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

Hi, everybody. Thank you for attending this webcast following last week EASL, pretty busy agenda, and I have to fit with a great pleasure to be back on a physical meeting. We have a great pleasure today and I really thank them because we have a great attendance. We have Professor Francque. We have Steve Harrison with us, and then we have Onno Holleboom also participating to what I think will be very interesting chat. And then on Inventiva side, of course, as usual, I'll be sharing the presentation in the Q&A with Pierre, the CFO and Co-Founder; and Michael, our CMO. Busy agenda. I'll give a very short update on how things are going at Inventiva then we'll pick up from there to give you an update on our Phase III NATIVE III trial. Then Steve will give us an update on the NASH field following EASL that would be a great, great session. Before we move to Michael, who will give an overview of the new data we presented at EASL. And we'll finish with our combo study, Onno will provide an update on this exciting trial. So let's move on the corporate base. I'll kind of skip the left box because all this will be covered extensively during this session. Maybe just highlight that we have been working for several years on initiative that's called the pan-NASH initiative. Throughout the time, the years have been enriched with very interesting scientific content, publication, papers, videos, really suggested you spent some time to review that because it's really interesting about the latest work that we've done on the NASH. Although that I'd like to speak about the collaboration with AbbVie. We're really excited by the progress of this compound. AbbVie has been communicated on the promising activity that's seen in the Phase I study. We have a look at that data. We have shared it with us, and we understand why they are excited. And we're really looking forward to this data being published. Otherwise, confirming the Phase IIb, which is currently ongoing, the data is expected or the trial is expected to finish in March, the 55 sites. So albeit large number of sites enrolled in the trial. Last time I checked, more than 40, I think 44, we're recruiting in Japan, in the U.S., in Canada, so a trial that is really moving ahead, and so data next year. And so certainly, we'll be looking at that important milestone for the company. Finally, what can we say about the cash position? So we have runway through Q1 '23. And this, I would like to stress is without including the recent EUR 50 million loan that we secured from the European Investment Bank, which has strengthened our position. So the last position in cash of EUR 80 million without the EUR 50 million from the European Investment Bank. So that was really my very short introduction, and I'll give the floor to them. Before moving into NATIVE III, just a highlight, we will focus today on planning and development. And there are 3 important trials. All of them are really I think important in the development of [ Lani ], of course, the pivotal Phase III. But also, we should not forget the study that is currently ongoing and that we expect to read out at the end of the year the study conducted by Professor [indiscernible] in patients with and type II diabetes. And then, of course, the combination trial, Lani plus [indiscernible], that we were today by. With that, I give the floor to Francque for an overview of the NATIVE III trial. Thank you.

Thank you, Frederic. So first of all, of course, the Phase III trial is based on the work that is done in the Phase IIb trial. So the NATIVE Phase IIb trial was a 24 weeks randomized double-blind placebo-controlled trial in adult patients with NASH and about 250 patients were randomized, and we selected patients with severe hepatitis and moderate to severe inflammation and liver cell damage. So the more active part of the spectrum of NASH trials and we excluded patients with cirrhosis. Now what is important as a conclusion from the Phase II trial that is meanwhile published in the New England Journal of Medicine is that lanifibranor met both the endpoints of resolution of NASH and no worsening of fibrosis and the improvement of fibrosis by at least 1 stage and no worsening of NASH. So lanifibranor is the first candidate molecule in Phase IIb to achieve statistically significant results on these both endpoints, which are important end points, as you know, in non-cirrhotic Phase III trials, both for the FDA and the EMA. And also, this important is that it also hit the endpoint of resolution of NASH and improvement of fibrosis so are present in the same patients. What we also reported then was that the efficacy on histology was supported by, amongst others, a statistically significant decrease in liver enzymes. There's also a significant and beneficial change in the lipid profile with an increase in HDL-cholesterol and a decrease in triglycerides on the LDL-cholesterol, the drug was neutral. And in patients with NASH and type 2 diabetes, which was a substantial proportion of the patients in the Phase IIb trial, we also demonstrated statistically significant reductions of fasting glucose and HbA1c and also fasting insulin. And that's with the continued favorable safety profile. So that was the top results of the Phase IIb trial. Now what is also important is that, of course, meanwhile, we did additional analysis on this very rich data set. And what we could additionally show was that lanifibranor's effect on the logical endpoints that I discussed in the previous slide were in the F2, F3 population, which consisted about 70% to 75% of the total study population, we're even numerically hiring those F2, F3 patients, and these are the patients, of course, that we need to recruit in the Phase III registrational trial for noncirrhotic NASH. Also, we could show that there were beneficial effects on cardiovascular risk biomarkers. And I just mentioned that in diabetic patients, you have an improvement in glycemic control, but that's also true in the prediabetic patients. Also important is to note that the improvement in the cardiometabolic health parameters are independent of rate change. So that's an important additional feature. We showed the results on histology, but there were also results in terms of noninvasive markers other than those that I already mentioned. And especially for the steatosis, there was an additional communication that this was also confirmed by the CAP measurement on the final scan. Also important is that NASH resolution responders were significantly more likely to be also improves in terms of fibrosis, which is what you would expect because we know that steatohepatitis and fibrogenesis are intimately linked. And as I said also on the previous slide, lanifibranor hit also the endpoint of NASH improvement and fibrosis improvement in the same patients. And finally, there was an analysis done on the Liver Sinusoidal Endothelial Cell in the process of capillarization, which is an important process in the transition towards more advanced fibrosis and especially once you get to the stage of cirrhosis. And also here in the noncirrhotic stage, we saw already abnormalities, and we saw a beneficial impact of lanifibranor on these abnormalities which is important also when we think about potential of these drugs -- of these drugs in the treatment of patient with cirrhosis although what I mentioned here are results in the patient of Phase IIb trial. So -- patients without liver cirrhosis. No coming to the Phase III trial and this is a little bit a slide with a lot of information but the design of the Phase III trial is a classical Phase III trial or design in the NASH space and it's what we are doing in Phase III since the first Phase III trial started by Intercept many years ago the REGENERATE trial. So the design is basically the same as for the other compounds in Phase III. So there is a first period of treatment in this case for 72 weeks. There's a qualifying baseline biopsy and then there is after this first period of treatment, also, a second biopsy to have histological of to assess a histological response and that should then be the basis for the accelerated approval in the U.S. or the conditional approval in the EU. And then, of course, the trial continues for capturing clinical benefit on the long run to get full approval in the U.S. and in the EU. So that's the overall picture. So a few more details perhaps and then we can go from left side of the slide to the right side for all the information that is mentioned here. But I am 1 of the 2 principal investigators of this trial. I'm happy to do this with Professor Arun Sanyal from Virginia Commonwealth. The main inclusion criteria are based on, first of all, what is required by the regulatory authorities and also what we have learned from our Phase IIb trial. So of course, it's patients with have F2, F3 in terms of fibrosis staging. And in terms of NASH, it's, of course, NASH with sufficient activity and we use a SAF scoring system so an activity of 3 or 4 according to the SAF scoring system to define the level of activity that is required for inclusion in the trial. There's a 1:1:1 randomization across placebo and the 2 doses. So the 800-milligram and the 1,200 milligram once daily doses and there will be a stratification for 2 factors for the diabetes, the presence or absence of diabetes, and for F2 and F3. And we also want, of course, that it is a global trial. So there is a world partition over the U.S. and the rest of the world, as you will also see in a subsequent slide. But it's also important in terms of the reading of the biopsies by the pathologists. So there is a central biopsy read, of course. And it will be done by 2 pathologists. And if they do not come to an agreement, there is a third pathologist to involve in case of discrepancies. And this is something that has been agreed upon with the regulatory authorities as a way to go to optimize the interpretation of the histological endpoints. So as I said previously, it's a classical design for a Phase III trial as we have been doing over the past years in NASH F2, F3 patients. The interim analysis in this case after 72 weeks of treatment looking for histological endpoints, as a primary endpoint, the composite endpoint of patients that have both NASH resolution and fibrosis improvement of at least one stage. And the key secondary endpoints are then the individual endpoint, so the NASH resolution without worsening of fibrosis and the fibrosis improvement without worsening of NASH. And then there are some other secondary endpoints that are highly relevant, of course, in this population. It's the glycemic parameters that will be checked after 12 and 24 weeks in patients with type 2 diabetes control. And in that population or in that group of patients, we will look for the proportion of patients with an HbA1c that has normalized. Another secondary endpoint is the composite endpoint of diabetic patients having both resolution of NASH and fibrosis improvement on the primary endpoint but restricted to patients with diabetes. We will look at the improvement in renal function and the reduction of cardiovascular risk and in the quality of life. So that's the list of main secondary endpoints. And as I said treatment period, 72 weeks. And then after 72 weeks if we have about 900 patients recruited in that cohort, then we should be able to analyze the results and go if the results are confirmative of what we have seen in the Phase IIb trial to go for eligibility for the accelerated and conditional approval. And then, of course, the trial will go on in the current design to capture clinical endpoints which are listed here. So the histological progression to cirrhosis, all-cause mortality, hepatic decompensation events and increase in MELD score to 15 or above, or liver transplants or the classical end point of all-cause mortality and liver-related events that then will be captured, of course, in the whole cohort that needs to recruit about 2,000 patients. So for the interim analysis, it will be done on the first 900 patients or circa 900 patients that have their liver biopsy done at 72 weeks of treatment. But for the total trial or for the full approval currently we need to enroll a total of 2,000 patients. So the trial is meanwhile, as you will see, is up and running. To achieve that number of patients included, of course, we need many sites to participate. And as I have said, it's meant to be a global trial. So there are sites in Europe, North America, South America, South Africa and in Australia. So in total, 24 countries are included in the trial, 23 have already full regulatory approval. I think everybody will understand that, of course, because of the war that have some decisions being taken. So the activities in Ukraine, they have been paused, although there were 10 sites qualified there and 3 sites were already screening patients apparently that is something that is currently put on hold. And also the trial was supposed also to run in Russia in 12 sites, but that has been decided by Inventiva to cancel that participation. So we end up with about 398 sites qualified and currently more than 200 sites have been activated in 2022. So ICON is the main global partner for this trial. But in the United States, there is also collaboration with Summit Clinical Research and with AES for additional recruitment networks. This is a time line, at least for the Part 1 of the trial. So as I said, the trial is already up and running and started in Q3 of last year with the activation of the first clinical sites and started screening. And as I said, it's a global trial, and we expect about 60% of the patients to be recruited in the U.S. and Canada, and 35% expected to be recruited in Europe. We expect to recruit for the first cohort, the first on average, 900 patients to have the last patient in the trial in the first half of 2023, which means with the treatment period of 72 weeks that we will have in the second half of 2024, the last patient, last visit and then of course, it's the data-based analysis. So top line results are expected in the first half of 2025. And with this, I think I have given you the most updated information on the Phase III trial, and I'm happy to pass it over to my friend, Stephen Harrison to give you an overview on the NASH field.

Thank you very much, Sven. And also Frederic for the initial introductory comments and for this exciting trial in the Phase III. So my task is to take you through an update of the NASH field and having just come out of the European liver meeting in London, very exciting, lots of data presented. And it is -- let me just say this, it's an exciting time to be in the field of NASH. We've had our ups and downs. I think we've learned a lot from those situations. We've learned what it really takes to move the needle in the setting of NASH. We're learning how best to diagnose those patients at risk for disease progression. We're learning more about what predicts an outcome. And we're learning how to target specific modes of action to really get after the underlying pathogenesis of this disease. Furthermore, one of the areas of NASH that we're learning more about is the extrahepatic manifestations of this disease. It's not just about the liver. These patients are obese [indiscernible] and they have diabetes or prediabetic. And so modulating glycemic control, getting after lipotoxic lipids helping atherogenic lipid profiles, all those are critically important as we look at the patient holistically. So with that in mind, let's take a bit of a dive and a walk through where we are. So I think it's important to understand, at least in the U.S. what the FDA's current thinking is. And here, you see a recent publication in May of 2021, highlighting the division of hepatology and nutrition at the FDA and kind of their thoughts on where we are with NASH. And I just pulled out 4 topics that I think are worth mentioning. So the Division of Hepatology and Nutrition at the FDA used NASH with liver fibrosis as a serious and life-threatening condition. And I think this is a critical statement and 1 that shows their real approach to this, how serious they are about helping to find a cure for this disease or at least an approved therapy. Patients with NASH are also vulnerable to other diseases. I mentioned this already in my lead statement, the investigational drugs should not worsen other comorbidities, such as cardiovascular disease, hyperlipidemia, metabolic disease and diabetes, but in fact, should try to help improve those. The accelerated approval pathway for drugs intended to treat NASH for liver fibrosis is appropriate because of the seriousness of the condition. And I think that, again, speaks to the fact that they want to look at these drugs from a data-driven perspective and continue to apply this accelerated approval pathway. This conditional subpart H approvable endpoint that we'll talk about in a minute. And then finally, Phase III studies demonstrating a successful treatment difference on liver histology surrogate endpoints and an adequate safety profile can receive accelerated approval with a requirement to verify and confirm the clinical benefit after approval. And as Professor Francque mentioned, this is exactly what we're trying to do with the NATIVE III trial. I think it's also important to realize that the therapeutic index of any drug is critically important to having a drug approved. What is a therapeutic index? Well, a therapeutic index involves safety and tolerability as well as efficacy and putting those 2 together provides us an idea of the therapeutic index and what is likely to be approved. So just looking again at this accelerated approval pathway. Here you see the first arrow illustrating the Phase III randomized placebo-controlled trial. Now after -- in this particular case, with NATIVE III, 72 weeks, patients will undergo a second liver biopsy. And if the primary endpoint is met, and there is a perceived safe and tolerable aspect of the drug then that's where the drug could have met a surrogate endpoint and potentially could get subpart H approval or conditional approval. Now you still have to continue to enroll patients and follow them in a Phase IV controlled portion of the trial because that's where we actually get the clinical benefit verification. So remember, the FDA approves claims, not drugs. We want to see that this drug changes the way a patient feels, functions or survives. So just to summarize again, the first part of the registration trial involves roughly 900 patients that undergo paired liver biopsy histopathologic assessment. If the primary end point is met and the drug is deemed to be safe and tolerated, then subpart H approval could potentially be given. But an additional 1,100 patients or so to a total of around 2,000 would subsequently be enrolled and followed again out to an outcome measure over time. Now that's the current thinking. And I want to mention here, just keeping with state of the art on this slide an alternative approach for NASH drug development. So what this shows is 2 parallel Phase III trials. Trial 1 is a composite clinical outcome event study where you have a Phase III randomized, double-blind, placebo-controlled trial for compensated cirrhotic patients due to NASH. And you're going to just follow those people over time. Trial 2 is a classic Phase III randomized double-blind placebo-controlled trial for F2 and F3 NASH patients, where a surrogate endpoint using histology is applied. Subsequently, the advantage of this is there's no need for a Phase IV confirmatory study when conducting the Phase III histology study for NASH with fibrosis. So I think this is potentially the way of the future. In fact, if you look at Madrigal and Resmetirom, this is exactly the route that they are going with announcing the soon to start enrolling MAESTRO Outcomes trial, which is essentially trial of 1 year. So that will allow for subsequent full approval with after a submission of a market application and then full market approval for NASH with fibrosis, including compensated cirrhosis. So I think this is a novel change that will be very helpful as we look to find additional therapies for NASH. Now currently, our available treatment options are all about lifestyle modification, diet and exercise. And the problem with this is while we know it works, particularly patients can achieve 10% body weight reduction or more. Unfortunately, the majority of patients are unable to lose that particular amount of weight and maintain that weight loss. Current pharmacologic therapy is really limited to a few therapies that we've kind of repurposed for use. So pioglitazone is one a PPAR-gamma agonist and then vitamin E. But both of those have their own limitations. So there is a high unmet medical need. And so when we begin to look at the requirements for a NASH treatment, Standard requirements include the current histopathologic endpoints for subpart H approval as outlined by the regulatory authorities, and those include resolution of NASH without worsening of fibrosis or regression of fibrosis by at least 1 stage without worsening of NASH or resolution of NASH and regression of fibrosis. Ideally, additional requirements for treatment would also include therapies that improve markers of cardiometabolic health. So when we begin to look at the therapeutic landscape for NASH, we have several different opportunities to target underlying pathogenetic principles. And so when we look here at a healthy liver, migrating to a steatotic liver, steatohepatitis, subsequent fibrosis and cirrhosis. What is important to understand is ideally, we want to target therapies that hit way up in the pathway. So they're very proximal because if we target pathways that are very distal often the liver has redundant mechanisms to supersede those blocked pathways. So what we've learned from the lessons of prior drug failures, is let's get after the drivers of NASH, the drivers of fibrosis. Let's tackle insulin resistance, gluconeogenesis, de novo lipogenesis, oxidative stress, which all lead to upregulation of pro-inflammatory mediators that drive stellate cell activation. And so you see that the majority of therapies being developed today are targeting very proximal they're working on this insulin resistance. They're working on de novo lipogenesis and modulating oxidative stress and subsequent inflammation. It doesn't mean that you can't have specific markers that target liver fibrosis or that target immune cell activation or microbiome or even genetic influences for the disease. However, what we've learned from our recent history is that we also want to target something upstream. We want to get after lipotoxic fat for sure. And also, we want to target oxidative stress and inflammatory cascades. Having that as a backdrop. Let's look at the competitive landscape. So currently, as already highlighted, there is no FDA or EMA-approved therapy. However, there are over 90 Phase II and Phase III industry-sponsored studies currently active. When we look at this bull's-eye target registrational drugs, drugs that have already been submitted to the FDA. In other words, a new drug application, we see on drug, obeticholic acid. Now that was based on a Phase III trial called the REGENERATE study, where there was a treatment effect delta of 11% on fibrosis when compared to placebo. The new drug application was submitted and unfortunately, it did not get approved. And we'll talk more about that in a moment. When we look at the second concentric ring or the first ring around the center, we see there are currently 4 ongoing trials. These are highlighted by the green dot. You see lanifibranor here, as already mentioned by Professor Francque with the NATIVE III trial. Additionally, there are trials with Resmetirom, which is MGL-3196 and we heard 1 of the Phase III trials at EASL last week and also semaglutide which is a GLP-1 receptor agonist that's in Phase III and then also a Aramchol, but it is currently on hold. That's an SCD1. There are multiple other drugs in the last contract we say Phase II that involves Phase IIa, which is usually an early study looking at noninvasive assessment for proof-of-concept on efficacy, mainly focused on safety and tolerability. And then Phase Ib is the phase is the phase of the study where you do paired liver biopsies and you get additional data on efficacy and dosing that can help inform the Phase III. Okay. Moving forward, I want to talk about a few of the trials, particularly those that are in Phase III. The first is the FXR agonist, obeticholic acid that I've already alluded to. And I want to dive into the Phase III clinical trial a bit more. So here, this is the traditional Phase III trial that I alluded to earlier, where you enroll a significant number of patients, you follow them in this particular case for 18 months, so around 930 patients were followed for 18 months, randomized in a 1:1:1 randomization scheme to low-dose Oca 10 milligrams or a high-dose Oca 25 milligrams or placebo given once daily. This is oral therapy. After 18 months, a repeat liver biopsy was performed. And what we found was that Oca or Obeticholic acid achieved the primary endpoint of fibrosis improvement of at least 1 stage without worsening of NASH. And this is illustrated in the graph below on the left, where you see placebo response of 12% treatment response with the high dose of 23%, giving you a treatment effect delta of 11%, and there was no benefit when we looked at NASH resolution. Unfortunately, pruritus was in about 50% of the patients in the high-dose Oca arm and there was an increase in LDL-cholesterol and a decrease in high density lipoprotein. Furthermore, there were some concerns around cholecystitis. As a result, this drug was not approved when the new drug application was submitted. Let's move to the thyroid hormone receptor beta agonist class of drug and specifically Resmetirom. I had the opportunity to present 1 of the Phase III trials at EASL this past week. So what is THR-beta? Well, what we know is that pyrite hormone is secreted in a pro hormone on state or inactive state by the thyroid gland. We call that T4. It's taken up by the liver and converted through DIO1 to T3 to T3, which is the active hormone. In humans, thyroid hormone receptor beta agonism has been shown to lower cholesterol, lower triglycerides, improved liver fat content, reduced lipotoxicity and improve NASH. As a result, you see here on the right, reductions in proton density fat fraction that were relatively robust and particularly at the 80-milligram dose around 50% relative liver fat reduction. When we look at NASH resolution, there was significant improvement relative to placebo, but not significant for fibrosis. However, when applying AI digital pathology in a post hoc manner, we find in the bottom right-hand corner that particularly when looking at F3 patients compared to placebo we were able to pick up a significant almost significant reduction in fibrosis. When you look at all patients together, 32% versus 12%. As a result of this, patients were -- 2 Phase III trials were launched. There was the registration trial called the MAESTRO-NASH trial, which is a 1-year trial the standard requirements to get in. You have to have NASH with NAFLD activity score of 4 more with F2 or F3 fibrosis. Treatment is for 1 year. There are 2 doses, 80 milligram, 100-milligram and placebo, randomization is 1:1:1. That trial is scheduled to read out in Q4 of this year. In parallel, there was the MAESTRO-NAFLD 1 trial that enrolled over 1,200 patients. Treatment was 80 milligrams once daily or 100 milligrams once daily or placebo in a double-blind randomized fashion, there was also a 100-milligram open-label arm. The results of that 1-year trial were read out last week, and it showed that the drug's primary endpoint was hit, which was safety and tolerability. In addition, there were key secondary endpoints to include atherogenic lipids and MRI liver fat content that were also significantly improved and those endpoints were met. Moving on, I want to mention the GLP-1 receptor agonist semaglutide. And that trial is -- this drug is actually in Phase III as well. How did we get to the Phase III trial? Well, this is the Phase II trial design in 320 patients with F1 to F3 fibrosis. Patients were randomized to 3 different doses of drug or placebo and treatment duration was for 72 weeks. When we look to the first graph on the right, we see resolution of NASH with no worsening of liver fibrosis, which was the primary endpoint, and there was a statistically significant difference compared to placebo of 59% versus 17%. And -- when looking in the B illustration here, improvement in liver fibrosis stage with no worsening of NASH. This was not significant relative to placebo. We see 43%, 32% and 49% for drug looking at the 3 different doses, placebo 33%. However, based on the NASH resolution and the primary endpoint being met the drug has moved forward into Phase III. What was mentioned in a late-breaker abstract by Professor Rohit Loomba was additional data in 70 patients who were treated with semaglutide and who had underlying well-compensated F4 fibrosis due to NASH. Unfortunately, the primary endpoint of fibrosis improvement with at least 1 page was not met despite the drug being safe and well tolerated in this population of patients. So let's shift gears to lanifibranor. So you've heard a lot about this exciting compound already. But this drug modulates 3 different PPARs. So PPAR alpha, PPAR delta and PPAR gamma. And the combination of these 3 PPAR isoforms addresses the key features of NASH. As you can see below, there are positive impacts on metabolism, steatosis inflammation and ballooning, fibrosis and vasculature. So by providing this balanced pan-PPAR agonist activity, we feel like that there is impacts that are significant in patients with NASH, both on NASH resolution as well as fibrosis improvement. So this is a small molecule, as I've already mentioned, that activates all 3 PPAR isotypes in humans. It's not a fibrate, it's not a TZD. It has a different chemical structure as illustrated on the right. It's given once a day, and as I've already mentioned, from the Phase IIb trial published in New England Journal of Medicine after only 24 weeks of therapy, there were beneficial effects on NASH resolution and fibrosis regression. As a result of this therapy, has been designated as breakthrough therapy and Fast Track designation in NASH, as granted by the FDA. Importantly, it is a favorable tolerability profile. Phase I trials with more than 200 healthy volunteers and the Phase IIa trial with 47 type 2 diabetic patients have been enrolled and found to be and has shown no major concerns, and from the Phase IIb trial, an additional 250 patients were treated. The FDA confirmation that nonclinical toxicology package is complete and acceptable for NDA filing is also very important. So when we begin to dive in to the results Phase IIb trial, I want to highlight what's in the dotted red rose, and that is resolution of NASH and no worsening of fibrosis, where you see relative to placebo, a dose response relationship, 19% for placebo 33% for the 800-milligram dose and 45% for the 1,200 milligram dose, significant whether you look at intent-to-treat or per protocol. When looking at improvement of fibrosis by at least 1 stage and no worsening of NASH. You see 24% for placebo, 42% for the high dose, which was significant. And when we look at per protocol, 29% versus 46% for the high dose, again, significant. Putting this in perspective, it's important to note that these are not head-to-head trials. So it's hard to compare apples to oranges. But just for the sake of what the landscape is looking like, I think this slide gives us some very good helpful information. So first, across the top, we see different drugs in development from lanifibranor on the left, the semaglutide on the right, and you see Intercepts, Ocaliva, Madrigal's Resmetirom, Glamed's Aramchol, and Akero's efruxifermin in between. It is important to note that the last 2 efruxifermin and semaglutide are injectables. When we look first at NASH resolution with no worsening of fibrosis, you can see lanifibranor highlighting again, 45% versus 19%, which was significant. We also found Resmetirom to be significant at 24% versus 7%, and semaglutide 59% versus 17%. When we look at fibrosis improvement with no worsening of NASH, we see, again, the significant improvement of fibrosis within Inventiva, lanifibranor, 42% versus 24%, and this is where we see the 11% treatment effect delta for obeticholic acid 23% versus 12%. So let me stop there. and turn over the podium to Michael Cooreman, the Chief Medical Officer of Inventiva, who will take you through a review of the lanifibranor EASL 2022 abstracts.

Thank you, Stephen, and I hope everyone can hear me. We had a couple of abstracts at EASL, which were all based on analysis of the Phase II data, the Phase II study NATIVE and were aimed to basically continue to build the scientific study about the efficacy of lanifibranor has been on pan-PPAR agonist on the metabolic immune aspects of NASH in addition to the condensing efficacy data on liver histology that were published in New England Journal of Medicine earlier. So the first abstract is about the effect of lanifibranor in relation to the weight gain that you can see in some patients and the fact that the markets of cardiometabolic health in those patients improve independent of any changes in rates that you can see. The design of study NATIVE is meanwhile familiar to the audience, I believe. So we have 6 months of treatment, and there were patients that are enrolled according to activity and fibrosis stages F0 to F3. And we had from 217 patients, 144 lanifibranor and [indiscernible] on placebo, patients who had [indiscernible] data both at baseline and at the end of treatment. And in the lanifibranor arms, you see a rate increase on average of 2.4 and 2.7 kilograms for both those, respectively, for 800 and 1,200 milligrams that has been well known and described as a key part of . Now we have divided the patients in 3 groups according to the percentage rate change. And you see on the right side of the table, that about a little bit more than half of the patients had stable way defined as a change of less than 2.5%. And 21% or 16% of the patients had a moderate increase between 2.5% and 5%. And 1/3 of the patients had an increase of an increase in rate of more than 5%. There are also some patients in the placebo arms that had a moderate increase of weight, and that's the analysis is relevant for the evaluation as well. The effect of rate or a change in rate or a modest rate increase that is described with PPAR agonist is not new, as I mentioned, it's a PPAR hormone effect, and therefore, it's well described for PPAR [indiscernible] results. And in summary, it has been shown as evidenced and anticipate increase results from an improvement or a maturation, if you wish of subcutaneous adipose tissue, which is insulin sensitive, so this metabolically healthy and positive and leads to storage of intricate in subcutaneous tissue. And the insulin resistance, and it was to see mostly domino and hepatic decreases and that was nicely shown in this recent study that was published a few years ago. Last year actually, where basically what matters here is the red bars and the green bars in this study, patients who were in pioglitazone arm who had some weight increase were here pictures in the red bars. And those patients who did not have pioglitazone but had to weight increase as a result from poor diet or in the green bars. And on the bottom, you can see that the relative change in visceral fat is a clear decrease from pioglitazone, whereas for the patients who failed diet there is an increase in visceral fat and same is true for liver fat. And those are, in fact, the fat localization that are associated with in insulin resistance and with a healthy metabolic profile. Just going to the data for -- from the lanifibranor study. We see on the left that with lanifibranor in all those all those with both those levels but also in our patients who have weight increase or not that Adiponectin goes up. And Adiponectin is very important, Adiponectin that relates to maturation of subcutaneous metabolically healthy adipose tissue. And you do not see below that, that effect with placebo. Now on the right, on the left side of the right tables, you see the effect of lanifibranor on a number of markers that reflect cardiometabolic health, specifically here in this slide, the [ CAP ], which is a quantification of hepatic steatosis, insulin resistance below that ALT transaminase levels and diastolic blood pressure. And the message here is what's above the figures show is that for patients who have no way change or a moderate rate increase of 5% or more, the -- all these markets improved to the same degree. So all these patients improve metabolically independent on whether or not they have a change in rate. In contrast, on the right side, I mentioned we had some patients who are in the placebo had a moderate increase in weight. So the red bars that you see that the marks of metabolic health then cut insulin resistance transaminases and blood pressure go up in these patients. So this takes the story that the lanifibranor, the rates -- the modest rate came to change is very different with regard to the patient's health from the weight gain that is seen in patients who have a metabolize in this case, the placebo group. The same applies for all other markets of cardiometabolic health that we measured in this study. So it includes the [ triglycerides ] HDL cholesterol, the apolipoproteins, fasting glucose and also has relevant CRP, which is an important cardiovascular health market and liver tests. So across the board for our cardiometabolic markers. So in conclusion, the data showed that lanifibranor addresses the metabolic immune aspects of NASH relating to the nonhepatic manifestations of the disease, as was explained also earlier. And that happens or that of course actually independent of a great change that you may see. These effects occur not unexpectedly in parallel with an effect on adiponectin, which improves which marks to mark for improved insulin sensitivity and so reduced insulin resistance. And again, this shows that the rating that has been described with deeper hormone effect is distinct in fundamental ways from the way it came that results from a healthy lifestyle. The second abstract looked at the effect of lanifibranor on the FAST score, the fast score and age correlation with the histological endpoint NASH resolution and improvement of fibrosis. The FAST score, we had here a total of 112 patients who had F2, F3. And for whom we had FAST score available at baseline and [ NEOT ] . FAST score is an algorithm that combines the 2 quantitative measures that you can do with FibroScan, the elastography and other hepatic fat mainly, sorry, a fibrosis and control the novation parameter, which is a quantitative market for steatosis for Fed and then the marker of hepatic injury inflammation AST levels. And the FAST scores gives a number between 0 and 1 that reflects the risk that the patient has active natural significant fibrosis and that's why it's used and usable for as a noninvasive test to get in here about the likelihood of a patient that -- who does have active disease and fibrosis. And the risk is defined as high of values over the 0.65 intermediate 0.35 to 0.65 and low below 0.35. Here, you can see that the FAST score declines nicely at the end of treatment compared to baseline in both lanifibranor treatment arms with a much lower effect on the placebo group. And if you look at which component of the FAST score is responsible for that, it is mainly the AST component and the steatosis component, which corresponds to what we see also in our biomarker analysis and reflects most likely the effect that effects on fibrosis, lag behind and taking into consideration that this endpoint was looked at after 6 months, which is a short time of fibrosis. This fits in the biology of the disease. Importantly, on the right side, treatment with lanifibranor led to a substantially high proportion of patients, in this case, 67% for both lanifibranor group, who actually moved from -- move to a low risk profile based on FAST scores. So in other words, a low risk of having NASH activity and fibrosis. So in other words, becoming substantially healthier. And the correlation between the change in the FAST score and NASH resolution and improvement of fibrosis and in biomarkers in treated patients is shown on this slide. Essentially, the FAST score response is more pronounced in the patients who have histological response defined as NASH resolution and fibrosis improvement. As you can see, the trend in lines on the slide. But for those patients who are on active drug and don't defined as responders histologically, you also see a substantial improvement of the FAST score. And as you remember from the previous slide, since the effect is mainly driven by the effect on steatosis and transaminase is actually also support that the effect on the more upstream events of the disease or promoted those patients who were not yet to reach in histological improvement for response. So in conclusion, the treatment of patients with NASH and fibrosis in stages 2 and 3 with lanifibranor for 6 months leads to a significant reduction of the FAST score in contrast to patients on placebo, the decreased correlated improvement in liver histology and biologic biomarker responses and clearly, this data support the histological data but also the potential use of the FAST score as a noninvasive test to monitor disease provision and response to treatment. And the last slide is a statistical analysis, which I will mention briefly that aims to identify markers that predict histological response with patients with non-silo treated with lanifibranor in other words, the target population of NATIVE. The study design, patients with were receiving lanifibranor were pooled here and also with end-of-treatment liver biopsies were selected so that we could have the correlation with histology. We had a total of 70 biomarkers that were evaluated that's related to [indiscernible] able information, tissue injury and fibrosis. And we evaluated the changes absolute and relative changes. And then a number of sequential statistical steps were done to narrow down the correlation of these biomarkers and the change that off with histological response. And that was done identifying a number of end points, of which 2, I mentioned here. One, the endpoint on is NASH resolution and fibrosis improvement. So the highest bar if you vision endpoint to NASH resolution and no worsening of fibrosis. For predictive marker of E1, which is NASH improvement and improvement of fibrosis from all the biomarkers tested, the pipeline for signature development began following the full of multiple statistical stringencies, identified 4 independent predictors for this response that were combined in the score, and they are baseline adiponectin, baseline Ferritin a relative change of MMP-9 at end of treatment and the relative change of transferring of EMT at end of treatment. And to make the study short when you look at a negative predictive threshold -- value threshold of 80% and a positive predictive value threshold. You can actually do a conclusion that this -- during these biomarkers is pretty predictive of histological response leaving only 20% of the patients in so-called base on. So it's a pretty good start for defining a noninvasive test for the endpoint E2, which is improvement of NASH and no worsening of fibrosis. The value that we keep out here using a similar sequential approach of [indiscernible] urgency or baseline CK-18, the absolute change of [indiscernible] acids at the end of treatment, the relative change of [indiscernible] that end of treatment and the other range of ALT at end of treatment. It's not a surprise that here you find more of or we come to a very low percentage of patients that are -- remain in the gray zone. So in conclusion, these exploratory assessment, highly statistically built. It's aimed to combine biomarker signatures that was allow noninvasive identification of histological response and the lanifibranor treatment in the patient population that we studied, and of course, such an approach needs to be further defined and validated in future studies, including [ N 83 ]. And with that, I will just briefly try to move the slide concludes that this is essentially a piece of information to be taken together, specifically the slides on the weight change and the FAST score that further provide information effect and support the data that lanifibranor is not only efficacious in improving liver histology in patients with NASH. But in addition to that addresses all the cardiometabolic risk factors that relate to cardiovascular risk type 2 diabetes in this 6-month treatment. And of course, that positions lanifibranor quite nicely as a drug that addresses the broader biology of NASH, and we will confirm these data in the larger Phase III study. With that, I will move on pass on to Dr. Onno Holleboom, who will talk about the legend study.

Thank you, Dr. Cooreman for that fantastic presentation and also passing the presentation to me. Let's see if we can get the slide here. Okay. So I will talk about the LEGEND trial, which is lanifibranor combined with SGLT2 inhibition in patients with NASH and type 2 diabetes. This is a Phase IIa trials, small trial, but very interesting, I think because there is common ground, a large portion of patients with type 2 diabetes and NASH and display typical features of the metabolic syndrome. You can think of NASH as diabetic component of the metabolic syndrome. And this includes, of course, something that we see in our clinics very often, abdominal obesity, dyslipidemia, hypertension, yes, you can bring them back to the route cause actually of insulin resistance. Type 2 diabetes is very prevalent. It's way more prevalent than type 1, of course, and indeed with our more obese and aging population, even in the global trend, this affects millions of people. And there is indeed also from histological cohorts in the work of [indiscernible] pretty good evidence that there's a strong concurrence, cooccurrence of NASH in patients with type 2 diabetes up to 37.3% and in some series, even higher. And that root cause really, we think, to be insulin resistance in adiposity or obesity your peripheral adverse tissue becomes insulin resistance, just shuts down basically and becomes inflamed and that leads to a large prepay acid flux towards the liver, which from stability studies, we know is a major contributor to NASH actually. And also in the hyperintense angiogenesis novice genesis is upregulated, so you get multiple [ visceral ] cycles, actually. And that's not just pathophysiology. We observed that in the clinic in our multi [indiscernible] NASH clinic and then those across the globe as well. So therapeutic compounds that address the upstream metabolic and immune mediated pathways of NASH may actually also be beneficial for type 2 diabetes and vice versa. And that's what's on trial now, of course, with several compounds. And indeed, it was also anticipated as we see in our current practice for many other elements of the metabolic syndrome such as type 2 diabetes and dyslipidemia and also hypertension. Combination therapy might be the way forward, especially if you want to hit both NASH and also address type 2 diabetes, preferably, of course, via complementary mechanisms of action. Sorry, moving to the next -- so here, you see the 2 compounds evolved in the LEGEND trial, which is lanifibranor, which has been elegantly and detailed -- elegantly detailed by previous speakers. And PPAR agonist. And on the right hand, you see empagliflozine, the SGLT2 inhibitor involved, which reduces proximal tubular reabsorption, sodium and also glucose, that's why it's approved for diabetes actually, it gives glucose secretion thereby better glycemic control, but also actually weight loss up to 2 kilos on average because you get calorie wasting actually. And the sodium excretion and also glucose secretion also trigger volume depletion to a certain degree, which is probably responsible for the fact that it's also beneficial for cardiovascular endpoints we have been shown for 3 SGLT2 inhibitors consecutively actually that it can -- that reduces heart failure and also indeed, cardiovascular events and also death. So a really powerful drug in the cardiometabolic arena that is moving up in many guidelines now across the board in the lines of treatment. Slide, next. So the rationale for doing the LEGEND trial is to actually utilize drug combinations targeting multiple aspects of the metabolic syndrome, indeed having the potential to address clinical outcomes in both type 2 diabetes and NASH and maybe even for both conditions. NASH is a complex path physiology, targeting multiple mechanisms. And with this combination, there is the potential for additive effects. And has been detailed by Dr. Cooreman in the previous talk, indeed, there's supportive data that lanifibranor via upregulation of a [ dip and nectin ] actually gives redistribution towards a more healthy metabolic healthy fat profile. And indeed, combining lanifibranor with SGLT2 inhibition may help to mitigate the lanifibranor-related and body weight increase, which was modest in the NATIVE trial, also up to 2 kilos about that. So evaluating this combination, we can study the potential additive effects on metabolic and also noninvasive [indiscernible] parameters because this will be a noninvasive non-biopsy study, which is also the way forward, I think, so that makes it very, very novel, innovative what will be addressed is liver steatosis inflammation and fibrosis by never multiscan, so MRI-PDFF, T2-star and also CET1, and the primary endpoint will actually be HbA1C as a gold standard for glycemic control, but that has also actually been shown to predict severity of ballooned hepatocytes and hepatic fibrosis, important elements of NASH disease activity. So here's the design of the LEGEND trial. I and the principal investigator together with Michelle Lai from Beth Israel Deaconess Medical Center and hepatologist there. What we'll look for are actually adult patients with type 2 diabetes. It can be on insulin, can be on GLP-1 recaps. Of course, not on any TZD or pioglitazone, which makes sense in this case. And there has to be either histologically proven NASH or characterization via MRI with CET1 with a value above 875 milliseconds or higher indeed. It's a double-blind comparison of lanifibranor versus placebo, which will allow for controlled assessment of body composition changes, also by MRI, and there's also an open-label arm of lanifibranor, empagliflozine, which will allow for proof-of-concept data to be developed on the use of this combination. It's a 24-week trial with a 4-week screening period and a 4-week follow-up period, 6 visits. And need noninvasive, so not a biopsy at the end and at the beginning and at the end, which will greatly aid recruitment, I anticipate. The primary outcome measure is HbA1c change and the secondary outcome measures, there's MRI-based imaging techniques for liver, but also for whole body, and indeed, we'll also look at glycemic and lipid parameters and inflammatory markers and changes in body fat composition. In addition, there's other outcome measures for safety and also exploratory which are, of course, adverse events, body weight, there's a [ PAPPK ] design involved and indeed, the intrahepatic triglyceride content CET1 and noninvasive fibrosis biomarkers for NASH. So to summarize, lanifibranor and empagliflozine are, I think, you need a promising combination to study in patients with NASH and type 2 diabetes, which firmly co-occur, and this will develop an important proof-of-concept data on combination looking at metabolic function because lanifibranor addresses disease pathways across the spectrum, as we've seen from previous speakers, from lipid and glucose metabolism to fibrosis, infecting stellate cells, whilst empagliflozine upstream on metabolic pathways, which may work synergistically with lanifibranor. And as endpoint HbA1c, in addition to being the gold standard biomarker for glycemic control is also related to the severity, as we've seen for balloon hepatocytes and hepatic fibrosis. When it comes to looking at body composition based on the mechanism of action and available data for pioglitazone, so purely PPAR-gamma agonist in combination with several SGLT2 inhibitors, indeed, it seems likely that we'll observe a weight reducing effect with empagliflozine, which may balance out the weight gain observed to lanifibranor. And due to the support that lanifibranor in uses our data that support -- to support the lanifibranor uses a fat redistribution, which favors subcutaneous fat that is more metabolically healthy through upregulation of adiponectin and reduction of insulin resistance. And lastly, looking at liver parameters, we'll look at an impact of combination of noninvasive markers for NASH and fibrosis and indeed also liver multiscan has managed and of course, also the safety profile of this combination. A final slide looks at the description of this Phase IIa study. It will run in 5 countries, 4 in Europe and the United States balancing out between Europe and the U.S., the number of patients included getting to a total site of a -- number of sites of 30. It's actually already started in the U.S., and we're going to start in Europe pretty soon. and top line results are expected mid next year, so in 2023. And with that, I'd like to give the word back actually to Dr. Cren.

Thank you very much. I'll be extremely brief. My conclusion so that we can move to the Q&A session whether the possibility and the operator will explain how to ask or a question, and then we already have quite a long list of questions in the Q&A that you can ask by written. Just 2 slides. This 1 effectively interesting. I will not go through the details, but really it's actually the chart that Professor Harrison presented. And when you look has all the data that we have been publishing since the results of the Phase IIb. We now have data that really show that we're active on all the key parameters that are requested by regulatory authorities, of course, the histology endpoint, but also we published data scatter fibrosis. So really now we're comforted and really excited by everything we have seen with [indiscernible] both on the histology markers, but also, of course, on the liver enzyme. The glucose metabolic with markers. We have done a deep dive on the profile and the effect of any of the patients beside type 2 diabetes. And also what Michael presented on the cardiovascular with smarter in the overall population, but also this is a that we presented at of the patient that gained weight when treated with that. Last slide before we move to the Q&A session, it's really what are the key endpoints or events that you should expect from us. They are all listed here. We just like to point out 4 clinical readouts that we are expected, 3 on [indiscernible] with starting this year with the result of the study conducted with Professor [indiscernible] patients with type 2 diabetes and [indiscernible] that will be followed by the clinical data from [indiscernible], maybe the publication of the fifth way, but certainly next year, the result of the Phase Ib that is currently ongoing in patients psoriasis. We will add next year the result of the patient also study combining lending with impacting floating, and of course, we're looking forward to the result, which we need to potentially conditional approval and accelerated approval in Europe and in the U.S. So with that, I will move to the Q&A, and maybe the operator can explain how to ask the question orally, and then we will move to the question that has been asked [indiscernible].

So let's move to the questions that have been asked in the Q&A. So there was a first question coming from Lucy from Jefferies. Please remind us about the decision to up of 72 weeks treatment given competitors pursuing shorter study in just 24 weeks? No, sorry, the competitor pursuing shorter trial and the fact that we showed efficacy in just 24 weeks in the Phase IIb, given trial costs and recent delays, would you consider for regulator to shorten to 52 weeks? Very good question. Maybe, Pierre, you want to take this one?

Sure. So well, initially, there are 2 options on the table. As mentioned by Professor Stephen Harrison, by his key benefit to risk evaluation and rich safety margin. So you need a certain amount of what we call safety population. So either you achieve this -- the numbers expected by 1 Phase III trial lasting 72 weeks. So the other option and that is the option that has been chosen, for example, by lanifibranor, by semaglutide, and by us or you have the other option, which is to pursue several trials of 52 weeks, and this is the option that has been pursued by Madrigal with resmetirom. So to your point about approaching regulators. So of course, we have, as you know, breakthrough therapy designation. So we have, I'd say, an open dialogue with FDA and is seeing we want to discuss with FDA relatively to the design of the Phase III trial is something that we can absolutely do.

Thank you, Pierre. Then we have a question from Lisa from Evercore. I assume that [indiscernible] professor I already said that relates to my data to his presentation for semaglutide has a great effect on ALT greater than resmetirom. What do you see this means in terms of benefit on NASH and fibrosis?

I was there. Yes. So Lisa thanks for the question. So I think it's important to realize that all of these measures of therapeutic efficacy are still needing to be validated. -- whether it's change in ALT PDFF reduction, change in more or less elastography, change in ELF, Pro-C3 or FibroScan or any other test. One of the lectures I gave at EASL was actually directed at everything that we have assessed on the noninvasive front, looking at the context of use of measuring therapeutic efficacy. And when we look at ALT, we have Rohit Loomba's paper on the FLINT trial, showing a 17 unit per liter reduction consistent with improvement in underlying histopathology. But we need to have that number validated in other studies and in other mechanisms of action. So I'd be cautious in looking at a specific number and then applying a correction factor for however, greater than that number, you see drugs hitting a mark. Because I mean I'm not -- I have no -- I have no data to support that if you lower ALT by 30 units per liter, but that's better than 17. I would challenge it a little bit and say I'm excited about where we're headed with biomarker development in the field of the context of use of specifically looking at therapeutic efficacy. What I would like to see, and hopefully, we can have this data at AASLD is actually kinetics of measuring therapeutic efficacy. In other words, if you drop ALT quickly, does that give you a better sense of what's happening at methodologically, then if you hit that later on in the time course. So just reflecting on semaglutide, I mean we saw the Phase II data. It's encouraging 56% versus 19%. And hopefully, that will read through in Phase III. But I think at the end of the day, what the field needs is drugs to get across the finish line to continue to rebuild enthusiasm in the field of NASH. And I think we're well on the way to getting there. But I would be cautious in reading through any specific reduction until we have data knowing what happens with different mechanisms of action.

There's another question from Lucy from Jefferies. Is there a risk that is the higher degree as on black box warning could be applied to [indiscernible] as some form of class effect despite different agonism profile? So that's never been raised by FDA or EMA, but I'd probably let Pierre answer and give more details on the difference, the substantial difference that [indiscernible] shown versus [indiscernible].

Yes, this black box warning is actually attached to a class of compounds called the [indiscernible]. And this is actually, as you know, lanifibranor is not a member of this class. It's not a [ trisindole ]. It's a different molecule. It's a [indiscernible]. So this black box label that is attached to [indiscernible] is not of course, automatically transferred to Lanifibranor or to any other PPAR out of the [ trisindole ] chemical class.

Question from Lisa, what is the predictive power of ALT on NASH resolution or fibrosis? How good of a predictor is it relative to other biomarkers? That's an excellent question. I don't know who wants to take this one.

I think we answered that 1 already. Must very good yes, that I didn't understand previously. Maybe Lisa has a clarifying question.

No, that was asked before so you probably answer that. Lisa has another one, fibrosis changed with the [indiscernible] drug will be impressive. Can you explain how such a dramatic result we've seen in such a short period of time in the 0 placebo rate?

I guess that's for me too. This is Stephen. So yes, when we look at efruxifermin in the Phase II trial, Phase IIa trial, essentially, it was a short trial, less than 24 weeks, 16 to 20. And in that population, there was an improvement in fibrosis, in particular, in those people that met a noninvasive target of a reduction of at least 30% in PDFF. So the only people that underwent liver biopsies in that trial were patients who had a relative reduction of liver fat content of at least 30%. So only 2 placebo patients hit that and underwent liver biopsy compared to a greater number of people in the efruxifermin treated arm. So the fibrosis benefit that was seen I believe in that fibrosis benefit. I'm a firm believer that fibrosis is dynamic and can change relatively quickly. I also showed that with aldafermin at 12 weeks, and we've seen that with other mechanisms of action and other drug studies. I think where we get hung up on is when we look at ordinal scores, sometimes it's very challenging for pathologists to see a one-stage change in fibrosis despite a change in college and content. And this is where the AI digital pathology field comes in. And one of the aspects of EASL really tried to dive into this a little bit more by showing that liver volume reduction and steatosis reduction actually could impact what is being seen by the necked eye by pathologists. In fact, one of the oral presentations I gave showed that when you apply a correction factor to liver volume reduction and to steatosis reduction. You actually can accentuate what can be shown with fibrosis improvement. And this is looking at Zone 2 in between the portal vein and the central vein. And what we showed was that there was no change in the volume of Zone 2. And so a pathologist can't see that change under the regular microscope. And so part of this, I think this debate about whether fibrosis improves quickly or takes years and years to show a benefit is kind of by the crude assessment that we have of looking at fibrosis under the microscope. And when we apply AI digital pathology with some correction factors, it becomes more apparent. And it also say that when we look at noninvasive tests, whether it's we now have blood-based markers for ELF and Pro-C3. We also have imaging-based markers in more or less elastography. And those also are helpful in showing a potential change in fibrosis. I would caution you, though, to ensure that you're looking at a responder analysis that points to the coefficient of variance for each of these NITs. For instance, MRI elastography has a coefficient of variance around 19%. And when you look at the Kiva publication, that's what you need to get over before you can have confidence that the change you're seeing in MRI elastography is a meaningful change. And so you can apply that to each of these noninvasive tests, and it's important to do that as well. I'm sorry for the long-winded answer, but this is a huge discussion point in the field right now is whether fibrosis can change quickly or it takes a long time. And I think it ultimately comes down to what mechanism you're utilizing to modulate fibrosis and how much of the upstream drivers of fibrosis you're actually getting after.

Thank you, Steve. That was very helpful. A question from Tom Smith from Leerink. When we anticipate the first DSMB meeting and clinical trial review? Maybe, Michael, for the benefit of everybody can you address that?

Yes. Also worked in the little response, but essentially the DSMB meetings are defined by the charter of the DSMB according to the number of patients in the mine. So there will be the DSMB meeting planned previously.

Excellent. Then we have a question I assume for Sven relating to NATIVE II and also a certain sense in NATIVE III, which as you know at the same screening approach in the Phase IIb which relates to why we prefer the FAST score over the is related to any mechanism of action.

Yes. The main reason for choosing that criterion for inclusion was that, and Steven also alluded to that, we have to take into account also the upstream drivers of the disease. And what is driving fibrogenesis is, of course, the level of damage and inflammation in the tissue. So what we really wanted to include our patients with highly active disease because these are the ones are most likely to benefit from a pharmacological drug that is efficient and are also less likely to show placebo responses. And so just to make a separation between steatosis and activity of the disease was the reason why we have chosen in the Phase IIb trial to select patients based on the activity score of the SAF activity system. So it's not the NASH [indiscernible] NAFLD activity score, but it's SAF activity score that just looks at inflammation and [indiscernible]. And by doing so, first of all, you see that you mainly select patients with F2, F3, although we did not -- in the Phase II did not exclude patients with minor degrees of fibrosis. But just by selecting on activity, you automatically enrich the population for F2, F3, which are the ones, of course, that are also a target population in Phase II sorry. So that's why we also decided to keep that same inclusion criteria for the Phase III in order to select the right patients for the mode of action of the drug. And from the patients that have been selected so far for and that have been proven to be eligible for the study. You clearly see that the selection of those patients almost coincides with the selection of F2, F3 patients. So it mainly comes to the close link between activity of the disease and progression of fibrosis.

So there are 2 other questions. And then once again, I think for on the phone, there is a possibility to ask the question. Or also the last 2 questions come from Ed Arce from H.C. Wainwright. So the first one, I read it at the BCP component is less for out in the FAST score over the 6-month study. Don't this have any implication on the likelihood of achieving the regression of fibrosis endpoint in NATIVE III? Who would like to take this question? Probably something from Michael I think he was more involved in the biomarker analysis.

I think if you look at histological response to another fibrotic use, of course, you are talking about 40%, 50%. If you look at the metabolic response rates to be high and the metabolic immune market. So anything we discussed before in that response to what was discussed in this meeting, she just mentioned it as well. You have this regulation of metabolism atherogenic lipid profile lipotoxicity, inflammation, cell death in [indiscernible], et cetera that are the drivers of fibrosis. And so it is quite reasonable to expect that any intervention that improves these upstream markers in aggregate for sure, will, over time, also lead to an improvement of fibrosis or at least a stabilization of fibrosis. And independent of the question how fast that can happen. But the NATIVE III, the interim analysis of NATIVE III at week 72, which is 1.5 years treatment will give us an answer indeed. So I think it is very promising that so many patients have an improvement of their metabolic immune profile related to NASH to expect that will have a visible effect down street on fibrosis as well. And that applies, of course, for the FAST score the way we see that it plays out, it is mainly driven by steatosis and the inflammation markers.

Thank you, Michael. Last question, at least on the Q&A from [indiscernible]. 2 of the 4 components to the predictive biomarker of P1 are related to [indiscernible] iron store and iron metabolism, which is a plausible pathogenic [indiscernible] rationally for iron to be predictive of natural solution and regression of fibrosis. Anybody voluntary?

I can probably take it Michael, probably also, but I think we should be careful to interpret these parameters just as being iron metabolism parameters. We know that there is some relation with iron metabolism, but is also closely overlapping with inflammatory pathways. So we should be careful not to say that these are just iron metabolism pathways, they are clearly closely related to inflammatory mediators.

Then just realize there were 3 pages of questions. So there are a lot more, so that's excellent. So Lisa for Stephen. How do you feel about the weight gain is landing is acceptable given the benefits? And once again, I want to absolutely come back to this notion of metabolic [indiscernible], but I'll let Steve answer that.

Yes. I think this is going to be an ongoing question. There's certainly -- it depends on what the weight gain is, right? If it's water weight gain with edema and we're unmasking right sighted heart failure, then I think there's a problem. If it's adding healthy fat, if you can use that term, and it's improving insulin sensitivity. It's improving atherogenesis, atherogenic risk profiles. And I think that's a different type of weight gain. There's also the perception of weight gain by patients. So I think what this gets to is the proverbial is the juice worth the squeeze, right? So if you're having a significant impact on histopathology, NASH resolution, fibrosis improvement, significant impacts on atherogenic lipid profiles and glycemic control, improving insulin resistance, regulating adiponectin expression, down-regulating inflammatory mediators. Then I think at the end of the day, we're leaving this big fat dent on the planet in the name of NASH. We're having an impact that's significant. And if patients are gaining a modest amount of weight, and it's a healthy weight, then I think that balances out. Alternatively, if at the end of the day, we're not seeing positive impacts pathologically on atherogenic lipid profiles and ASCVD risk, and we're gaining weight and it's water weight or edema. And I think that becomes an issue. A Phase II trial such as the big trial that was done with lanifibranor tells us a couple of things. It gives us an idea about safety and tolerability. And it tells us which dose is best to potentially move forward. It also tells us a dose that's likely to be affected. And so the purpose of a Phase III trial, such as the Native III is to enroll enough patients and follow them for a long enough period of time, where we're able to really answer the question that was brought up earlier about what's the duration and the number of patients that the FDA is looking for to answer the question of therapeutic intent or what's the therapeutic index. Are you getting a positive impact on efficacy and at the same time, is the drug safe and well tolerated. And I think the NATIVE III trial is designed to answer that question. The other thing is there's a DSMB that's going to be tracking this very closely, and we'll have -- again, all of these are going to be adjudicated. So I'm very optimistic about what we're hopeful to see and certainly hopeful that we're not going to have any issues with unmasking right-sided heart failure or that sort of thing.

No other Question. That we may more to the financial positions where I can take to, for example, there is 1 about our financial perspective with EUR 80 million of cash and EUR 50 million bullet loan from the European Investment Bank. That are not sufficient to go into 2025. So what are we doing for that? Are there any pharma partners to support the rest of the trial, et cetera? So clearly, yes, our -- without the EIB loan the financial visibility until Q1 of '23. And we're working on many options. All of you are aware that the financial markets are, for the moment, difficult for all biotechs on both sides of the [indiscernible]. We have worked on that since I would say, day 1 since we have had the results. So we look at other options. So one would be the loan with the European Investment Bank. We're also looking at nondilutive. Specifically, we're seeing that [ lani ] has a great future in areas where we're NASH very prevalent like China, and we're working actively there. We see it a certain sense duty to make sure lanifibranor area, in that geographic area, a [indiscernible] and Inventiva not be, I would say, the clinical experience and infrastructure to conduct a trial in such a country. So we are looking at potential partnering options in Greater China and also we're looking at Japan because Japan is an area, geographic area that where there are very many established pharmas and also a NASH population that also needs to acquire and similar to Greater China. This is a country where we think we do not have the infrastructure capabilities to develop the company on our own. We're also looking at other non-duty forms such as a royalty deal. So -- but that I would say are early discussion. So let's cover the financial part. There is another question, and I do not know who can cover that. Which is a question about do we have any plan to investigate [indiscernible] activity through specific histology biomarkers such as [ AFHH ]? Which I personally have not heard. So I don't know if somebody can take that.

Well, I can -- we do not actually at this point. We do talk with companies that provide machines related computer at histology and paying some of them actually are related to histological markers depending on the method. So that's something we are looking at right now, but we have your complete plans.

Thank you. And with that, I think we have come to the end of the questions that have been asked through the Q&A platform, both in the content web access and orally. So just to conclude, I would like once again to thank our participants. We feel order really to do to support, and we know there is a lot of hard work on the set in the NASH field and it's a beauty for Inventiva to push forward planning, and we're really honor to once again to [indiscernible] support. And then also, thank you for all the persons that listen, I see that we still have after close to 2 hours, quite a lot of people at that stage for the world. So thank you very much to everybody and for listening and participating to this post EASL webcast. Thank you very much, and have a great rest of the day.