Inventiva announced the publication of promising results from its Phase 2b NATIVE clinical trial in the Journal of Hepatology Reports, demonstrating that lanifibranor, a pan-PPAR agonist, can reverse critical vascular changes in patients with metabolic dysfunction-associated steatohepatitis (MASH). The study provides new insights into how the drug targets liver sinusoidal endothelial cells (LSECs), potentially preventing progression to cirrhosis.
Key Clinical Findings from Phase 2b NATIVE Trial
The analysis of liver biopsies from the Phase 2b NATIVE study revealed that LSEC capillarization occurs early in disease progression, even before MASH onset. Patients with MASLD showed higher LSEC capillarization compared to those with normal histology, with further increased capillarization observed in patients with MASH.
The study evaluated LSEC alteration using CD34 staining, which showed higher density in patients with MASLD or MASH compared to patients without MASLD. Importantly, CD34 staining was strongly associated with liver fibrosis and to a lesser extent with inflammation.
Following 24 weeks of lanifibranor treatment, CD34 staining on liver biopsies was reduced in a dose-dependent manner. End-of-treatment biopsies from Phase 2b NATIVE showed improvement in LSEC capillarization in patients with MASH treated with lanifibranor compared to placebo.
Preclinical Models Demonstrate Broader Vascular Benefits
Two preclinical models for MASLD and MASH revealed that vascular modifications appear at early stages of disease development, even before inflammation and fibrosis. The models showed that lanifibranor's effects potentially extend beyond capillarization reversal, normalizing intrahepatic vascular resistance (IHVR) demonstrated by normalization of portal vein pressure and the ex-vivo measured transhepatic pressure gradient.
These effects were superior to those observed with single PPAR agonists, suggesting that as a pan-PPAR agonist, lanifibranor could represent a comprehensive therapeutic approach for MASH, fibrosis regression, and the prevention of progression to cirrhosis.
Clinical Significance of LSEC Dysfunction
LSEC dysfunction is increasingly recognized as a key contributor to the progression of chronic liver diseases. The dysfunction is characterized by loss of fenestrations (defenestration) and by capillarization, which disrupts hepatic microcirculation, leading to impaired substrate exchange, increased intrahepatic vascular resistance, and elevated portal pressure.
This dysfunction also promotes a pro-inflammatory and pro-fibrotic environment, facilitating the progression from early-stage liver disease to more advanced conditions such as fibrosis and cirrhosis. The histological evaluation from the NATIVE Phase 2b trial demonstrated that LSEC capillarization occurs in the very early stage of the disease.
Expert Commentary
Kris V. Kowdley MD, Director of the Liver Institute Northwest, Washington, commented on the significance of these findings: "The liver sinusoidal endothelial cells (LSECs) play a crucial role in the vascular changes seen in liver diseases, including MASH and cirrhosis. Capillarization of these cells appears early, even before the onset of MASH. The results from the Phase 2b NATIVE trial with lanifibranor show a correlation between LSEC capillarization and both the stage of fibrosis and inflammation, along with evidence suggesting that lanifibranor can reduce this capillarization. These findings strengthen our confidence in lanifibranor's potential to help prevent progression to cirrhosis and associated clinical events."
About Lanifibranor
Lanifibranor is an orally available small molecule that acts to induce anti-fibrotic, anti-inflammatory and beneficial vascular and metabolic changes by activating all three peroxisome proliferator-activated receptor (PPAR) isoforms. The drug is designed to target all three PPAR isoforms in a moderately potent manner, with a well-balanced activation of PPARα and PPARδ, and a partial activation of PPARγ.
Lanifibranor is the only pan-PPAR agonist in clinical development for the treatment of MASH. The FDA has granted Breakthrough Therapy and Fast Track designation to lanifibranor for the treatment of MASH. Inventiva is currently evaluating lanifibranor in the NATiV3 pivotal Phase 3 clinical trial for the treatment of adult patients with MASH.
The robust dataset from the NATIVE Phase 2b trial combined with the additional data from preclinical models points to potential benefits of lanifibranor as a pan-PPAR agonist targeting the multiple components of the disease.
