A.G. (Onno) Holleboom1, A.G. (Onno) Holleboom2
(1) Amsterdam UMC, Vascular Medicine, Amsterdam, The Netherlands. (2) Amsterdam UMC, Vascular Medicine, Amsterdam, The Netherlands.
Background and Aims:
The complex pathophysiology of MASH may require combination therapy, We compared lanifibranor alone and combined with an SGLT2 inhibitor versus placebo.
Method:
The LEGEND trial enrolled 39 patients (33 completers) with MASH and T2D, randomized 1:1:1 to lanifibranor (L), lanifibranor with empagliflozin (L+E) and placebo (P) for a treatment duration of 24 weeks. MASH was diagnosed per historical liver biopsy or MRI imaging (cT1 or cT1+PDFF). Change in HbA1c from baseline (BL) to treatment week (TW) 24 was the primary efficacy endpoint. Circulating biomarkers included liver enzymes, inflammation and fibrosis markers, lipid and glucose metabolism; MRI-based imaging included hepatic steatosis (PDFF), MASH composite disease activity and fibrosis (cT1), visceral (VAT) and subcutaneous (SAT) adipose tissue, spleen and liver volume.
Results:
Both L and L+E improved HbA1c versus P (both p<0.001, FAS); 50% in both active arms reached HbA1c < 6.5% at TW24, with 58% and 80% HbA1c decrease ≥1% for L and L+E versus 0% for P, respectively. Liver tests (ALT, AST, GGT), fibrosis markers (TIMP-1, P3NP, Pro-C3), insulin, HOMA-IR, hs-CRP, ferritin, glycemia, lipid profile (HDL-C, Triglycerides) improved and adiponectin increased 3-fold in both L (p=0.009) and L+E (p=0.004) arms compared to no increase for P. Patients had a mean weight increase of 3.6% with L at TW24, while this remained unchanged with L+E and placebo. The ratio VAT/SA shifted favorably toward SAT for both L and L+E compared to placebo (-18% and -5% vs +2%, respectively). Improvements of hepatic steatosis and composite MASH activity + fibrosis were observed for both L and L+E with mean relative MRI-PDFF changes of -49 and -41% and mean absolute cT1 changes of -82 and -85 ms respectively. Spleen and liver volumes decreased with L and L+E compared to placebo. L and L+E were safe and well tolerated.
Conclusion:
Lanifibranor combined with an SGLT2-inhibitor has comparable beneficial effects on MASH as monotherapy, including a shift towards SAT, without observed weight gain.