Lanifibranor therapy resulted in both NASH resolution and fibrosis reduction in the phase 2b NATIVE study in patients with non-cirrhotic NASH, compared to placebo. PPAR signaling is involved in common pathways of NASH and type 2 diabetes (T2D) . We evaluated the association between the effect of lanifibranor on glycemic control (GC) and NASH markers.

Methods: NATIVE included 247 patients, randomized to lanifibranor 800, 1200 mg/d or placebo for 24 weeks of treatment; 228 patients completed the trial. Efficacy in NASH was measured with SAF score (primary endpoint) and NASH-CRN grading and fibrosis staging. Biomarkers for insulin resistance (IR) , GC, lipid metabolism, inflammation, liver enzymes and imaging of hepatic steatosis by continuous attenuation parameter (CAP) were analyzed at baseline (BL) and end of treatment (EOT) . Correlations between HbA1c (≤6, >6 - ≤7 and >7%) at BL and HbA1c change from BL to EOT with improvement in biomarkers and histologic features of NASH at EOT were assessed.

Results: T2D was present in 103 (42%) patients. The composite endpoint of NASH resolution and fibrosis improvement in the overall and T2D group for lanifibranor (pooled data) versus (vs) placebo was 26% vs. 7% (p<0.001) , and 26% vs. 3% (p=0.003) , respectively. Irrespective of T2D status, lanifibranor improved fasting glucose (FG) , IR, lipid metabolism, C-reactive protein, and liver enzymes. In contrast to placebo, lanifibranor improved mean HbA1c from BL in the overall and T2D group, -0.41% and -0.66%, respectively. In the lanifibranor group, BL HbA1c correlated with BL NASH activity and fibrosis; HbA1c decrease at EOT correlated with improvement of FG, insulin, IR, liver enzymes, HDL-cholesterol, triglycerides, ApoB, ApoB/ApoA1, CAP and histologic improvement of steatosis and ballooning.

Conclusion: GC correlates with NASH severity. The improvement of metabolic markers of NASH and hepatic steatosis with lanifibranor treatment is consistent with its beneficial effect on GC.


M.P.Cooreman: Employee; Inventiva Pharma. S.Francque: None. L.Dzen: Employee; Inventiva Pharma. P.Huot-marchand: Employee; Inventiva Pharma. J.L.Junien: None. P.Broqua: None. M.F.Abdelmalek: Advisory Panel; Akero Therapeutics, Inc., Bristol-Myers Squibb Company, Inventiva Pharma, Madrigal Pharmaceuticals, Inc., NGM Biopharmaceuticals, Novo Nordisk, Consultant; Hanmi Pharm. Co., Ltd., Research Support; Akero Therapeutics, Inc., Allergan, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Celgene, DURECT Corporation, Enanta, Enyo Pharma, Hanmi Pharm. Co., Ltd., Intercept Pharmaceuticals, Inc., Inventiva Pharma, Madrigal Pharmaceuticals, Inc., NGM Biopharmaceuticals, Novo Nordisk, Poxel SA, TARGET PharmaSolutions, Inc., Viking Therapeutics.

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