Positive Phase 2 Data Shows Benefit of Lanifibranor with Empagliflozin for MASH, T2D

Onno Holleboom, MD, PhD

Credit: Academic Medical Education

Inventiva Pharmaceuticals has announced positive results from an interim analysis of the phase 2, proof-of-concept LEGEND trial evaluating lanifibranor in combination with empagliflozin in patients with metabolic dysfunction-associated steatohepatitis (MASH)/nonalcoholic steatohepatitis (NASH) and poorly controlled type 2 diabetes (T2D).¹

Results showed LEGEND achieved its primary efficacy endpoint by significantly lowering hemoglobin A1c (HbA1c) in both the lanifibranor arm and in the lanifibranor with empagliflozin arm compared to placebo, also achieving statistical significance for multiple markers of liver injury, markers of glucose and lipid metabolism, and hepatic steatosis.¹

“These LEGEND results provide valuable insights on the complementary mechanisms of action of an SGLT2 inhibitor and the panPPAR agonist, lanifibranor. MASH is a multifaceted disease that we believe will benefit from combination therapies in order to properly address the full cardiometabolic spectrum of the disease,” Michelle Lai, MD, PhD, Beth Israel Deaconess Medical Center and co-principal investigator of the trial, said in a press release.¹

A peroxisome proliferator-activated receptor (PPAR) agonist designed to target all three PPAR isoforms, lanifibranor induces antifibrotic, anti-inflammatory and beneficial vascular and metabolic changes. While other PPAR agonists target 1 or 2 PPAR isoforms for activation, lanifibranor is the only panPPAR- agonist in clinical development for the treatment of MASH/NASH and was granted Breakthrough Therapy and Fast Track designation for the treatment of MASH/NASH in 2020.^1,2

Though sodium-glucose cotransporter-2 (SGLT2) inhibitors have been around for more than a decade, dating back to the initial FDA approval of canagliflozin (Invokana) in 2013, their role continues to expand to new patient populations. Empagliflozin (Jardiance) earned approval in 2014 as an adjunct to diet and exercise for improving glycemic control in adults with type 2 diabetes and later earned approvals for reducing cardiovascular death in T2D, heart failure with reduced ejection fraction regardless of diabetes status, heart failure regardless of ejection fraction, and most recently, chronic kidney disease.^3,4

A multicenter, randomized, 24-week treatment, placebo-controlled trial, LEGEND seeks to assess the safety and efficacy of lanifibranor in combination with the SGLT2 inhibitor empagliflozin for the treatment of patients with non-cirrhotic MASH/NASH and T2D. The trial is double-blind for the placebo arm and lanifibranor 800mg daily arm, and open-label for the combination of lanifibranor 800mg daily and empagliflozin 10 mg daily arm.¹

According to the release, as planned per protocol, the interim analysis was done once half of the 63 planned randomized patients with MASH completed the 24-week treatment period or prematurely discontinued treatment.¹

Results showed the study achieved its primary efficacy endpoint with an absolute reduction in HbA1c at week 24 among patients treated with lanifibranor alone or in combination with empagliflozin, experiencing decreases of 1.14% and 1.59%, respectively, versus a 0.26% increase in the placebo arm.¹

Patients treated with lanifibranor and lanifibranor/empagliflozin also experienced statistically significant reductions in hepatic steatosis (-47% and -38% respectively) as measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF), compared to placebo (0%). Additionally, 83% of patients treated with lanifibranor alone and 67% treated in combination with empagliflozin showed a ≥ 30% reduction in hepatic fat, compared to 0% in the placebo arm.¹

Statistically significant effects were also observed for several secondary and exploratory endpoints, alanine aminotransferase, aspartate aminotransferase, and insulin resistance Additionally, markers of liver inflammation and fibrosis were assessed for the first time with lanifibranor and showed a significant effect with lanifibranor alone and in combination with empagliflozin.¹

Patients treated with lanifibranor in combination with empagliflozin maintained a stable weight throughout the 24-week study, addressing the moderate, metabolically healthy weight gain sometimes observed in patients treated with lanifibranor alone. A significant relative reduction in the visceral and subcutaneous adipose tissue ratio was also observed in patients treated with lanifibranor alone (-5%) or in combination with empagliflozin (-17%), compared to an increase of 11% in patients under placebo.¹

“The study was designed as a proof of concept and these results are significant and strengthen confidence in the potential of lanifibranor to address the specific metabolic unbalance in patients with T2D while also addressing steatosis and fibrosis, a hepatic consequence of insulin resistance,” Onno Holleboom, MD, PhD, associate professor at Amsterdam University Medical Center and co-principal investigator of the trial, concluded.¹

References:

1. ^{Inventiva. Inventiva announces positive results from the Phase II, LEGEND, Proof-of-Concept study combining lanifibranor with empagliflozin in patients with MASH/NASH and T2D. Press Releases. March 18, 2024. Accessed March 20, 2024. https://inventivapharma.com/wp-content/uploads/2024/03/Inventiva-PR-Results-LEGEND-EN-03-18-2024.pdf}
2. ^{Inventiva. Inventiva receives FDA Breakthrough Therapy designation for lead drug candidate lanifibranor in NASH. News & Events. October 12, 2020. Accessed March 20, 2024. https://inventivapharma.com/inventiva-receives-fda-breakthrough-therapy-designation-for-lead-drug-candidate-lanifibranor-in-nash/}
3. ^{Campbell P, Iapoce C. 10 Years of SGLT2 Inhibitors: A Decade of Redefining Cardiometabolic Care. HCPLive. March 29, 2023. Accessed March 20, 2024. https://www.hcplive.com/view/10-years-of-sglt2-inhibitors-a-decade-of-redefining-cardiometabolic-care}
4. ^{Campbell P. Empagliflozin (Jardiance) Receives CKD Approval from US FDA. HCPLive. September 22, 2023. Accessed March 20, 2024. https://www.hcplive.com/view/empagliflozin-jardiance-receives-ckd-approval-from-us-fda}