Inventiva presented final analysis data from the Phase 2 LEGEND trial, evaluating lanifibranor in combination with empagliflozin for patients with metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes (T2D), at The Liver Meeting® of the American Association for the Study of Liver Diseases (AASLD). The study achieved its primary efficacy endpoint by significantly lowering HbA1c levels in both the lanifibranor arm and the combination arm compared to placebo, suggesting a potential treatment strategy for this patient population.
Key Findings from the LEGEND Trial
The LEGEND trial included patients with MASH and T2D, with a Hemoglobin A1c (HbA1c) between 7-10% at screening. The trial was double-blind for lanifibranor and placebo, but open-label for the combination of lanifibranor and empagliflozin. Key results include:
- HbA1c Reduction: 50% of patients achieved HbA1c levels below 6.5% at week 24 with lanifibranor alone or in combination with empagliflozin (p<0.001).
- Significant HbA1c Decrease: 58% of patients on lanifibranor alone and 80% on combination therapy experienced at least a 1% decrease in HbA1c at week 24, compared to 0% in the placebo group.
- Improvement in Hepatic Steatosis: Patients treated with lanifibranor alone and in combination with empagliflozin showed significant improvements in hepatic steatosis, with reductions of -49% and -41%, respectively, measured by MRI-PDFF.
- Fibrosis Reduction: Composite MASH activity and fibrosis, measured with cT1, improved by -86 ms and -75 ms, respectively, in the lanifibranor and combination groups.
- Adiponectin Increase: Adiponectin levels increased by a mean of 3-fold in patients with T2D and MASH treated with lanifibranor (p=0.009) and the combination (p=0.004), compared to no increase in the placebo group.
- Weight Management: While the lanifibranor-only group saw a small weight increase of 3.6%, weight remained stable in the combination therapy group. The ratio of visceral abdominal fat to subcutaneous fat decreased in both lanifibranor groups (-5% and -18% respectively, vs. +2% in placebo), indicating a shift towards metabolically healthier adipose tissue.
- Improved Liver Function: Liver function tests (ALT, AST, GGT) and markers of liver fibrosis (TIMP-1, P3NP, Pro-C3) improved with lanifibranor, alone or in combination with empagliflozin. Other cardiometabolic health markers, such as insulin sensitivity (HOMA-IR), inflammation (hs-CRP), ferritin, glycemia, and lipid levels (HDL-C, triglycerides), also showed improvement in both treatment groups.
Expert Commentary
Dr. Michael Cooreman, Chief Medical Officer of Inventiva, stated, "We believe that the results on the combination of lanifibranor with empagliflozin not only confirm the benefits of lanifibranor as a monotherapy for patients with MASH and type 2 diabetes but also support a treatment paradigm for combination therapy for this patient population."
Dr. Nezam Afdhal, Chief of Gastroenterology, Beth Israel Deaconess Medical Center, Professor of Medicine, Harvard Medical School, added, "The exciting new data from the LEGEND study, which evaluates the combination of lanifibranor and empagliflozin, confirms that lanifibranor has the potential to target the underlying biology of the disease. Additionally, LEGEND should alleviate the concerns about weight gain, as this can be managed with sGLT2 inhibitors or other treatments like GLP-1 agonists, which are treatments of choice for T2D management."
Implications for MASH Treatment
The LEGEND trial suggests that lanifibranor, particularly in combination with empagliflozin, holds promise for addressing both the liver-related and metabolic aspects of MASH and T2D. The combination therapy appears to mitigate weight gain concerns associated with lanifibranor monotherapy while enhancing HbA1c reduction and improving liver health markers.
