The study, a grant-supported collaboration with Ghent University Hospital researchers, evaluated the effect of lanifibranor on PH independently of hepatic condition.
The preclinical study utilized two distinct mouse models to investigate portal hypertension through different mechanisms. The first model, Partial Portal Vein Ligation (“PPVL”), induced an increase in portal pressure with vascular modifications in the splanchnic compartment, without affecting the liver itself. The second model, common Bile Duct Ligation (“cBDL”), resulted in liver fibrosis and cirrhosis, leading to an elevation in portal pressure. Mice in the PPVL and cBDL models received daily treatments of lanifibranor for 7 days and 14 days, respectively, at two doses (10 and 30 mg/kg) to assess the effect of lanifibranor on PH, as measured by portal pressure.
In the PPVL model, lanifibranor was observed to reduce portal pressure in a dose-dependent manner and with a statistically significant effect, with a decrease of 28% at 10mg/kg (p=0.03) and 39% at 30mg/kg (p=0.001). This improvement of PH is attributed to the vascular amelioration within the splanchnic compartment, including a reduced blood flow in the superior mesenteric artery (p=0.07), a significant decrease in endothelial cells staining (indicative of reduced angiogenesis), and a statistically significant reduction in vascular wall thickness, which correlates with the decrease in portal pressure.
Furthermore, analysis of the mesenteric vascular architecture through vascular corrosion casting revealed structural modifications in the mesenteric vasculature demonstrating angiogenesis and vascular arborization that were reversed following treatment with lanifibranor.
In the cBDL model, lanifibranor was observed to reduce, in a dose-dependent manner, portal pressure and spleen weight with a concurrent improvement of fibrosis. In addition, LSEC dysfunction and hepatic angiogenesis, as associated with fibrotic PH, were shown to decrease. These results suggest that lanifibranor has the potential to ameliorate PH through its direct antifibrotic effect.
PH is a significant complication of advanced chronic liver disease, including cirrhosis and MASH, and can also develop in the earlier stages of Metabolic dysfunction Associated Liver Disease (“MASLD”). It is expected that a reduction of portal pressure would be most beneficial in patients with advanced fibrosis or patients with cirrhosis and could contribute to the prevention of decompensation events. The preclinical study suggests that lanifibranor treatment improves PH in both fibrotic and non-fibrotic models. These results underscore the potential of lanifibranor to prevent PH by addressing both intra-hepatic conditions such as fibrosis and LSEC dysfunction but also extra-hepatic condition such as mesenteric vasculature expansion through its anti-angiogenetic effects. These findings suggest that lanifibranor may hold potential as a therapeutic option for patients with clinically significant PH.
Prof. Sven Francque, M.D., Ph.D., Antwerp University Hospital, said: “The study’s results highlight the potential of lanifibranor in addressing the challenging issue of portal hypertension, which is a major driver of decompensation in advanced chronic liver disease such as MASH, but also occurs early in MASLD. The interrelationship between portal hypertension and clinical complications in liver disease is critical but we have few therapeutic options. A treatment protocol addressing portal hypertension may pave a way to better address the complex multimodalities leading to the development of MASH, of fibrosis and of advanced chronic liver disease. We thank our colleagues from Ghent University Hospital for their participation, support and expertise in leading this important study.”
Publication details
| Publication title: | “The pan-PPAR agonist lanifibranor reduces portal pressure independent of fibrosis reduction through the splanchnic vasculature.”
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| Authors:
| Anneleen Heldens, Christophe Casteleyn, Louis Onghena, Milton Antwi, Sara Neyt, Benedicte Descamps, Christian Vanhove, Xavier Verhelst, Sarah Raevens, Hans Van Vlierberghe, Lindsey Devisscher, Ruth De Bruyne, Jean-Louis Junien, Guillaume Wettstein, Anja Geerts, Sander Lefere. |
| Online version: | doi: 10.1016/j.biopha.2025.117826. Online ahead of print. PMID: 39805191. |
About lanifibranor
Lanifibranor, Inventiva’s lead product candidate, is an orally-available small molecule that acts to induce anti-fibrotic, anti-inflammatory and beneficial vascular and metabolic changes in the body by activating all three peroxisome proliferator-activated receptor (“PPAR”) isoforms, which are well-characterized nuclear receptor proteins that regulate gene expression. Lanifibranor is a PPAR agonist that 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. While there are other PPAR agonists that target only one or two PPAR isoforms for activation, lanifibranor is the only pan-PPAR agonist in clinical development for the treatment of MASH. Inventiva believes that lanifibranor’s moderate and balanced pan-PPAR binding profile contributes to the favorable tolerability profile that has been observed in clinical trials and preclinical studies to date. The FDA has granted Breakthrough Therapy and Fast Track designation to lanifibranor for the treatment of MASH.
About Inventiva
Inventiva is a clinical-stage biopharmaceutical company focused on the research and development of oral small molecule therapies for the treatment of patients with MASH and other diseases with significant unmet medical need. The Company is currently evaluating lanifibranor, a novel pan-PPAR agonist, in the NATiV3 pivotal Phase 3 clinical trial for the treatment of adult patients with MASH, a common and progressive chronic liver disease.
The Company has a scientific team of approximately 90 people with deep expertise in the fields of biology, medicinal and computational chemistry, pharmacokinetics and pharmacology, and clinical development. It owns an extensive library of approximately 240,000 pharmacologically relevant molecules, approximately 60% of which are proprietary, as well as a wholly-owned research and development facility.
Inventiva is a public company listed on compartment B of the regulated market of Euronext Paris (ticker: IVA, ISIN: FR0013233012) and on the Nasdaq Global Market in the United States (ticker: IVA). http://www.inventivapharma.com
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