Inventiva ("Inventiva" or the "Company"), a clinical-focused biopharmaceutical company focused on the development of orally administered small molecules for the treatment of steatohepatitis associated with metabolic dysfunction ("MASH") and other diseases with unmet medical need, announced the publication in the peer-reviewed scientific journal Biomedicine & Pharmacotherapy of the results of a preclinical study demonstrating that lanifibranor could reduce portal hypertension.

The study, a funded collaboration with researchers at Ghent University Hospital, evaluated the effect of lanifibranor on portal hypertension (PH), independent of liver condition.

The preclinical study used two distinct mouse models to study portal hypertension by different mechanisms. The first model, portal vein partial ligation ("PPVL"), induced an increase in portal pressure with vascular changes 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 elevated portal pressure. Mice in both mouse models received daily lanifibranor treatments 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 reduction of 28% at 10mg/kg (p = 0.03) and 39% at 30mg/kg (p = 0.001). This improvement in portal pressure is attributed to vascular improvement in the splanchnic compartment, including decreased blood flow in the superior mesenteric artery (p = 0.07), a significant reduction in endothelial cell count (indicative of a reduction in angiogenesis) as well as a statistically significant reduction in vascular wall thickness, which is correlated with a decrease in portal pressure.

In addition, analysis of mesenteric vascular architecture by vascular corrosion molding revealed structural changes in mesenteric vasculature, demonstrating angiogenesis and vascular arborization that were prevented by treatment with lanifibranor.

In the cBDL model, lanifibranor was observed to reduce portal pressure and spleen weight in a dose-dependent manner, with concomitant improvement in fibrosis. In addition, LSECs dysfunction and hepatic angiogenesis, associated with fibrotic PH, have been shown to decrease. These results suggest that lanifibranor has the potential to improve PH through its direct anti-fibrotic effect.

HPT is an important complication of advanced chronic liver disease, including cirrhosis and MASH, and can also develop in the early stages of liver disease associated with metabolic dysfunction ("MASLD"). It is expected that the reduction of portal pressure is more beneficial in patients with advanced fibrosis or cirrhosis and may contribute to the prevention of decompensation events. The pre-clinical study suggests that treatment with lanifibranor improves PH in both fibrotic and non-fibrotic models. These results highlight the potential of lanifibranor to prevent portal hypertension by acting on both intrahepatic impairment such as fibrosis and LSEC dysfunction, as well as extrahepatic impairment such as the expansion of mesenteric vascularization through its anti-angiogenic effects. These results suggest that lanifibranor may represent a potential treatment option for patients with clinically significant portal hypertension.