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

Good morning, good afternoon. Thank you for standing by, and welcome to the Inventiva's KOL Webcast Event from EASL 2021. [Operator Instructions]. I must advise that the conference today is being recorded, Tuesday, the 29th of June 2021. I would now like to hand over to your first speaker today, Mr. Frederic Cren, MA/MBA, Chairman and CEO and Co-Founder. Please go ahead.

Thank you, operator, and, and thank you, everybody, for attending. It's always a pleasure to organize this event and for us today, it's a great pleasure to have with us Professor Sven Francque, who is the Chairman of the Department of Gastroenterology and Hepatology of the University Hospital at Antwerp. Him and his team conduct clinical research and his unit is a partner in several research consortia supported by the European Commission. And of course, Sven worked with Professor Abdelmalek from Duke, [indiscernible] of our positive Phase IIb NASH study with lanifibranor. Today, we are also very pleased to have with us Professor Alkhouri who is VP of Academic Affairs, Chief of the Transplant Hepatology and Director of the Fatty Liver Program at the Arizona Liver Health, ALH. And prior to joining ALH, Dr. Alkhouri served as a Director of the Metabolic Center at the Texas Liver Institute. He is a member of the AASLD NASH Special Interest Group and we have asked him to give us an update on the NASH field following what I would qualify as a very intense and pack day at EASL. After his speech, Sven will present new analysis that we conducted on lani to show the effect of lanifibranor on cardiometabolic markers. We already provided data showing how impressive lani efficacy is on histological endpoint. In last week at EASL, Sven presented new data on what else can lani do on cardiovascular disease. As the audience probably knows, more NASH patients are going to die of cardiovascular disease and progressing to cirrhosis. And so having a drug like lani with a positive cardiovascular profile is of great importance. Sven will go through what lani can do on the lipid profile, on the lipoprotein, insulin sensitivity, blood pressure, et cetera, showing what we believe is a very positive cardiometabolic profile, which can be added to this -- to the unprecedented histological profile that we share. Sven will also provide new insights on lani efficacy on F2, F3 patients, which, as you know, is a population of target of our Phase III. And Michael, our CMO, will provide an update on NATIVE 3, our single pivotal Phase III study, whose implementation is going according to plan with the patient enrollment on schedule and planned for Q3. I know that today, we're going to speak about NASH, but I want to take a minute to highlight a very significant event that took place for Inventiva. On April 30 of this year, when AbbVie announced that cedirogant, the ROR gamma we discovered -- that was codiscovered by Inventiva and AbbVie team, achieved clinical proof of concept in patients suffering from psoriasis. But beyond the positive news, we are extremely encouraged to hear and here I quote AbbVie senior management that with cedirogant, AbbVie will be looking for that Humira like efficacy or greater in [indiscernible]. We feel thus far very optimistic about the potential of cedirogant in psoriasis as well as other autoimmune disease. And I remember that we have -- on cedirogant, we're eligible to tiered royalties from mid- to single to low double digits. So with this positive news and with the progress we are making with lani, we're looking forward to seeing our pipeline progress and soon having a Phase III asset and a Phase IIb asset in 2 very promising and commercially attractive indications. So with this short intro, let me now give the floor to Naim, and hear his perspective on how the NASH field is evolving. Naim, the floor is all yours.

Thank you for the kind introduction. It's a real pleasure to be with you today. So my task is to give a brief update on the NASH field. Let's move on to the next slide, Slide 4. So when we talk about an update in NASH, there are 2 main areas that we are interested in, in terms of drug development. The first one is non-invasive test to predict response to treatment. We all know that we have 2 efficacy endpoints that the FDA gave us as a path for accelerated FDA approval and Phase III trials. And these are NASH resolution without worsening of fibrosis, or fibrosis improvement by one stage and no worsening of steatohepatitis. And recently, the FDA said also, you can try to achieve both these endpoints. And I think the idea behind achieving both is to decrease the placebo response rate. But obviously, this will require that you do a biopsy at baseline, a biopsy at the end of treatment, which is not the way to move forward when we take these medications to the general population. So we need NITs to predict response to treatment without a repeat biopsy. So we saw a lot of promising data in the last couple of years. I think we've all heard about reduction and liver fat fraction on MRI-PDFF. And the threshold that's emerging is more than 5% absolute reduction or 30% relative reduction from baseline, and this has been associated with improvement in the NAFLD activity score, NASH resolution. More new data showing that ALT reduction by 17 units from baseline, also predicts histologic response. And now there is emerging data on the use of measuring liver elastography through MR elastography, liver stiffness with the FibroScan machine or what we call corrected T1, which is done through an MRI with the company called Perspectum. And reducing MR elastography by 15% from baseline may predict project improvement, a reduction in corrected T1 by 88 milliseconds or about 20% from baseline might be predictive. And now there's data on reduction in liver stiffness by 20% to 25% from baseline, which may predict histologic response. So I think these are encouraging data, and I really hope that, in the future, in the next 5 years or so, we can move away with designing trials without needing liver biopsies. But at this point, I think liver biopsy is still the main outcome that we need to achieve in Phase III trials to get FDA approval. So this is just a quick update on noninvasive tests. Let's move on to Slide #6, talking about future treatment for NASH. So on Slide #7, we have an overview of the NASH pipeline. And you can see that we have a robust pipeline where we can target actually every step of the drug development and progression from insulin resistance, lipid metabolism with several drugs to lipotoxicity, oxidative stress followed by inflammation and immune activation, hepatocyte injury and then all the way to having antifibrotic drugs. And as I said, we have drugs in each of these categories. And there are several drugs now in Phase III trials that I listed here. This is not a comprehensive list, but these are the most promising drugs including semaglutide, lanifibranor, Resmetirom and obeticholic acid, and I'm going to discuss each of these very briefly. Next slide -- so we'll start with metabolic targets. Next slide, please. The first drug I want to discuss is Resmetirom, which is the drug with Madrigal. This is the most advanced drug we have now in Phase III. And this is a selective thyroid hormone receptor beta agonist that can induce all the positive effects when targeting the thyroid hormone excess without the thyrotoxicity. And We had a Phase IIb trial that was positive, and you see the design for the trial at the bottom of the slide. Let's move on to next slide, Slide #10. So here, we're showing some data from the Phase IIb in terms of fat reduction on MRI-PDFF at 12 week and we have more recent data also looking at later time points in terms of fat reduction. But you can see that with the high dose Resmetirom, there was robust reduction in liver fat on MRI-PDFF. If you actually look at the figure in the middle in terms of achieving that threshold of 30% relative fat reduction from baseline with the high-dose Resmetirom, this was achieved in 75% of patients. And then if you look at NASH resolution in patients that achieved fat reduction, this was achieved in 39% with Resmetirom, and this was higher than the placebo response rate at 6%. Next slide, please. So on Slide 11, you see lanifibranor. This is -- you're going to hear way more about lanifibranor in the following presentations, but this is a pan-PPAR agonist that has a pleiotropic effect. It targets PPAR alpha, delta and gamma. Next slide, please. So here, you see the main results from the Phase IIb trial in terms of achieving the histologic endpoints. So lanifibranor actually met the endpoint for NASH resolution and no worsening of fibrosis, 45% compared to 19% in the placebo arm, and this was significant. In terms of fibrosis improvement by one stage, this was achieved in 42% with lanifibranor high-dose 1,200 milligrams. And then if you look at the resolution of both NASH and the improvement in fibrosis, this was achieved in 31% with lanifibranor. And here, you can see that the placebo response rate was definitely lower than what we see for either endpoint alone. So this is when you raise the bar, you see lower response rate in the placebo arm, but you can see that lanifibranor is able to achieve both endpoints. Next slide, please. So on Slide 13, you see some data on semaglutide. This is the novel GLP-1 agonist. This is the paper that has been published in the New England Journal of Medicine. They had different doses, but let's focus on the high-dose semaglutide, which is 0.4 milligram once daily, and this is equivalent of the dose they selected to move forward with, which is 2.4 milligram once weekly of semaglutide. This was, again, a Phase IIb with histologic data. Next slide. So here you see the NASH resolution and no worsening in liver fibrosis. And if we focus on the high-dose semaglutide in the dark blue, you see that, that endpoint was achieved in almost 59% of patients, and this was significantly higher than placebo. So I think this is one of the highest rates we've seen for NASH resolution, but actually, there was no effect on fibrosis improvement. And as far as we know, semaglutide has -- GLP-1 has no receptors in the liver. So we do believe that these positive effects are mediated through weight loss. Next slide. Slide 15, we're going to discuss one drug related to what we call the gut-liver axis or bile acids, and this will be obeticholic acid. Next slide. Here, you see the design of the REGENERATE trial. This is also a Phase III. We have the interim analysis data at 18 months with histologic endpoint. And if we move on to the next slide, this is where you see the main findings from the REGENERATE study, the interim efficacy data at 18 months. They actually achieved the fibrosis improvement by one stage and no worsening in NASH in 23% with obeticholic acid 25 milligrams daily versus only 12% with placebo, and this was significant. They did not achieve the NASH resolution endpoint. However, obeticholic acid had several issues, including significant pruritus. Pruritus occurred in 50% of patients on OCA 25 milligrams daily. There was worsening in lipid profile, increase in LDL cholesterol and decrease in HDL cholesterol. And as you heard earlier, cardiovascular outcomes are the major drivers of outcomes in the NASH space, so any drug that worsens your lipid profile is going to be problematic. There was a signal also of increased incidence of cholecystitis. And more recently, there are some concerns about hepatotoxicity in patients with cirrhosis. So I think based on the totality of the data, the FDA issued a complete response letter to Intercept, and we have a Phase III trial looking at obeticholic acid in cirrhotics called the REVERSE, and we will have the results at the end of this year. Next slide, please. So on Slide 18, this is something we created recently. I call this the NASH drugs scorecard. This is a way to compare different drugs. And when I developed this, I thought about what are the most important aspects of a drug when you think about all these different NASH drugs. And first is the route of administration. So now we have drugs that are oral, and I think this is the preferred route. And then we have injectables, and we have to take that into account. And then we look at efficacy endpoints, and these can be divided into hepatic efficacy endpoints and we discussed NASH resolution, fibrosis improvement. This is for Phase III and Phase IIb. But for earlier drug development, also PDFF data, ALT and other investigational biomarkers. So these are the hepatic efficacy endpoints and the more you meet the better, but the most important ones are the histologic ones at this point. And then we have metabolic efficacy endpoints and the effects on metabolic syndrome components. You want to look at weight reduction ideally, improvement in dyslipidemia and improvement in insulin resistance. And of course, when you assess weight, it's important to know if it's bad weight gain where you're accumulating more visceral fat versus a relatively benign weight gain, where you're actually moving the fat from the visceral adipose tissue into the peripheral adipose tissue. And then you want to look at adverse events. Obviously, this is a main driver, and we know with the effect of medications like semaglutide in diabetes that many patients cannot tolerate higher doses and many patients have to come off these medications. So you have to keep in mind the adverse event profile. Next slide, please. So in the next few slides, I just want to share with you also some data on combination therapies. This is from a presentation I did last year at the last AASLD meeting, looking at the combination of semaglutide, the GLP-1 agonist, cilofexor, which is an FXR agonist. So similar, but not really similar to obeticholic acid and firsocostat, which is what we call a de novo lipogenesis inhibitor. So we looked at the combination of all these 3 drugs. Next slide, please. So on Slide 20, you see that the study design, this was proof of concept. We did not have a placebo arm, so everyone received semaglutide and we tried to achieve the dose of 2.4 milligram weekly, but we had to dose escalate slowly to mitigate the GI side effects. And then we added the other drugs to semaglutide. So we had semaglutide plus firsocostat, semaglutide with low and high dose cilofexor, and then we had triple combination therapy, semaglutide plus firsocostat plus cilofexor and patients were required to have NASH on biopsy or a clinical diagnosis of fatty liver and some significant fibrosis based on FibroScan. And in the next slide, Slide 22, you see some efficacy data. This is fat reduction on MRI-PDFF. And I just wanted to compare the triple combination therapy of semaglutide, firsocostat, cilofexor to semaglutide monotherapy. Here, we show that more patients in the triple combo achieved more fat reduction on MRI, and the fat reduction happened early as early as 12 weeks, and it was sustained through week 24. In fact, we raised the bar, so we looked at patients that reduced their liver fat by more than 70% relative reduction and this will give them almost 1/3 of patients with the combination arms versus only 7% with semaglutide monotherapy. So I think we have several mechanisms of action, several drugs to choose from, and I do believe that combination therapy is going to play a significant role in the future. Next slide, please. So here, you see what I call the NASH drugs Game of Thrones. We have all these different families. We have the house of FXRs like obeticholic acid, the house of PPARs like lanifibranor, house of GLP-1 agonists, thyroid hormone receptor beta and antifibrotics. And we will see who will emerge as the winners in this Game of Thrones. Next slide, please. So my take-home message is that noninvasive tests are rapidly replacing liver biopsy to determine disease severity and response to treatment. So stay tuned. And [indiscernible] a lot of promising data and results from several clinical trials with several NASH therapeutic agents with also combination therapy. So with this, I want to thank you for your attention, and I will hand it to Professor Sven Francque for the next presentation.

Thank you, Naim. Sven, your -- the floor is yours.

Okay. Thank you. Thank you, Frederic, for the introduction and for the invitation. So my first slide shows you a little bit the complexity of the PPAR field. It was also already in Naim's presentation in another format. But just as a reminder, the field of PPARs, which are nuclear receptors, consists of 3 isotypes in the human body: the alpha, the delta and the gamma. And these isotypes are differentially expressed in the different tissues and play also different roles in several aspects that are very relevant to a nonalcoholic fatty liver disease. They play an important role in metabolism, lipid metabolism as well as glucose metabolism and energy metabolism. So they play a role in steatosis and inflammation, but they also play a role in fibrogenesis. And also very important, both for the liver and for the cardiovascular system, is the impact of the different PPARs on the vasculature, inside the liver but also outside the liver. And what is important for lanifibranor, and you can go to the next slide, is that it has a balanced action, agonistic action on these 3 PPAR isotypes. And that's a unique characteristic of this drug. It's important to highlight, I think, that it's chemically different from other PPAR drugs known so far like the TZDs, like pioglitazone that have already been mentioned or fibrates. The results have been shown by Naim already on fibrosis regression as well as NASH resolution on the population of the NATIVE Phase IIb trial results, which I presented last year at the AASLD, so the American Association of the Study of the Liver Annual Meeting. The drug also has in the Phase II trial, but also in Phase I trial and also in a Phase II trial with diabetic patients, very favorable tolerability profile and safety profile. And also the nonclinical toxicology package has been reviewed by the FDA and is accepted for NDA filing. So the drug has received Breakthrough Therapy and Fast Track designation by the FDA already some time ago. Next slide. What is important in terms of our indication to treat patients with NASH is that we know that patients with NASH, of course, if they have advanced disease, they will, in the end, also have liver complications and they may die from liver-related complications, especially if they are already cirrhotic or nearly cirrhotic. But what you can see from the left side of this graph is that all-cause mortality also already goes up in patients with F2 and F3. And that all-cause mortality is -- just a fraction of that is liver related and the bulk is cardiovascular disease. And we have argument that nonalcoholic fatty liver disease contributes to the development of cardiovascular disease. So that's a very important point. But importantly, mortality already starts to get worse if you have F2 and F3. So it's not just the advanced F3 or F4 patients. Next slide. So I presented at the meeting of EASL last week 2 ancillary studies on the results of the Phase IIb trial. And the first one was really looking into patients with F2 and F3 because for the NATIVE trial, I will remind you that we did not set a criterion, a lower criterion for inclusion in terms of fibrosis. We excluded patients with cirrhosis, but we did not exclude patients with F1. We focused on active disease, very active steatohepatitis. And as you will see, this resulted in a selection of a high proportion of F2, F3 patients, but the analysis that was presented last year, which is the main analysis of the trial was on the whole population, including the F1. Now because F2, F3 is the target population for drug development in Phase III for noncirrhotic NASH, for cirrhotic NASH there is another set of criteria, it's important to look into the results of the Phase IIb trial how the drug performs in this specific subpopulation of F2 and F3 in terms of efficacy, but of course, also in terms of safety. Next slide. So just as a reminder for the design of the trial, it was a paired biopsy trial. Patients were randomized to receive placebo, lanifibranor 800 milligrams once daily or lanifibranor 1,200 milligram once daily for a treatment period of 24 weeks. We included patients with active disease. We based on the SAF activity, which combines lobular inflammation and ballooning. And as I said before, we excluded patients with cirrhosis. Patients were stratified according to the presence of diabetes. You can go to the next slide. So in total, 247 patients were randomized and treated in the trial. And that's the population for the primary analysis that we presented last year and of which also Naim showed a slide with the main results. Now from that overall population randomized into the NATIVE trial, about 2/3, to be precise 188 patients, had F2, F3 fibrosis, and that's the population that we were looking into for this analysis. And as you can see, they were equally distributed over the 3 treatment arms. And also in terms of treatment discontinuation, there were no differences between the 3 arms, which is important, of course, also for the protocol analysis. Next slide. What were the results in terms of the endpoints in histology? On the left-hand side, you see in the upper panel what was defined as the primary endpoint. Primary endpoint was a reduction of 2 points of that SAF activity score. Again, we focused on the inclusion of highly active steatohepatitis and first wanted to study the efficacy of the drug on the activity of the steatohepatitis. As you can see, there is a clear dose-dependent significant benefit of the drug compared to placebo. Now the left bottom slide is one of the key secondary endpoints, which is the classical NASH resolution without worsening of fibrosis. So 1 of the 2 FDA endpoints, as Naim mentioned. And here again, you see that there's a clear dose-dependent and highly significant effect of lanifibranor on the endpoint of NASH resolution. On the right-hand side, the upper panel is the other classical secondary endpoint being fibrosis improvement without worsening of NASH. And again, you see that there is 48% of patients in the high dose of lanifibranor significantly different to placebo. But in placebo, here, you have a high rate of responders too of 30%. And then if we combine that -- also explained by Naim, if we go for the composite endpoint of a patient that needs to achieve NASH resolution and fibrosis regression as a responder, then again, you see, first of all, a clear reduction in the placebo rate and a highly significant benefit dose-dependent of the drug. So in the F2, F3 population, these are the results. Next slide. So the next slide goes back to the analysis we presented last year, and that will be soon published, we hope. The results in the overall population shown by Naim is in light green here. That's 247 patients of the trial. And on -- in the dark green, you see the results that I just showed you on the previous slide, restricted to the patients with F2 and F3. And as you can see, these results are, first of all, quite similar. And second, numerically, the results in the F2, F3 population tends to be even a little bit better than in the overall population. Next slide. If we then look at other markers that can tell you something about the severity of the liver disease, we can look at the liver enzymes. And you see here that both doses of lanifibranor give you already early in treatment after 4 weeks a clear decline in ALT, in AST and in gamma GT, whereas in the placebo group, there is not much that changes. Next slide. If you look at it in another way, namely in normalization of liver test, it's also an important endpoint. We did not select patients based on the liver enzymes. They were selected based on histology. And we know that if you do that, patients with NASH may have normal liver enzymes, and you can see those patients with normal liver enzymes in dark green here. So about 30% of patients baseline already had normal liver enzymes, which is not a surprise. But at the end of treatment -- and you can look at the left upper panel, by the end of the treatment in placebo that rate of patients with normal liver enzymes remained more or less the same. But in the patients treated with lanifibranor, up to 75% of patients achieved normalization of ALT by the end of the treatment, which is another way of showing improvement in liver damage. Next slide. We also looked at markers of inflammation and fibrosis to make the long story short. Here, you see again that there is, compared to placebo, a significant benefit for both arms of the trial on these noninvasive markers of inflammation and fibrosis. Next slide. In terms of safety, the overall safety profile in F2, F3 was virtually the same as in the overall population. Most reported side effects were headache and some gastrointestinal discomfort. If you -- as you can see from the upper part, drug-related serious TEAEs were only reported 1 case here in the placebo arm, which was a case of cardiac insufficiency and so none in the 2 lanifibranor arms. Talking about drugs, as Naim also showed you in one of his last slides with his score, you have to also look at the side effect and some side effects are of particular interest in the field of PPARs. We know that drugs that have a PPAR gamma component in their activity, they make you gain weight or they can make you gain weight. This is also the case for lanifibranor with about 2-kilogram weight gain in the 800-milligram dose and 2.7 in the 1,200 milligram treatment arm. But it's important to emphasize that this weight gain is accompanied by histological improvement, as I said, and also with metabolic improvement, as I will show you later on, and probably reflects, as we have seen with other PPAR gamma -- or drugs with PPAR gamma activity, the shift from visceral adipose tissue to subcutaneous adipose tissue. So what happens is that the adipose tissue improves its function. That's also reflected by biomarker in the blood, which is called adiponectin that goes up. So the adipose tissue is healthier. So it can do what it's supposed to do, namely accumulate calorie reserves. And so the healthy fat, the subcutaneous fat will expand and that's why they gain weight. But it's healthy fat and the deleterious fat, the visceral fat will diminish. Fluid retention can also happen with these drugs and was reported more frequently in the treatment arms than in the placebo arms, but all but one were moderate or mild and could easily be treated. And as said, the one case of cardiac insufficiency that was considered a drug-related serious TEAE was in the placebo arm and none on the lanifibranor arms. Next slide. So as I already said, cardiovascular disease is a very important cause of death in these patients. And we also have arguments that the presence of NAFLD and NASH contributes to that. You can go to the next slide. I here repeat once more, the overall mortality that goes up in F2 and F3, but again, this is one of the reasons why we go for F2, F3 patients also for the treatment in noncirrhotic NASH patients. Next slide. I am on slide 39, which is again the complicated slide about the different actions of the PPAR. But in terms of having an effect on the cardiovascular system, it's important that PPARs play a role in metabolism, in inflammation, but also in the structure of the vasculature inside the liver, but also outside the liver. Next slide. So what we examined in the Phase IIb trial, so in NATIVE, in terms of cardiovascular risk biomarkers are, of course, the lipid profile and not just the triglycerides and the HDL cholesterol and the LDL cholesterol, but also relevant apolipoproteins that are known to play a role in agenesis. We looked at inflammatory markers. We studied glucose metabolism, of course, fasting insulin -- fasting glucose and fasting insulin. And we also looked at blood pressure. Next slide. Just not the details of the overall population that is -- that would be -- take us far too long, but just to remember that about 40% to 45% of patients had type 2 diabetes. And then we can go to the next slide, which is 42. Also, 70% of the patients had the metabolic syndrome. And you can here see the details of that. With arterial hypertension being present, it's the bottom line of the table, arterial hypertension being present in about 60% of the patients. Next slide. So in terms of the effect of lanifibranor, and here, we are talking, again, about the overall population of 247 patients randomized so not restricted to F2, F3 patients. You can see from the left cartoon that HDL cholesterol goes up already at week 4 and even tends to increase a little bit more over time, whereas, in placebo, it remains stable. On the left-hand side, the triglycerides, they clearly go down on lanifibranor. The LDL cholesterol was unchanged. Next slide. This is the table with the apolipoproteins. I cannot show you graphs as I did in the previous slide because these were only measured at baseline and at week 24. But again, you see that with the exception of APO-A1, all the markets clearly improved on both doses of lanifibranor compared to placebo where they are unchanged. Next slide. Of course, diabetes and glucose metabolism is also crucial when you talk about cardiovascular disease. Here, you see that lanifibranor lowers your fasting glucose already from week 4 of treatment. And in terms of insulin, which was only measured baseline at the end of treatment, again, you see a clear drop in fasting insulin on both doses of lanifibranor. So a clear improvement in insulin sensitivity. Next slide. In terms of patients with diabetes, which is also important, I think, is that also in that population, you see a clear improvement of glycemic control, with HbA1c that significantly drops with both doses of lanifibranor compared to placebo. Next slide, also an important one is about the blood pressure, which has been shown to increase with some of the PPAR drugs. Here, we show on the left-hand side that there is no effect of lanifibranor on the systolic blood pressure. But on the diastolic blood pressure, there is an improvement. So there is a significant lowering of the diastolic blood pressure illustrated on the right-hand side, which is also advantageous in this population. So this brings me to the conclusions of the 2 clinical presentations that we had last week at the EASL conference. So next slide. So first of all, in F2 and F3 patients with NASH, we showed, with lanifibranor, significant efficacy on all primary and secondary histological endpoints. What I did not show you is that the efficacy was similar in patients with and without diabetes. I showed you that serum markers of liver injury, inflammation and fibrosis also improved, so that further supports the results that we're seeing in histology. And the safety profile is clearly favorable and comparable to the overall population. We also saw beneficial effects on a broad panel of cardiovascular disease biomarkers, lipid metabolism, insulin resistance, inflammation, blood pressure. So I think all these findings support the Phase III trial, NATIVE III, which Michael will talk later on. And this trial will select only patients with F2 and F3 fibrosis. Next slide. Now Inventiva also had a poster presentation on preclinical work they have been doing on a combination therapy and Naim already talked about the potential of combination therapies. So the lanifibranor with the action on the 3 PPARs is already a kind of a combination therapy in one drug. But here, that tested the combination of lanifibranor with firsocostat. Firsocostat is -- and you can go to the next slide. Firsocostat is an ACC inhibitor, so acetyl-CoA carboxylase inhibitor, which means that it impacts on an enzyme that is key in the synthesis of lipids. So in the new formation of lipids, it's a crucial step, that enzyme, and it's blocked by firsocostat. So it has an impact on de novo lipogenesis, DNL, which is happening in hepatocytes and which is an important mechanism in giving rise to steatosis in patients with NAFLD. Next slide. So what they did was in the rodent model, mice that were treated with a diet that induces NASH for 3 weeks, 1 week on diet alone and then the subsequent 2 weeks were on potential of placebo vehicle in this case and lanifibranor or firsocostat or the combination of both. Next slide. In terms of reduction of liver fat, you can see that there was a clear reduction of liver fat. And the most important reduction was with the combination of both, although lanifibranor also reduced hepatic cholesterol by itself, but the combination of both drugs was more potent in reduction of liver fat. Yes, you can go to the next slide. And also in terms of steatosis and inflammation, you see that both drugs have efficacy, but -- especially in steatosis but also in inflammation, the combination of lanifibranor with the ACC inhibitor improved even more the histological scores. Next slide. And this is also true for fibrosis. On the left-hand side is just the score of fibrosis, which was diminished by combination therapy, but you should be aware of the fact that these animals do not develop so much fibrosis, so they have low-stage fibrosis. On the right-hand side, it's the morphometric analysis. It's the percentage in the sirius red stain. And here, you see that lanifibranor and firsocostat do reduce the amount of fibrosis, but the combination has a stronger signal on the reduction of the amount of fibrosis. Next slide. And this is my last result slide showing also an impact of the individual components and for most of the results, a more potent effect of the combination of growth on markers of inflammation and fibrogenesis supporting the results in histology, which brings me to my last slide about this preclinical work. Again, these were not -- this is not clinical work, it's preclinical work, but the combination of lanifibranor and firsocostat reached greater efficacy than monotherapy on hepatic lipid content and on several issues of the liver histology, which is an example of how 2 compounds with a different mode of action can lead to even further and more pronounced improvement in NASH and fibrosis, and that is indeed, as Naim also showed you, an important concept to study and to implement in clinical trials. I thank you for your attention.

Thank you, Sven. I'll now give the floor to Michael Cooreman, our CMO, who will present an update on the NATIVE III trial.

Thank you, Frederic. Thank you, Sven. The first slide, just an over a few of what I'll cover briefly. I will talk a bit about design, which consists of 2 parts. And it's important to mention that Part 1 is meant to obtain accelerated approval in the United States from FDA and the corresponding approval in Europe and European Union is conditional approval. And then Part 2 is aimed or meant to obtain full approval by the FDA. It also defines FDA criteria. Accelerated approval is obtained based on surrogate endpoint histology and full approval based on outcome improvement. Let's say a few words about the central reading of liver histology. That's obviously a critical part of the evaluation of efficacy of the drug and about where we are now, clinical operations of the study, and as Frederic mentioned during his introduction, we are on track with our preparations to start the study very soon. Next slide. So we plan -- lanifibranor has Breakthrough Therapy designation. We plan on single in agreement with the FDA, randomized, double-blind, placebo-controlled Phase III study in multiple centers, of course, on the long-term efficacy and safety of lanifibranor in adult patients with noncirrhotic NASH, and we focus on those patients who treat -- who need treatment most. Those sort of patients who have NASH activity and fibrosis stages F2 and F3 and Sven spoke about that why these patients are the ones that are in need of pharmacological treatment. Below screening is based on a number of criteria, including liver histology. Part 1 is in 72 weeks treatment, so 1.5 years. The study has 3 arms, placebo and 2 doses of lanifibranor, 800 and 1,200 milligrams one daily and that is based on the results of the NATIVE study, the Phase IIb study. And so the Phase III study will give us further information about the efficacy and safety of both these doses. The biopsy then at week 72, which will be used for the primary efficacy endpoint at that point for accelerated approval based on the improvement of NASH activity, inflammation and injury and fibrosis. And then the Part 2 essentially consists of additional patients, which are recruited as well as the patients who are in Part 1 who will continue treatment. And that part is up to a maximum duration for those who are first enrolled of 7 years, and it's event-driven to clinical outcomes. There will be biopsy to determine the progression to cirrhosis, and of course, to increase the position of that planning. We will -- can apply markers of clinical suspicion, including imaging to define when the patient may have progressed to cirrhosis. Next slide. The study design, it's equally randomized for the 3 arms. We will stratify the patients according to the presence or absence of type 2 diabetes. We know that there are differences in progression rates of NASH between patients who have diabetes and those who don't have over diabetes. And then within the F2, F3 patient population, we'll also stratify for F2 and F3 histologically. Statistical power is 90%, which gives us a high level of stringency for the statistical analysis of the study. And we enrolled patients who are adults, 18 years and older. And for the inclusion criteria, among the several inclusion criteria, we used the histological SAF score, which actually is meant as a diagnostic tool here to identify the patients who are in -- who would require treatment. So there is more of a focus on the SAF score on activity and -- I mean, inflammation and injury. Patients have to have steatosis of 1 or more, activity of more than 3, which is a combination of inflammation and cell injury or ballooning and they have to have fibrosis F2 and F3. And that's part of the inclusion criteria. The endpoints evaluation is based on the CRL histological criteria. The central biopsy review is done by 2 pathologists plus a third one who will be involved in case of discrepancies between the 2 histologists. And that is required for the analysis of Part 1. The next slide. The primary efficacy endpoint for Part 1 is evaluated at 72 weeks. We'll have about 900 patients in that part, which means about 300 in each arm. And the primary endpoint is a composite endpoint of patients having both resolution of NASH and improvement of fibrosis or -- of at least one stage, which corresponds to what Naim mentioned earlier, as it's of relevance for patients with NASH. We have secondary endpoints, key secondary endpoints. We have the endpoint, which correspond to the FDA guidance for noncirrhotic NASH, NASH resolution and no worsening of fibrosis and improvement of fibrosis and no worsening of NASH. And then several additional secondary endpoints, efficacy endpoints, which give more information about the efficacy of the drug, of course, liver tests, the biomarkers of glucose metabolism, which as Sven presented our data from the NATIVE study is very relevant including patients with type 2 diabetes who have an elevated HbA1c, the proportion of patients who will have an HbA1c below 6.5% at week 12 and week 24. The effect on glucose metabolism is, of course, visible relatively early compared to effect on fibrosis. Biomarkers of lipid metabolism, we just spoke about those and adiponectin will be measured and then several questionnaires, which assess quality of life and -- including general quality of life questionnaires, such as SF-36, which are very informative. And then questionnaires, which are more designed for liver-specific -- for liver conditions such as NASH, chronic liver disease questionnaire. Safety endpoints, of course, will be evaluated in the Phase III study. And then we have a number of exploratory endpoints, among which I mentioned the cardiovascular events. The occurrence of MACE, major adverse cardiovascular events, such as myocardial infarction and stroke. And this is, of course, also an endpoint that is evaluated from the safety angle, but we also look at it as an exploratory efficacy endpoint, given the beneficial effect of lanifibranor on all cardiovascular risk factors that we have measured and presented earlier. And then additional biomarkers of disease biology. As I mentioned earlier, Part 1 is meant to obtain accelerated approval by the FDA and conditional approval by the EMA. Next slide. Part 2 is the -- what matters for full approval based on an improvement of patient outcome. And outcome is here measured as the time to first clinical event, clinical event having to do with liver-related clinical events, all-cause -- and all-cause mortality. And with regard to the liver-related clinical events, progression to cirrhosis histologically and manifestations of hepatic decompensation. The first manifestations of hepatic decompensation are hepatic encephalopathy, bleeding from upper gastrointestinal varices and ascites. And then, of course, also worsening of the liver function, which is measured with a MELD score, a composite score, including bilirubin, which is a liver function test. And liver transplantation -- the need for liver transplantation, which may occur in these patients also before they decompensate, for example, when an HCC, hepatocellular cancer, is found. Next slide. Just to mention the central reading of the liver biopsies, not to go into details, but I'd just point out that this is a well-defined and sophisticated procedure in order to make sure that the variability between readers in time is minimalized. And this has also been discussed in detail with the FDA and has been approved by the FDA. So essentially, we have 3 expert pathologists who will divide the work among them, and specifically for Part 2 to -- sorry, for Part 1 to evaluate efficacy we'll make use of these 3 expert pathologists. Next slide. From a clinical operations perspective, this slide gives an overview of the high level of the steps towards headline results for Part 1, which are the basis for an NDA submission. So we are currently almost -- we will have the first site active early July, and have -- to have the first patient -- first visit, first patient and in other words, in the third quarter of 2021. And that's on track with our planning. The ambitions -- but the goals are high, but we have, I think, all our team efforts and motivation in place and operational aspects to meet those. The aim is to have enrollment of Part 1 done in 1 year. So the last patient first visit for Part 1 will be in the second half of 2022. That leads us to the last patient last visit in the first half of 2024, and the headline results in the second half of 2024 with an NDA submission then in 2025. Next slide. We have a partner to -- of course, to run the study and it's PRA Health Services (sic) [ PRA Health Sciences ]. The protocol is finalized. We have -- we target to have a total number of sites of 300, and the feasibility is ongoing. Today, as of mid-June, more than 150 sites are qualified based on this procedure or process that PRA has done. And based on the feasibility information, from those 150 sites, we would be able to enroll actually the required number of patients in Part 1, as planned. So that's a good position to start, I believe. Around 2/3 of the patients, 60% will come from North America, specifically from the United States and from Canada and 1/3 will be enrolled in different European countries. So that's how the patients are divided geographically. Next slide. That was my last slide. So thank you.

Thank you, Michael. Now we can move to the Q&A. Operator, I'll let you take over for questions.

[Operator Instructions] We have first question coming from the line of Zegbeh Jallah from ROTH Capital.

A well-thought-out presentation, was very enlightening. And then regarding my question, I think the first one just has to do with the cardiovascular effects. I don't remember you thinking about looking at MACE initially. So I was just wondering what's driving that now? And then can you just comment on how you're thinking that should help you stay competitive from a commercial perspective.

Thank you for this question. If I understand, you were asking what we expect from MACE with regards to -- could you repeat because there was some resonance on my side?

Sure. So I was just wondering the rationale behind looking at some additional cardiovascular markers because I don't imagine that you had initially said you'll be looking at MACE. And then was just wondering how you're thinking that could competitively position you commercially relative to other folks.

Yes. Thank you. So the rationale is that it has to do -- there are several reasons. And I think the most important ones are that lanifibranor as a pan-PPAR agonist addresses multiple aspects of NASH as well as related -- biologically related metabolic diseases such as atherosclerosis and type 2 diabetes. So by treating NASH, we do have a benefit on other aspects of what defines the prognosis of patients. And I think that sets us also apart from some other compounds in development for NASH. So as Sven also mentioned, and there is a lot of literature on that, patients have a risk of morbidity and mortality related to cardiovascular events. And these processes have to do with metabolism and inflammation, of course. And these are the same underlying processes that drive NASH essentially. So we have shown in our Phase II study, as expected from pan-PPAR agonist, that all these aspects are improving. So that's why we look at MACE not only from a safety aspect, which is important, but also from an efficacy endpoint as an exploratory angle because we do not plan -- or we don't power the study to see a certain effect size that leads to a statistical significant result that would be -- would not be the goal because we do position NASH as a liver drug, and so it will be evaluated or is evaluated by the Liver Division of the FDA. But of course, showing that -- the clinical data show that patients benefit from treatment with lanifibranor not just based on biomarkers for metabolic diseases, such as atherosclerosis, but that there may also be a difference in actually occurrence of MACE is an important scientific medical message that we hope we will achieve. And from a commercial point of view, I think the key advantage of lani remains is capabilities in a short period of time to resolve NASH and at the same time, reduce fibrosis. This is why, as a primary endpoint, with this combined endpoint of NASH resolution and fibrosis, which go to repeat and show again, we can meet in the Phase III and that will be, hopefully, reflected in the labeling and will definitely set us apart compared to the competition, which is only coming after either fibrosis or NASH. And then finally, we should not forget that we have a very positive profile or positive effect on insulin sensitivity. And given roughly 40% of our population with NASH also has type 2 diabetes, it is certainly a unique profile that will benefit from a commercial point of view.

And then the last 1 here for me, it's just that the results are looking really good from NATIVE. And so we're just wondering about the combination that you're thinking about. I mean it does look like you could have increased efficacy with a combo as you've shown here. And so I was just wondering when can we see some additional preclinical data. And are you now really thinking about a combination with firsocostat? And then lastly, if Naim can just comment on some of his thoughts around noninvasive tests for NASH because that was something you mentioned I think a lot of folks are interested in understanding that area is evolving because that could really expand patients getting tested and then treated.

Okay. So I'll let Pierre answer about the noninvasive tests and what we're doing there. On the preclinical work and on combination, yes, we did this work with [indiscernible], I think the results are quite interesting. Talking about combination, I think there are, for lanifibranor, opportunities in terms of combination probably more interesting than the one with the ACC inhibitor. We're ready -- we have received a lot of questions about why don't you combine it with an [indiscernible] or GLP-1. So that could be an opportunity. But clearly, for us, today, the objective is to successfully deliver on the NATIVE 3, and this is really what will drive the value of the company and the value of lani because lani as a monotherapy drug has definitely a high chance to make it to the finish line and a high chance really to address the key features or the key problem of NASH patients, which is NASH resolution and fibrosis. So the noninvasive test, Pierre, what is the latest?

Yes. Sure. Thank you for the question. So relatively to noninvasive test, firstly, imaging cap fibroscan. This is something that we will be communicating at the forthcoming ASLD. We have proposed an abstract there. So we will hopefully be able to present some nice correlation between the efficacy of lanifibranor on statuses lipid through CAP. We have, in the native trial, generated a database of information on more than 80 circulating biomarkers. You have seen some of them published like Pro-C3, for example, or the MAX score of [indiscernible] where we see a consistent improvement of the circulating biomarkers, which is consistent with the mechanism of action of lanifibranor as an anti-inflammatory and anti-fibrotic drug and also consistent with the histological data that we have obtained in native. And this -- with this database, we have actually put in place a collaboration with [ Professor Geron Boursier ]. And we are actually analyzing this database through different covaluative analysis to be able to identify signature related to lanifibranor response. And so this is work ongoing. And hopefully, the data generated could be communicated next year.

We have our next questions coming from the line of Etzer Darout from Guggenheim.

This is Paul on for Etzer. I guess one for the experts on the call. I wanted to get your comments on the risk of sampling variability with histological assessment of NASH. Obviously, a bigger problem for smaller studies than a larger Phase III, but I'm hoping to get your commentary on any current approaches to minimize variability and how that might translate to the central biopsy approach in the Phase III study?

[indiscernible], this is for you about the histology.

Yes. Well, I think that we should be realistic that you have indeed with the liver biopsy, the problem of the sampling variability. But you should not forget that with all the noninvasive tests that we are using, there is also variability, whether it's blood-based biomarkers or liver stiffness or whatsoever. So there is always variability. What is important is, first of all, to try to reduce the placebo rate. And I think there the example is clearly shown that by combining NASH resolution and fibrosis improvement, you clearly reduce the placebo response rate. So that's a first important element. And then second, you need to look at a comprehensive set of markers being it histological markers, imaging markers, broad-based several markers that must make you confident that the results you are looking at is a real result. So it will be important in the future to rely on several lines or levels of evidence of which the biopsy is one and then the noninvasive tests are others, but they all have their limitations, including also the noninvasive tests. When it comes to the way that the biopsies will be read in Phase III, I think that this is a robust way of looking at biopsies that has been agreed upon with the FDA and that makes it more comfortable. We see now a lot of analysis coming from also artificial intelligence on the biopsy. And what you sometimes see is that there seems to be a difference between what they said by artificial intelligence and what they said by the pathologist, but it mainly goes all in the same direction. So if you have pathologists that in batch read biopsies all in the same way, you get quite a robust result. And there might be a difference in interpretation. But if it's read at one time point and it's read always in the same way, the results are quite robust. And that's also something we learned from recent analysis with confronting the results of the read by the pathologist, with the read by our artificial intelligence, showing in the end that in terms of trends or differences, there is quite a robust result if you do it in the right way.

Great. That's really helpful. And then just one follow-up for -- and it's event management. I'm wondering if you could provide us any incremental color on sort of site activations in the Phase III across countries, given the wide range of COVID impacts across the globe right now and what your sort of expectations are there relative to maybe a few months ago with COVID pressure?

Yes. Thank you. That's an important point. I think if I had this question half a year ago, it would have been more of a concern. I think we clearly see that the clinical research sites are almost back to normal now. And certainly in the United States, with the successful vaccination campaigns, clinical research sites or 80% to 100% back to normal. So this crippling effect of COVID-19, which was so devastating for clinical research in 2020 has improved considerably. And looking forward, we are optimistic that what happened last year with clinical research will be part of something we remember from history. So it looks like most sites are -- have everything in place to deal with what is left of COVID-19. I'm pretty much aware -- very well aware that the effects on -- let's say, the impact of public health strategies and vaccination is not equally distributed. But we are planning on where to initiate which sites actually, and that's just coincidentally, but it does correlate, means that the areas where we will be able to start study first or actually these areas, which are actually -- which have done very well with COVID-19 and have very high vaccination rates. So in summary, I think that COVID-19 will not have a measurable impact going forward.

We have our next questions coming from the line of Lucy Codrington from Jefferies.

Just a few there. So firstly, for Professor Sanyal. A notable absence from the list of drugs to watch was [indiscernible], which I appreciate isn't yet in Phase III, so that's why. But I just wonder how you would position that by your kind of NASH scorecard, given the data we've seen to date? You also mentioned that oral was the preferred route. But I wonder how acceptable a twice-daily drug would be for these patients given most are asymptomatic? And is a subcutaneous injection really that much of a disadvantage, given around half of the patients are diabetic, and therefore, maybe used to injecting? And then just on the native data we've seen so far, have you disclosed what the overall effect of lanifibranor on weight in the trial was aside -- I know we know that the cases of weight gain, but what the overall effect was?

So [ Professor Sanyal ], there was a question for you about you would put the GF21 in your math. And then maybe for [indiscernible] or yourself about the subcutaneous if it is a problem in your clinic?

Yes. I mean, obviously, we've seen promising data on FTF21 agonist. They are not all created equal in terms of potency and the downstream signaling. It depends on which receptors you signal to. But I think they do have issues. I think what we've seen with Akero was very limited sample size. The lack of [indiscernible] placebo arm because the biopsies were done in all these patients that responded based on PDFF. The cirrhosis data was also very limited in terms of the sample size and patients in the placebo arm. So you have to take that data with a grain of salt. I think the injection piece is important. I mean we see it with semaglutide, other GLP-1 agonists from injection site reaction to the GI side effects. And of course, they vary a lot between the front compounds. But I do believe that taking an oral medication is definitely the preferred route for patients. And as we mentioned, in a combination therapy, potentially also there is the concept of initially hitting hard with the combination and then transitioning to something that's more tolerated that you can take as a field. So maybe initiate 2 drugs with an injectable and oral medication and then after 1 year or 2 years transition to just an oral drug. So there is also a space for combination here. But again, with the FGF21, you have potent compounds, but you have to look at the data carefully, especially when you're looking at the placebo arm and how the biopsies were conducted.

Excellent. Thanks you. Lucy, can you repeat your question about weight? We could not get your question.

Sure. And thanks to Professor Sanyal for that answer. It's very helpful. The weight piece was just whether you disclosed what the overall kind of effect of lanifibranor was on weight in the native trial? So was it -- aside from the patients that we know there were instant weight gain, but was there any weight you're seen? Or was it weight neutral on an overall basis?

Yes. So as it means, there is a mean increase of 2.4 kilos with low dose, 2.7 kilos with a high dose. This is the mean, of course, but the variability -- I mean, in the population, there were people -- patients losing weight, people neutral and people gaining weight. So it's -- so I guess that is what was your question, right?

Sorry, yes, of course.

We have the next questions coming from the line of Jean-Jacques Le Fur from Bryan Garnier.

Probably for the experts. We're looking at the European draft guidelines, it appears that Europe is asking for co-primary endpoints for a successful trial. And I am a bit surprised to see Madrigal Novo Nordisk except Inventiva, but at least these 2 companies not to conduct a trial with co-primary endpoint. So the question is with the interaction you have with the EMA, do you think these guidelines since their draft may change? Or does that mean that Inventiva is a clear and a very clear advantage in Europe compared to all the competitors and at least the 2 I just mentioned? So how do you see the things evolving there?

Maybe [indiscernible], the European.

Yes. It's, of course, difficult to know how the EMA will evolve in its thinking about it. But it is clear that they are not convinced if you just hit the endpoint of fibrosis regression, but nothing on NASH or the other way around, which can make sense. Anyhow, I think that EMA will probably consider other arguments, but there must be at least a signal on both the steatohepatitis and the fibrosis because they are also intimately linked. So it makes sense, I think. And here, indeed, a compound that has an impact on both, which is also the most convincing, has probably a clear advantage. But it's difficult to know whether EMA will have a different point of view in the future. And if it will be open to other arguments.

We have the next questions coming from the line of Derek Archila.

It's Derek from Stifel. Just a couple of questions for the docs on the line. Maybe talk about [indiscernible] first. You talked a little bit about the noninvasives in a couple of questions ago, walked through some of that. But I guess, for MRE, CT1, LSM, can you just remind us how prevalent these technologies are in clinical practice today versus just in the research setting?

Yes. So I mean, that's a great question. And as I said, liver biopsy might be the way for Phase III trial now and for FDA approval, but it's not what we do in clinical practice. So if you look at patients in a hepatology practice, only 3% to 5% ends up getting a liver biopsy. So we are managing with these noninvasive tests. I think ultrasound-based technologies are probably the most common fiber scan machines, they are expensive, but they are becoming more and more common in the United States. And then we have several other ultrasound-based technologies such as [indiscernible] histography, acoustic radiation for [indiscernible], they all can estimate liver scan accuracy similar to fiber scan. And then in terms of the corrected T1, now in the United States, we have a CPT codes. This is becoming more and more available, it's just a software upgrade to an existing MRI machine. MRE is making also its way to becoming more and more commercially available. But I agree, I mean, it's work in progress, and these are not available in smaller GI practices or for primary care physicians or endocrinologists. But I think ultrasound-based technologies are, at least in the United States, I would say, are available in one form or the other. And I think related to the data, I mean, the data started with the REGENERATE, looking at improvements in liver stiffness on FibroScan. But we also have now a lot of data using the fast core that incorporates [indiscernible] measurements from the fiber scan machine for [indiscernible] and AST and the liver enzyme. And we're seeing also other scores using MRE plus PDFF plus AST. So I think the same way we talked about combination drugs, we're going to see combination biomarkers as well.

Awesome. Great. And then just a question on Atlanta Fibers versus weight gain. So we've talked about this, and we've heard the folks that have Inventiva talked about this in terms of the good and the bad weight gain argument. I guess my question is more around in real clinical practice, if patients are gaining weight or they're seeing weight gain, do you think that will have any impact on adherence to lanifibranor? I can direct that to Dr. [indiscernible] or any of the other KOLs on the line.

So I'll take a shot at this. But I think, obviously, for the patients, I mean, getting weight although it's the good weight gain, it could be impactful for certain patients. We also have to see if -- when we do the Phase III, if there is any differentiation between the United States patients and the European patients if we see more weight gain in the United States. So I think it takes a lot of education by the providers once we hopefully have the medication approved to say that this is not a magical pill and you still need to do the lifestyle modification, you still need to think about what you're going to consume throughout the day and try to minimize the weight gain. And we'll have more granularity also on potentially predictors of which patients are more likely to gain weight. And this also opens the window for combination therapy with drugs that may induce some weight loss. So maybe a combination of semaglutide with lanifibranor where you can augment a signal for fibrosis with semaglutide and mitigate the weight gain with lanifibranor. This is my own speculation, it has nothing to do with Inventiva. But when I think about combination, it's not just efficacy but also mitigating any potential adverse events or unwanted side effects.

Got it. And then maybe last question for Frederic. So just you guys laid out the time lines for the Phase III in terms of, again, enrolling patients, last patient in and hope when we would get data. So I guess, can you just talk us through how you feel kind of the news flow gap or the catalyst gap between now and the readout of the Phase III?

So yes, [indiscernible]. So this is, of course, a relatively long Phase III, and it's a single Phase III. So we do not have second Phase III open label to -- on which we can communicate. But we are lucky to have secured that we only need to do a Phase III. That's a great achievement. And so it's double-blind, randomized. So there will be asset for DSMBs on which we will communicate enrollment, et cetera. There will be no efficacy data coming from that study until the results are published. Catalyst online will come from the study we have ongoing in Type 2 diabetes patients with NAFLD with results that are expected next year, and that will be an important study because it will hopefully confirm the antidiabetic properties of the compound. We have plans, nothing concrete because, as I said, we need first to really get the Phase III of the ground, but there are certainly opportunities to combine lani, Naim mentioned GLP-1, there is also, I mentioned, SGLT2, we established a study with ACC inhibitor. Also that could be additional results. And then finally, there is also, given our mechanism of action, given the antifibrotic properties of the drug and especially given the need in the market, a rationale to develop [indiscernible] for patients, so of course, once the Phase III is out of ground, that could also be other CapEx. And then we should not forget that Inventiva is not only lanifibranor. We have a fantastic opportunity with our partner AbbVie with a compound that will initiate Phase IIb in psoriasis. They have the development of what we know from psoriasis, the development are shorter. So the compound is a result as supportive, could quickly move towards the market, and that certainly provide important catalysts for the company, certainly in a different area like autoimmune disease, but in an area where there is a huge commercial opportunity for [indiscernible]

There are no further questions at this time on the phone lines.

We have actually a question on the -- by internet. There is a question from Lenny of KBC. The first one, I read it, they say that there is a case that the 800-milligram dose consistently perform either as well or better than the 1,200 when looking at the noninvasive biomarker data, yet clinical biopsy data clearly favor the high dose. What can explain this discrepancy? A very good question. Pierre Broqua, do you want to take a stab at?

Yes, sure. Thank you, Lenny, for this question. Well, we were actually very excited to see this data because for us, this is a promise of future antifibrotic activity to be displayed on histological readings on a later stage. So this is also the reason why we are excited with this Phase III and part one of 72 weeks because I think that it will give the best opportunity for the low dose to show a significant improvement of fibrosis in patients with NASH. And this base, as you've noticed already, a significant reduction of fibrosis-related biomarkers after 6 months of treatment with the low dose. So we interpret that by saying that, well, the signal on the [ segregating ] biomarkers is actually preceding the improvement of fibrosis as measured histologically. So yes, we can expect a significant effect of the low dose on improvement in fibrosis in -- when duration is longer than 6 months.

Thank you, Pierre. There was another question by [indiscernible] combinations, but we addressed that. And then there is a last question from [indiscernible], which ask us a question about what is the level of confidence we have in our new [indiscernible] regarding competencies in NASH in patient recruitment, referring to the fact that when we did the Phase IIb, we had some difficulties in achieving? And then there was a question about the COVID, which you already addressed. But maybe you can talk, Michael, about PRA, and why we chose?

Sure. I mean we chose PRA because their experience in conducting NASH clinical trials. And obviously, once [indiscernible] study as ambitious as the one we have, it's a matter of making clear -- setting clear expectations and have not been complacent. So it's one thing to start the study on time, but we also need to end it on time. And I think we have had very constantly and clear communications with everybody involved within Inventiva and with PRA and given PRA's expertise and also their experience and their expertise, I think we are confident, of course, clinical research also has its degrees of predictability, monitoring what's going on in the study on a daily basis part of addressing that. In addition to the part that it's also important to mention, I believe that we do have very good Phase II data, and that brought lanifibranor on the map, if you wish. I speak with cholic hepatologists regularly, and everybody is well aware about the Phase IIb data globally essentially. So that's a leverage we have that we have to use also to our benefit, I believe, in everybody's benefit at the end also in patients benefit. So we can -- we believe we have an advantage. It's always an advantage to have Phase II data when you do clinical research, and the positive data from lanifibranor will help us and are part of PRA. And I think also the many investigators we work with in the staff to help us achieve these goals. But we will certainly, on a daily basis, with the entire team, look at this and make adaptations where necessary.

Second part of the question to see how confident we are, we can achieve good improvement in the first 150 pre-identified targets.

We already have those.

We already have those. That's a tick. And of course, that number is increasing daily. So that was at mid-June. I don't have the figures today, but it's probably above 150. And of course, the objective is to reach the 300 side. And then the last question was about would the Phase II trial in combination with an ACC inhibitor would make sense, just given the preclinical data we have published, it certainly makes sense? Now as we said, there are also other mechanism of action. Naim mentioned GLP-1. That would also make sense in combination with lani. I think these were all the questions we have, and we are approaching the end of the session, I would, first of all, I would like to thank [ Professor Cury ] and Professor Frank because without our daily support and help, we would not be here on the verge of initiating a Phase III, and it's great to be -- to have the support of, I would say, an increasing KOL network, and we feel very honored and very lucky of the supported [indiscernible]. And then, of course, like to thank all of you for attending and for following us. I think we really are on the verge of a very exciting period for Inventiva with the drug lani, which really has the potential to make it to the finish line. So thank you very much for attending, and we look forward to seeing you soon at the next event or SSD conference. Thank you, and have a great day.

Ladies and gentlemen, that does conclude our conference for today. Thank you for participating. You may now disconnect your lines. Thank you.