Lanifibranor improves NASH in 24-week trial

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.

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 metabolism. PPARs 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 appropriate measure

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 placebo group.

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 treatment stopped.

Lanifibranor will enter phase 3 studies in 2021.