Inventiva S.A. (IVA) Earnings Call Transcript & Summary

So I will discuss indeed another aspect of the pathophysiology and also potentially a therapeutic target in MASLD/MASH. Now this brings us back to basic physiology of liver hemodynamics. So when normally, there is a very low vascular resistance inside the liver. So the blood coming from the intestinal system via the portal vein goes through the liver. And there's very little pressure difference between before the liver and after the liver. Because this is a low resistance vascular bed. When you have a chronic liver disease, the vascular resistance can increase and then the portal pressure will also increase, which is, of course, important because this will lead to what we then call portal hypertension, which is a hallmark of advanced chronic liver disease, but can also occur in earlier disease stages. Although it's also important for the rest of what I would like to explain is that when portal hypertension gets severe, there is another contributor to the increase in portal pressure, so not just the reduced vascularity in the liver, so the increased resistance in the liver, but there is also a contribution by splanchnic phase of dilation, which means that there is an increased flow from the heart to the gastrointestinal system and hence an increased inflow of blood in the portal system, which will even further increase portal pressure. Now coming back to the vascular resistance inside the liver. Of course, if you then look at the microscopy, we have the normal architecture of the liver sinusoids, the endothelial cells, they have holes in its fenestrae [indiscernible] so there is an easy exchange between the blood and the space of this surrounding the blood vessels and also exchange with the [ hepatocytes ]. When you have changes here, when you have a so-called capillarisation, which means that the holes in the sinusoidal endothelial will close, and you get the base of membrane here. That is a structural [indiscernible] that is called capillarisation, and it's one of the elements that structurally will increase the vascular resistance inside the liver. On the other hand, we should also take into account the roll of the stellate cells, which are below the endothelial in the space of this in the quietest state that contain a small amount of contractile fibrils. That also allows them to regulate a little bit the vascular tone. So changes in the intrahepatic vascular resistance can be both structural, but also functional. And of course, if you have progressive fibrosis, surrounding those liver sinusoids, you will also have a structural increase of the intrahepatic vascular resistance. Now this is something that we already long time ago hypothesized to be important in the pathophysiology of MASLD and occurring very early in the disease. And indeed, the hypothesis is, and we meanwhile confirmed that already early in disease, you have an increase in the intrahepatic vascular resistance by structural components, which is, amongst others, the narrowing of the sinusoids but I will show you that it's more complicated. And that -- and there is a functional component, there is hyperreactivity to vasoconstrictors constructors and reduced vasodilatory activity. Increased vascular resistance will lead, on the one hand, indeed, to portal hypertension, so already early in disease, which in more severe cases, may also lead to that contributing factor of splanchnic perfusion. And in terms of what happens inside the liver that increased vascular resistance will lead to a decrease in blood supply, hypoxemia hypoxia of the liver tissue, which will then trigger inflammation and other deleterious processes. And as I said, we have a lot of arguments for that preclinical evidence that there is indeed an increase in portal pressure that for different flows, your portal pressure is high. You have here the normal sinusoidal structure. You see here in a model of MASLD that architectural structure is completely disrupted. And we have also, as measured here by direct measurements of tissue oxygen tension, clearly hypoxia of the liver tissue, which can be modulated if you improve the liver blood flow. Now what is important is to know that the 3 PPAR isotypes are very closely involved in the regulation of the vascular biology inside the liver. And as you can see here from this slide, and I will not detail it, but you see that the different isotypes play a role and all the contributors to intrahepatic vascular tone, the sinusoidal cells, the hepatic stellate cells, the macrophages that are surrounding that are also present in that area, but at the inner side of the endothelial [indiscernible] and the hepatocyte. So there's a complex interplay between those different players, adding to that, also the interaction of platelets with the endothelium and the 3 PPAR isotypes are involved in all these different processes in a very complex manner. It also means that there is a potential here of improving that by targeting the PPAR isotypes. Now what has been shown in preclinical data is the following. First of all, what we have seen in the model of MASLD but in an early model of mainly purely steatosis. Again, we can confirm the increase in portal pressure, but it could also show that with lanifibranor, you get a complete normalization of that portal pressure. We also tested it with different isotype mono-agonists. Some of them are partially restore portal pressure, but it's only the [ pan-PPAR ] agonism that you completely distort the portal pressure to normal. And you also see here with some of the functional tests that you clearly need the pan-PPAR agonism to completely normalize the functional component, and there's also an impact on the structural component of these vascular alterations. This is what you see here in terms of the structure. So you see again the completely disruptive structure, if you compare it with the normal structure in case of severe steatosis, not still the hepatitis, yet severe steatosis. And you see with lanifibranor, that there is a net improvement, not complete normalization at this stage, but the net improvement also structurally in the architecture of the liver sinusoids, which is also illustrated by CD34 staining, which is immunohistochemical stain, that illustrates that capillarisation that I explained previously, and you see with lanifibranor that you get an important decrease of the capillarisation, which is induced by the diet. So with the diet early in steatosis, you get already an important capillarisation, again, structural [indiscernible] of the characteristics of the sinusoids, and you restore it with the pan-PPAR agonist lanifibranor which you's do not achieve with the different mono-agonists. Now the previous results were on a model of severe steatosis, not steatohepatitis. We tested it in another model that was a model also of steatohepatitis, so at more advanced disease. But as you can see here, you see the same results, increase in portal pressure, restoration of the normal portal pressure on normal intrahepatic vascular resistance with the pan-PPAR agonist. And also here, you see again that you have the functional restoration with the pan-PPAR agonist. And again, the results are not on the slide, but you do not achieve that with the different mono agonists. Now this was first the model of steatosis, then a model of steatohepatitis. If we then go to a model of cirrhotic portal hypertension, which is in this case, a toxic model. So it's not a MASLD model, there are very few or no good cirrhosis, MASLD cirrhosis model. But here, again, you see that with a pan-PPAR agonist you improve the structure of the endothelium with reappearance of the fenestrae to have a reduction of portal pressure, reduction in intrahepatic vascular resistance, you have less signs of portal hypertension, so less steatosis and also less fibrosis and some other data illustrating that also in a cirrhotic model with the pan-PPAR agonist lanifibranor we have a drastic improvement of the vascular biology both structurally and functionally. And also here, this was not achieved with other compounds. And then finally, coming back to the fact that in severe portal hypertension, you have that contribution of the splanchnic vasodilation, well, in a model, which is ligation of the [indiscernible], which means that you reduce, of course, a pre-hepatic form of severe portal hypertension and without, of course, an intrahepatic component. What you see here is, first of all, of course, that increasing portal pressure. But with the drug you have that a significant decrease of portal pressure, and you have also a reduction in the hyperflow through the splanchnic circulation, which is also illustrated by reduced weight of the spleen. And you also see here in those corrosion costs that with the model you have disruption of the vascular architecture in this case, not on the liver, but of the splanchnic circulation, and you see a net improvement structurally also illustrated by CD34 staining when the animals are treated with lanifibranor. Now these are preclinical data. Do we have clinical data on that? Well, we had done a subsidiary analysis of the biopsies from the Phase II trial of lanifibranor, which has been published, as you know, in the New England Journal of Medicine and what we have observed with the CD34 stain, so again, staining for the capilarisation of the liver sinusoids, what we see is that there is indeed increased capilarisation of the liver sinusoids already in the non-cirrhotic stages of the disease because these patients -- this is an analysis of the baseline biopsies. These were patients that did not have or they did not have cirrhosis. And what we observed was that it was present in relation to the presence of steatohepatitis and not or less pronounced when there was no steatohepatitis. So importantly, also illustrated here, we see it early in disease. I think that is an important conclusion. It's not only in the most advanced stages. And as I said, these were all non-cirrhotic patients. But even in earlier stages, you see it, but the more severe it is in terms of fibrosis and also the more severe it is in terms of information. The 2 components were significantly positive. You see that the capilarisation increases. So it's an early phenomenon and the more severe the disease is, the more pronounced it is. It's hence, a phenomenon that occurs not only in the cirrhotic stage of the disease. What happens then with the effects of lanifibranor in these patients? Well, what we clearly observed was that the patients treated with lanifibranor and had a histological response had a clear decrease in the CD34 stain, meaning that there is improvement in capilarisation, which is also a shown here is the improvement in capilarisation in the very portal and in the [indiscernible] area. So you see that lanifibranor has a positive effect on these operations, structural operations of the liver vasculature, and these are the clinical data that we retrieved from the biopsies from the Phase II trial. Which brings us to this more global concept. What do we need if we treat patients with MASLD, of course, we have in the pathophysiology of the disease, the metabolic drivers of the disease, then the more intrahepatic drivers of steatohepatitis that will cause progressive fibrosis. But once you go more down the road and more to the more severe stages of the disease, you have also the contribution of vascular alterations to disease [indiscernible] early and getting more important once you have a more severe disease. And in terms of targets, of course, you need to tackle the metabolic drivers of the disease. You need to tackle the inflammatory processes, but these become when you have a very advanced disease, they become less relevant because the portal hypertension and vascular alterations become a predominant driver of disease decompensation. So if you want to also have some benefit at these stages, most likely you will need also to tackle those vascular elements. And I think it's important to note that the drug like lanifibranor tackles these metabolic drivers, the inflammatory drivers, but also the vascular biology hence, with the potential to have benefits along the disease spectrum, including the more severe stages of the disease. So this brings me to my conclusions. First of all, I think it's clear that MASLD is associated with vascular changes at all stages of the disease and that these changes in the vascularity are both structural and functional. The 3 PPAR isotypes are closely involved in the regulation of liver vascular biology and with the pan-PPAR targeting a drug like lanifibranor, you see a restoration of those -- the liver vascular biology in animal models, which is clearly superior to the mono-agonist, but we also have clinical data, in this case, mainly based on the capitalization by the CD34 state that this is also clinically relevant and not only in early disease, but also a more advanced disease. I think it's also important to highlight that the [indiscernible] lanifibranor are relevant along the disease spectrum also in the cirrhosis and portal hypertension and non-cirrhotic portal hypertension models and also what we know about the role of vascular mechanisms in general in advanced disease and liver cirrhosis.