, participants in the
lanifibranor 1200mg group were significantly more likely to experience a
2-point reduction in SAF score compared to the placebo group (49% vs 27%,
p = 0.004). When the analysis was restricted to those who completed treatment and
underwent follow-up biopsies, the proportion in the lanifibranor 1200mg group who met
the primary outcome increased to 55% (34% in the placebo group) (p = 0.015).
The high response rate in the placebo group suggests either
that participating in this clinical trial had effects on the behaviours of
participants or that SAF is a relatively insensitive marker of changes in
underlying liver disease; response rates of this magnitude have not been
reported in other NASH treatment trials in the placebo group, and analysis of
secondary outcomes in this study did not show such pronounced effects in the
The 800mg dose of lanifibranor was not associated with
significant improvement by the primary outcome measure.
Lanifibranor 1200mg also resulted in improvement of fibrosis
by one stage and no worsening of NASH in 42% compared to 24% in the placebo
group (p = 0.011) and resolution of NASH and improvement of fibrosis in 31% (compared
to 7% in the placebo group, p < 0.001). Results were similar when the analysis
was restricted to patients with F2/F3 fibrosis. There was no difference between
diabetic and non-diabetic patients.
Lanifibranor treatment was also associated with significant
reductions in ALT and AST by week 4 and in triglycerides by week 14. Glucose
control, fasting insulin and HbA1c also improved in patients with diabetes.
Treatment-related adverse events were reported more
frequently in the lanifibranor recipients, most commonly diarrhoea, fatigue and
nausea. Five participants withdrew due
to adverse events, including two in the placebo group.
Weight increase was also observed in the lanifibranor groups
(+2.7kg in the 1200mg group). The investigators say that weight gain reflected
an improvement in adipose tissue function and a shift from visceral to
subcutaneous fat storage. Sven Francque said that weight gain plateaued after
Lanifibranor will enter phase 3 studies in 2021.