Lanifibranor efficacy in NASH evident in diabetics and non-diabetics

The efficacy of lanifibranor in reducing histological markers of non-alcoholic steatohepatitis (NASH) is comparable in patients with and without type 2 diabetes (T2D), according to the phase IIb NATIVE study presented as a poster at AASLD 2020.

The overall study population comprised 247 patients with biopsy proven, non-cirrhotic NASH, with a Steatosis-Activity-Fibrosis (SAF) activity score of 3–4. They were randomized 1:1:1 to receive once-daily doses of lanifibranor 800 or 1,200 mg or placebo for 24 weeks. The present analysis compared the subpopulation with T2D (n=103; mean age 56.3 years, 60.2 percent female, mean BMI 33.1 kg/m²) with non-diabetics (mean age 51.6 years, 56.9 percent female, mean BMI 32.7 kg/m²).

Eighty-two and 67 percent of diabetics and non-diabetics had a non-alcoholic fatty liver disease (NAFLD) score ≥6, and more diabetics than non-diabetics had fibrosis stage F2/F3 (80.6 percent vs 72.9 percent). Antidiabetic treatments were comparable in the three treatment arms, with most patients (82.5 percent) on metformin.

The primary endpoint – a 2-point reduction in SAF activity score without worsening of fibrosis – was comparable in patients with and without T2D, be it in the lanifibranor 800 mg (45.5 and 38.0 percent) or 1,200 mg groups (51.4 and 47.9 percent). [AASLD 2020, abstract LP9]

Lanifibranor was also effective in patients with and without T2D with regard to NASH resolution without worsening of fibrosis* (lanifibranor 800 mg: 33.3 and 32.0 percent; lanifibranor 1,200 mg: 42.9 and 45.8 percent).

Similar results were noted for fibrosis improvement** and no worsening of NASH (lanifibranor 800 mg: 30.3 and 26.0 percent; lanifibranor 1,200 mg: 45.7 and 39.6 percent) and NASH resolution and fibrosis improvement (lanifibranor 800 mg: 24.2 and 18.0 percent; lanifibranor 1,200 mg: 28.6 and 33.3 percent).

“[The findings indicate] that patients with diabetes responded equally well to the drug as non-diabetics,” said study author Professor Sven Francque from the Antwerp University Hospital, Antwerp, Belgium.

The decrease in ALT levels with lanifibranor was apparent from week 4 and similar in patients with and without T2D. Patients with T2D also experienced reductions in fasting glucose levels from week 4, with the lowest median decrease of 0.7 mmol/L.

Both doses of lanifibranor improved lipid profile with an increase in HDL-cholesterol and decrease in triglyceride levels, evident from week 4 and apparent at all time points. HbA_1c levels reduced from week 14 (lowest median decrease, 0.5 percent) and was evident at all time points with both lanifibranor doses.

“We know that NAFLD increases the risk of developing T2D, and T2D is associated with a higher risk of having more advanced fibrosis. Furthermore, NAFLD patients are at higher risk of cardiovascular (CV) disease and T2D is a strong risk factor for CV complications,” said Francque.

It is important to assess how diabetic patients respond to NAFLD treatments which may differ from the response of non-diabetics, he continued. Whether the treatment has a beneficial or deleterious effect on diabetes control also warrants examination, he said.

“In the T2D subpopulation of NATIVE, lanifibranor produced major improvements in key histological endpoints … after 24 weeks of treatment similar to non-diabetic patients,” said Francque. “This was accompanied by clinically meaningful improvements in glycaemic control and lipid profile, meaning there is a significant beneficial impact on these major CV risk factors.”

“These data further add to the positioning of lanifibranor as a promising drug for the treatment of patients with NASH,” he concluded.