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

Good day, and thank you for standing by. Welcome to the Inventiva's Call Webcast Event from AASLD 2021 Conference Call. [Operator Instructions] And please be advised that today's conference is being recorded. I would now like to turn the conference over to your speaker today, Frederic Cren. Thank you. Please go ahead.

Thank you, and welcome to everybody to our traditional webcast from AASLD. I'm very pleased with Pierre and Michael to welcome you. And today, we have a very, I think, exciting program and especially a very exciting panel of KOLs that are joining us. So today, we share the floor with Professor Afdhal, he is the Chief of the Division of Gastroenterology at Beth Israel. In Boston, he is a Professor of Medicine at Harvard Medical School and Dr. Afdhal's clinical expertise focuses on the management of the complication of liver disease, including cirrhosis and portal hypertension. His research has been on liver fibrosis, NASH, hepatitis B and C. Professor Afdhal will also be joined by Professor Schattenberg, a Professor of Medicine and Director of the Metabolic Liver Research Program at the University Medical Center of Mainz in Germany. Professor Schattenberg launched the Metabolic Liver Research Program at the University Medical Center in Mainz and his main research interest focus on translational signs of liver injury, the development of therapeutic intervention and novel biomarker in acute and chronic liver disease. Professor Schattenberg and Professor Afdhal will be reviewing the 5 abstracts and posters that we presented at AASLD. And on top of that, Professor Afdhal will also present an overview of the NASH field. On top of this, we also are joined by Professor Lai, an Associate Professor of Medicine at Harvard Medical School And Director of the NAFLD Center at Beth Israel Deaconess Medical Center in Boston. She founded the NAFLD Center at Beth Israel and her main research interested on biomarker and population health approach to streaming and diagnose of match. She's also the co-PI of the combination trial between lani and Empagliflozin, and Professor Lai will present the study design and rationale during this webcast. And then we also have the pleasure to welcome Professor Cusi, the Chief of the Division of Endocrinology, Diabetes & Metabolism in the Department of Medicine at the University of Florida, Gainesville, who will give us an update on the Phase II planning in Type 2 diabetic patients that is currently running at the University of Florida. During today's webcast, you'll also be able to measure that we are moving full steam in the implementation of our pivotal Phase III NASH, that NATiV3 with lanifibranor that joined the selected club of companies in Phase III in NASH with what we believe are the strongest and best data published so far in NASH. We have also recently announced the design of a very exciting trial combining lani with empagliflozin. And we believe this trial will further position lani as a drug of reference in NASH, especially among patients with NASH and Type 2 diabetes. Finally, with this study, we are looking to release the continued stream of clinical results in the outcome. Next year, we are looking forward to publish the data of lanifibranor in patients with Type 2 diabetes and NAFLD. In 2023, the result of the combination study between SGLT2, empagliflozin and lani. And of course, in 2024, the pivotal results of lanifibranor in patients with fibrosis F2, F3 stages. Besides that, as you know, Inventiva, we have other programs we are extremely excited by the progress of lanifibranor that have been announced by our partner AbbVie, and we're looking forward to the start of the Phase IIb in 2021 and of the result of this trial in cirrhotic patients that are expected in 2022. Today, we have a very full agenda. So as time is precious. I'll now turn to Michael for the first presentation and an update on lanifibranor in NASH and the NATiV3 trial.

Thank you, Frederic, and good morning, everyone. I will give a brief overview of what we are doing in the Phase III study, the pivotal study with lanifibranor in patients with NASH, the NATiV3. So if you go to the next slide, Slide #5 gives a short overview of what we have done in clinical development with lanifibranor so far. The Phase IIb study NATIVE was recently published in -- the results were recently published in New England Journal of Medicine at very strong efficacy data and was the basis for breakthrough therapy designation by the FDA. So it was a Phase IIb study where lanifibranor was given for 24 weeks to doses were tested 800 milligram and 1,200 milligram once daily. And to summarize the results, it's the first investigational compound that reached both endpoints, efficacy endpoints that are recognized by both the FDA and the EMA as the basis for approval for accelerated and conditional approval, respectively, namely resolution of NASH and improvement of fibrosis with the statistical significance. And lanifibranor also has a favorable safety profile and a good safety profile. So that's what has been done so far. What we have started now what is ongoing is a Phase III study, the study that aims to -- for registration, making lanifibranor available to patients essentially. The study is done in patients who have active NASH, of course, but also significant fibrosis defined as F2, F3 according to histological staging. The study has 2 parts. There is a Part 1, which is aimed to achieve -- to have approval, accelerated approval. And that's with a treatment duration of 72 weeks, 1.5 years. And there, the primary endpoint will be histologically improvement, as I mentioned for the Phase II study. There is an extension Part 2, which is between 5 and 7 years, and that Part 2 will -- looks at outcome benefits of lanifibranor compared to placebo, which is the basis for full approval. We keep -- we have kept the inclusion criteria and the patients, the target patient population, as close as possible to the Phase IIb study. And the primary end point is both NASH resolution and improvement of fibrosis, which is a high bar and is based on the results of the Phase IIb study that I just mentioned. So that's ongoing. And in addition to that, we have another Phase II study ongoing in patients with fatty liver disease and Type 2 diabetes, which will be detailed further by Dr. Cusi. And we are starting a combination treatment of lanifibranor with an SGLT2 inhibitor, empagliflozin, in the proof-of-concept study, which I think is a very attractive combination in patients with NASH. And so Dr. Lai will cover that in more detail. And then in addition to that, we are also considering and actually are preparing, a pivotal study in patients with NASH, who have progressed to compensated cirrhosis with the aim to document outcome benefit with lanifibranor. The next slide, please. This is a little bit more in detail what the Phase III study looks like. It's a randomized, double-blind, multicenter, placebo-controlled, both looking at the efficacy on histological endpoints NASH resolution and fibrosis in Part 1, as I mentioned, and then also in the same study with an extension in Part 2 to document the outcome improvement. In order to do that, we'll have 3 biopsies screening at the end of Part 1, so at 72 weeks in, first, roughly, 900 patients and then a biopsy at the end of the study to document progression of disease to cirrhosis. In Part 1, you'll notice that we've kept 2 doses, 800 and 1,200 milligram, and that's also based on the data from the Phase IIb study that show essentially that both doses work well and that the 800-milligram may well be as potent as 1,200 milligram on the fibrosis endpoint that you treat longer than the 24 weeks of the Phase II study. The principal investigators are Dr. Francque from the University of Antwerp and Dr. Sanyal from Richmond, Virginia. And inclusion criteria, we focus on patients who have active disease. That's why we use the SAF score, which with a focus on inflammation and tissue injury as well as significant fibrosis, F2 and F3. And then, of course, randomization and statistical powering are all, as you would expect for a Phase III study. Just to know the biopsy, we have spent a lot of effort, I think, to have a very robust way of evaluating the biopsies, which are critical, of course, for the inclusion and for the efficacy evaluation. So we have 3 expert pathologists who will look at digitalized license and who are working very well together to have as much as possible consensus on the histological evaluation. So that's a very active program that we have set up. The primary endpoint, I mentioned that its histology. In addition to that, we have a number of key secondary and secondary efficacy end point that, to a large extent, focus on the document or the further documentation of broad efficacy scope that lanifibranor has in patients with NASH, who often also have other metabolic conditions, such as Type 2 diabetes. And we have -- we know from the Phase II study, that lanifibranor as a PPAR agonist has beneficial effects on these endpoints and those are listed as the secondary endpoint. So an improvement of renal function is one of them, composite endpoints in -- or endpoints in diabetic population in diabetic patients, where we also look specifically at the effect on the histological endpoints for the liver disease, which was the same for non-diabetic patients from the data from the Phase II study. So all those data will provide a package for accelerated approval in the U.S. and conditional approval in Europe. And then the Phase II, as I mentioned, is meant to document outcome improvement. Of course, if patients have F2, F3 fibrosis, the most obvious outcome that we want to prevent, we aim to prevent is progression to cirrhosis, which will be documented histologically. We have, of course, tools to detect noninvasive Phase as well in order to be able to direct the timing of the biopsy accordingly. And of course, additional clinical endpoints, mortality, hepatic decompensation events, progression of the MELD score, which reflects the worsening of liver function or liver transplantation. And this data will provide the basis then for full approval. Next slide, a few words about the central reading of liver biopsies to -- or the 3 pathologists that we have, Zack Goodman, Carolin Lackner and Dina Tiniakos, all 3 well-known and with a high level of expertise in this field. We use digitalized biopsies. And the slides will be reviewed in parallel by 2 pathologists, and we have a third pathologist in case there is some disagreement between the 2 pathologists. Part 1, the histologically -- the histological eligibility criteria will be read at the end of treatment as well, so that we -- the pathologists will review the biopsies at the end of the treatments, both the ones that were just for entering the study and those at the end of treatment. And then again, at the end of Part 2, there is a third biopsy to document progression of cirrhosis in the front treatment arms. The next slide gives a short overview of operational aspects where we are with the study. We started activating sites in September of this year as planned, and that is an actively ongoing process. So it's both on a daily basis, new sites are added at this point in the United States and soon also in Europe. Approximately 60% are -- of the sites are coming from the U.S. and Canada and about 35% from Europe. We also have sites in South America, South Africa and Australia. And the plan is in the second half of next year to have the last patient, last visit in Part 1. And accordingly, treatment duration is 1.5 years in the first half of 2024 to have the last patient, last visit. And then at the end of 2024, the second half of 2024, to have the results from Part 1, which will then be the basis for the submission for approval. With that, I pass on to Dr. Afdhal for an update on the NASH field.

Thank you, Michael. Thank you for inviting me to speak at this meeting. So can I have the next slide, please? When we look at the pathophysiology of NASH, we as hepatologists -- next slide, please. We as hepatologists think of NASH as a liver disease because we see cirrhosis and the complications of cirrhosis. But in fact, as you can see from this slide, NASH is really a systemic disease with involvement of multiple different areas of the body, including the adipocyte, the gut, the muscle and, of course, the liver. Perhaps more importantly, regulatory authorities are interested in the liver as the target and the endpoint for approval of NASH-related studies. The mechanistic pathways of NASH have been well described, and there are multiple targets that are amenable to many different approaches. I think it's worth pointing out that liver disease is reversible, including cirrhosis and the primary reversibility of liver disease is actually through the mechanism of alteration of the effectors that result in liver damage and liver injury. This has been extremely well proven for many different diseases, including viral hepatitis and alcohol, and data is emerging from these liver biopsy studies that the same is true for NASH, both prevention of progression and reversal of liver injury, including reversal of cirrhosis. Next slide, please. So from the regulatory perspective, what we're really interested in is what is the pathway for drug development. You all know this that the FDA and EMA have agreed to an accelerated pathway through the Subpart H with surrogate endpoints. The current surrogate endpoints for conditional approval include improvement and reversal of NASH and improvement of one stage in fibrosis. But this also requires, overtime, for a full approval, clinical meaningful benefit, which means an outcome that, in fact, impacts patient survival, functional status and quality of life and the surrogates are meant to reflect this result in final approval. This pathway is undergoing with the aid of perhaps all of the industry partners that we work with significant modification as we keep trying to create the ability to have rather than liver biopsy, other methodologies that the regulatory authorities will accept as a conditional pathway for approval in the Subpart H, but still with the final approval requiring clinically meaningful impact. Next slide, please. This is a busy slide, but it essentially shows all of the multiple different pathways that are affected across the progression of NASH from simple steatosis to the steatohepatitis to fibrosis and then on to the development of cirrhosis. And these targets include targets that impact insulin resistance and gluconeogenesis, lipogenesis and transportation of lipids in and out of the liver, the various apoptotic pathways that result in liver injury and liver cell death, oxidated stress that leads to inflammation and activation of systemic immunity. And then finally, of course, liver fibrosis and all the cofactors involved in the extracellular matrix. Listed on this slide are all the potential different targets, and you're well aware that some of these are proving to be of interest in progressing and others, unfortunately, have not delivered on the promise. And perhaps the most complicated and difficult targets are those that are involved in the reversibility of liver fibrosis. Next slide, please. I really like this slide because this slide reminds me of the heyday of hepatitis C. This slide is what we call the universe of NASH slides. So what we have is a multitude of Phase II and Phase III industry-sponsored studies that are currently underway to identify drugs that can be used with NASH. It is worth pointing out that there is no FDA or EMA-approved drug. And obviously, what we're really interested in is approval, a better cholic acid, as you're well aware, is currently in a kind of registration freeze, if you want, but at the regulatory authorities. What's interesting is that there are some Phase III studies that are ongoing, and I want to address a few of these studies a little bit just to give us some background information. So next slide will show what's happening with the obeticholic REGENERATE Phase III clinical trial. These are big clinical trials with thousands of patients, almost 2,500 in this study who have fibrosis, secondary to NASH treated with 2 different doses of obeticholic acid versus placebo. This study did meet one of its primary endpoints, which was fibrosis improvement by one stage or more. You can see here that in this study, there was approximately the higher doses, almost 1/4 of the patients had a 1-stage improvement in fibrosis. It is worth knowing that the placebo response was relatively low in this study in comparison to some other studies. But one of the issues with this study was that there were problems with both pruritus, the side effect and some issues relating to lipid profile problems, including increases in LDL and decreases in HDL. I will point out here, and it's worth the audience knowing that the use of statins in liver disease is getting more and more attention. And the idea that statins not only improve the lipid profile that can have pleiotropic effects in terms of improved effects on liver fibrosis and risk of preventing, both liver failure and liver cancer makes that is actually an interesting addition to a drug like obeticholic acid. Next slide, please. There's a lot of excitement about Resmetirom. Resmetirom is a thyroid beta receptor agonist. As you know, this results in a variety of different beneficial metabolic activities, including lowering of LDL cholesterol, lowering of triglycerides, reduction in liver fat, which may essentially reduce lipotoxicity and oxidated stress resulting in improvement in NASH. These are the results of the Phase II study that's highlighted here, which was a 36-week liver biopsy, an MRI-PDFF-based study, with patients randomized to Resmetirom versus placebo. And you can see here that, as expected, there was a significant reduction in relative fat by MRI, and there was a 1-point reduction in fibrosis particularly in those patients who have more advanced fibrosis, such as F3 fibrosis. Overall, it did not cause a resolution of NASH. And it is an interesting study and Resmetirom has moved forward to Phase III. Next slide, please. Let's look at Semaglutide. Now this is important because this is an approved drug, and this is available and it's certainly being used with increasing usage in primary care in the United States for both the treatment of diabetes and also more recently for the treatment of obesity. The GLP-1 agonist have a significant benefit as a secondary benefit that's shown in this slide on NASH resolution. They showed at the higher doses of 0.4 milligrams, a significant improvement in NASH compared to placebo. But they did not have an effect on liver fibrosis. Again, this is extremely interesting, and Semaglutide is moving forward on to further Phase III studies. What's of interest in this study is that this is actually quite a long study, it's 72 weeks. And the majority of 72-week studies do show some benefit in liver fibrosis. But here, you can see there was very, very limited benefit. The PPARs are a very interesting therapeutic target for NASH. We have had studies with PPAR agonists, such as pioglitazone, but lanifibranor is an interesting pan-PPAR agonist, which affects all of the different pathways of NASH, including the metabolic pathways, the stenotopic pathways, inflammation, fibrosis and also has effects on vascular injury, which is of great interest, particularly when one thinks of long-term outcomes, reduction in portal pressure and decreased intrahepatic vascular resistance are really important factors that can help in terms of improving the long-term patient outcomes. Lanifibranor affects all of the different PPAR pathways. Next slide, please, and has what is described as a balanced PPAR agonist activity. It is not a fibrate or a or TZD, I can never say that word. It is a once-daily oral, which is excellent, and it has shown in Phase IIb studies, both an effect on NASH resolution and a 1-stage improvement in fibrosis. It is obviously in a breakthrough therapy and being fast tracked by the FDA. Safety profile appears strong in the over 200 healthy volunteers of 250 patients treated with this agent to date. Next slide, please. This slide really looks at the comparison of lanifibranor in the Phase II study, looking at improvements of 2 points in the activity score resolution of NASH and improvement of fibrosis. You can look at this in detail later, but essentially, what this slide shows is its statistically significant improvement in both one stage of fibrosis at the higher dose of 1,200 milligrams in both the ITP and the per protocol population. And in addition, shows an improvement in the resolution of NASH and no worsening of fibrosis at all of the doses that were studied. So this is the first drug that we have seen to date in a Phase II that has resulted in an improvement in both of the key endpoints for regulatory approval by the FDA. Next slide, please. And this is a comparison of efficacy across drugs in development. This is not a head-to-head trial. This is simply just showing you the 2 key endpoints of NASH resolution with no worsening of fibrosis and fibrosis improvement with no worsening of NASH. And as you can see, in terms of the significance, the only one that has shown an improvement in both of these remains lanifibranor. So this is an exciting time. It's also exciting to have seen Michael's data on both the planned Phase III trials, the combination studies, which we're going to hear about, and also to see data about the timeline and the fact that these studies have now started, which is very exciting for us. Next slide, please. My second talk is going to focus really on some of the abstracts that were presented at AASLD. Next slide, please. The first abstract that I'm going to review is an abstract that looks at hepatic steatosis in patients with NASH. Next slide, please. And this is the native Phase IIb trial, which was, again, a 24-week treatment trial, here, this is being presented, and this is an analysis to look at the correlation between the CAP score and the liver fat based on biopsy-determined liver fat. Next slide, please. Why this is important is that once drugs are approved, in clinical practice, we will need to have technologies that are more simple and safer than liver biopsy to follow patients to see successive treatment. This will be true, both for physicians to monitor successive treatment, but also equally, I believe, for payers to continue to pay for novel treatments for NASH. What this first slide shows is a correlation between the CAP score, which is derived from a simple 5-minute FibroScan which is a noninvasive test to look at the liver and the level of steatosis grade on the liver biopsy according to the NASH CRN. There was a good positive correlation between these, giving us some cutoffs that are very useful in clinical practice. Next slide, please. Perhaps more importantly is actually what happens when you have success with a drug like lanifibranor in terms of reduction in the CAP score overtime. And what this slide shows is that as there is an improvement in the steatosis grade. There is also a reduction in the mean CAP score overtime. And this obviously seen much more significantly in the patients that were treated with lanifibranor than placebo, but it gives the clinician an opportunity to use a test that is simple and noninvasive to monitor one of the steps of efficacy to see that the treatment is actually working. And I think that is the key factor with this study. Next slide, please. And then you can see here in a different way, very nicely graphically shown, the correlation between the changes in CAP score and the changes in histological grading of steatosis. And so what you see is that in patients that progress or have no change, really, the CAP score stays the same, but there's a nice reduction, overtime, in the CAP score with nice findings that you can say that if somebody has, for example, a 30-point improvement in CAP that, that's associated with a reduction in hepatic steatosis. So in summary, this study shows that CAP by FibroScan, good correlation with histological grading. And you might say, well, didn't you know this before, but the answer is actually no. This is one of the first studies that has shown this. And lanifibranor, we know from the biopsy, has a significant reduction in steatosis, but we now know that there's a potential to measure this effectively in clinical practice and that these changes in CAP correlate with changes in histology. Next slide, please. Lanifibranor also has significant metabolic effects, and we know that it works well in patients with diabetes. But there's also the ability to look and see what happens in patients with pre-diabetes. Next slide, please. So this slide shows the improvement that occurs in glycemic control in patients with NASH and Type 2 diabetes. So what you see is both improvements in hemoglobin A1c and also improvement in the fasting glucose in patients treated with lanifibranor. And this is data from the native study. So very nice illustration of its benefits for metabolic control and diabetics. Next slide, please. Now what about the pre-diabetic patients. NASH is a disease of insulin resistance, and insulin resistance is a hallmark of pre-diabetes. So what they were able to do in this study is evaluate from the full set of patients, those who have diabetes and those that were nondiabetics. Then to look at the nondiabetics further and define those who had prediabetes as defined by a fasting glucose that was elevated between 5.6 and -- sorry, 6.9 million micromills and then normal glycemic patients. And then they were able to look at these different patients treated with both placebo and lanifibranor, the 2 different doses and see what happens to those treated with lanifibranor. And the key endpoint here is that amongst the prediabetics, you actually had a significant proportion of the patients, almost 70% overall that resulted in normal glycemia at the end of treatment versus only 11% in the placebo arm. This is very important because some people might worry about weight gain with lanifibranor, but here, you show that lanifibranor actually reverses one of the key metabolic abnormalities, even in those patients who are not fully diabetic. And just equally as importantly, nothing bad happens to normal glycemic patients, you don't make that hypoglycemic, and they have no issues in relationship to that. Next slide, please. This just shows you the actual levels of fasting glucose and fasting insulin. Remember, insulin resistance is developed by the hormone, where you can determine it by the hormone, which is the fasting glucose and the fasting insulin. And you can see that in the pre-diabetic patients, both of these parameters were significantly improved by the use of lanifibranor. Next slide, please. And then finally, the hemoglobin A1c, again, significant reduction HOMA-IR for insulin-resistant significant reduction. So overall, even in patients that are prediabetic, next slide, please, who have hyperglycemia, but no diabetes you see the good metabolic effects of lanifibranor and glucose metabolism. And I think this, again, is important, especially when one is considering the fact that this is a metabolic disease and anything that improves metabolism in these patients as well as the liver disease is going to be a beneficial effect across all populations treated. Thank you for your attention. I'm going to turn this now over to Professor Schattenberg to review further abstracts.

Well, thank you, Nez. This is Jörn Schattenberg, and it's a pleasure to be here, and thank you for the nice introduction. I'll take it over. And next slide, please. I'm going to start out by discussing 3 abstracts quickly and will be happy to take questions during the Q&A, down the line. So the first abstract is entitled, liver sinusoidal endothelial cells, LSEC. And we explored -- or the -- capitalization of those cells was explored during lanifibranor treatment in the NATIVE trial. Next slide, please. This shows the background and overview. And in case you haven't heard of liver sinusoidal endothelial cells, it's a specialized cell type that's essential to the liver and actually separates the blood flow from the both hepatocytes, which is the most prominent cell mass in the liver, but also the stellate cell that are responsible for producing scar during NASH and inflammation. And it's interesting to see what happens, a, during the disease itself, but also under treatment with lanifibranor. And therefore, this exploratory research study was performed on liver biopsies that were obtained within the Phase II trial in a subset of patients, and we use CD34 immunostaining and quantification of this immunostaining to detect the degree or the density of LSECs in the liver. And next slide, please. This is going to be the first data set that I'm going to showing from the NATIVE -- from the Phase II trial here. And you're going to see on the slide, both on the left-hand side, the degree of hepatic fibrosis and on the right-hand side, the hepatic inflammation score as determined by the pathologists by blinded reading. And by the little dots that are next to the box plots actually picked the CD34 positive area, showing you that you get an increase of CD34-positive stained cells, both with increasing fibrosis, but also with increasing inflammation scores. Next slide, please. And this details the data in a little bit more depth, looking at the spatial distribution of CD34-positive LSECs in the liver, distinguishing both periportal and lobular areas. And you see the blue area in the graph which depicts low staining or no staining and the red area, which depicts high staining. And looking at both periportal and lobular inflammation and both fibrosis stages and inflammation. You've seen what I've shown you previously that there is an increased staining density with more severe disease. Next slide, please. And this is, again, a little different way to look at it, but what it shows you is that there is an improvement with treatment and you actually see the 3 types of staining we used for the CD34, looking at it morphometrically and the periportal space and lobular area and the positive or negative standing and what you see across the 3 treatment arms, placebo, 800 and 1200 mg of lanifibranor is a decrease. So it seems to be -- this type of staining seems to be affected by treatment. Next slide, this brings me to the summary of this first research abstract. This is an exploratory slide looking at the density of LSECs and the liver. Now why is that interesting? The LSEC compartment is critical for the mediation of liver injury and fibrosis. And in this abstract, we're actually showing that it was depending on the disease stage, but also being affected by treatment. And this opens up a hypothesis to look at that further studies and potentially the effect of lanifibranors on this cell type, which could add beneficially during treatment. So the second abstract I'm going to be discussing is a little bit more clinical and comes down to what Nez has already discussed. It's entitled treatment response to the pan-PPAR agonist lanifibranor in the NATIVE study, NASH resolution and fibrosis improvement are correlated. Now this seems logical, but remember that during histological assessment, the pathologists scores these clinical -- these pathological features of NASH independently. And you do sometimes get disconnect of these scores. And therefore, we explored the combined endpoint in this abstract. Next slide, please. This is the first reminding you of the treatment response in the NATIVE trial in both the entire study population and only the F2-F3 study population, which showed similar numbers with lanifibranor 800 and 1,200 being superior to placebo to achieve the combined endpoint NASH resolution and fibrosis improvement in the same biopsy. Now next slide. This is a busy slide, but I'd like to spend a few minutes detailing what it actually depicts. So on the left-hand side, you're going to see the NASH resolution as it's called by the pathologists. Again, NASH is a -- it's the face value of the biopsy, the pathologist looks at it and says, well, this is NASH or not. So it's a result. And you see that according to the 2 groups, NASH resolution, no or yes, separated by the treatment arms, placebo 800 and 1,200 milligrams, the change of fibrosis, which is depicted in color is displayed here. And bottom line, a complex slide, but what it shows you, you get increasing green area, meaning fibrosis improvement if you have NASH resolution. Now that's biological plausible, and it will seen so more with the treatment arms. And importantly, in the treated groups that did have NASH resolution, this was significantly higher, the fibrosis improvement, compared to the non-NASH resolution. Now a different way to look at that is actually to look at the blue area. Now that's significantly smaller, but you'll see that this is worsening of fibrosis. Now in a short trial, you're not going to see a lot of worsening of fibrosis. But the important message here is that in patients that did show a NASH resolution on biopsy, you also had lower degrees of NASH resolution. Now the numbers are small, so there's no big ability to compare between the different treatment arms. But I think this is an important message. We have those aspects that can be discussed. If you improve fibrosis, that's fine. That's a green area. But it could also be beneficial to just have no change, no progression and/or prevent the progression, so decrease the worsening of fibrosis. And then on the right-hand side of this slide, this is also shown by lobular inflammation. Now be reminded that lobular inflammation is one histological aspect of NASH, which is separately semiquantitatively scored in the NASH score. So it's one of those histological features that is scored by the histopathologists. And here, you do see a similar trend when patients improved lobular inflammation, that was all a higher degree of fibrosis improvement. Next slide, please. And this kind of is the same picture detailing, again, a little bit more on the ballooning of hepatocytes. This is the second aspect of the disease activity score in the SAP. So small numbers, maybe a little bit more diverse pictures, but bottom line, same story. If you have improvement in ballooning, there is more fibrosis improvement, which is depicted by the green area. And interestingly, there was also a similar picture seen in the steatosis improvement. Next slide. Bottom line, when we look -- when we see NASH resolution or improved ballooning and lobular inflammation, there's an improvement of hepatic fibrosis, this was more so seen in the lanifibranor arms, and these analysis support the biological plausible linked to aim at NASH resolution and achieve fibrosis aggression. So next slide, which brings me to the last abstract. I'm going to go over this a little bit more quickly. I think it's interesting, but it's a preclinical model. So importantly, this is not a clinical data from the NATIVE trial, but the preclinical model. It's a hamster model, next slide, please, where we used our high-fed diet to induce a metabolic NASH phenotype and also a certain degree of diastolic heart dysfunction over 20 weeks. And hamsters were actually treated and then examined cardiographically. And if you go to the next slide, you see, a, on this slide, the effects of the NASH-inducing diet on the metabolic phenotype, something we see in a lot of those animals, you can feed the animals and then have a negative impact on triglycerides, cholesterol, hepatic fatty acids content, HOMA-IR. And in this clinical study, we used a pioglitazone. So another PPAR, but a pure gamma agonist, not a pan-PPAR as in the case with ll and look at the differences. And in this metabolic model, actually lanifibranor was superior to pioglitazone to effect the benefit -- show benefits on the metabolic features during the model. Next slide. And also true for the histological assessment in this animal model, so lanifibranor superior to pioglitazone here and improving liver histology. Next slide, and then actually, the interesting slide of this abstract where the cardiovascular function in this animal was assessed. And here, albeit not being a cardiologist, I'd like to highlight that there was an improvement of several ratios that you can measure and to assess the diastolic dysfunction. And this was interestingly achieved by both lanifibranor and pioglitazone, making an argument for the case that this is really mediated by the gamma agonist of the PPAR. And next slide, please, concluding -- conclusions from this preclinical model is that lani, but not pioglitazone, it improves the metabolic and NASH phenotype. But interestingly, the PPAR gamma subunit seems to be mediating the effects that are beneficial for diastolic dysfunction in this model. And with that, I'd like to thank you and actually hand over to the next presenter, which should be Dr. Cusi.

Thank you very much, Jörn. Great presentation as usual. I'm Kenneth Cusi, I'm the Chief of the Division of Endocrinology, Diabetes & Metabolism at the Department of Medicine, University of Florida. And I'm going to share with you study that -- and where we're trying to understand the basic mechanisms of action at a metabolic level of lanifibranor. So I believe this audience is now well educated on the role of non-alcoholic fatty liver disease as a cause of future cirrhosis. But what we wanted to share here was a little bit some recent studies from this year, probably the first study in the United States looking at how often patients with Type 2 diabetes just going for a regular follow-up have, not only steatosis, but we're really interested in knowing that what was the degree of moderate-to-advance fibrosis, what we call F2 to F4. And as we can see in the first 3 bullets about 15% to 20% had F2 to F4 as measured with by liver steatosis measurement by FiberScan. And then this is a major problem because in the United States, there are about 30 million people with diabetes, the vast majority Type 2 diabetes, which would -- if this number would be confirmed in a larger population would mean that there are nearly 5 million people with moderate-to-advance fibrosis, which are largely not being diagnosed. Now why does this happen? Again, there are many pathways. This is a complex disease, but there have been a couple of actionable targets. Among them is the role of insulin resistance, which is elegantly discussed before. And what really is many times not fully understood is that obesity is associated with a larger fat mass or larger adiposity, but this is an extremely sick tissue. As an endocrine organ, sick adipose tissue leads to lipotoxicities, in this case, we're talking about the liver because this flow of fatty acid promotes a state in which the hepatocyte cannot adapt to this and triggers a number of pathways poorly understood in humans, what we think that implicates this regulated mitochondrial function activation of downstream inflammation and fibrogenic pathways. So as I'd like to summarize for the audience, this -- there are 2 approaches. One is weight loss. And again, we know how difficult that is, but it's always important. And the other is reversing the biology of adipose tissue, which is what lanifibranor does. But we're going to examine that closing and as I'm going to tell you in the next couple of slides. The second aspect that's equally important is that this excess deposit of triglycerides in the liver, leads to the atherogenic dyslipidemia, so typical of our patients with NASH. And as you all know, cardiovascular disease is the #1 risk factor. Now here, I'm going to share with you the study that we are doing in patients with Type 2 diabetes in NAFLD, we are studying a total of 34 patients with Type 2 diabetes without excessive hyperglycemia, as you see there, and any one can see that shouldn't be higher than mainly half. Of course, it should not be pioglitazone or insulin as it complicates a little bit of complex measurements that we are doing. And we are going to be studying patients with hepatic steatosis of 10% or greater, and that have been on to a stable weight for the prior 3 to 6 months. In the ongoing study, we are doing a number of state-of-the-art measurements of liver fat. As you can see there by MR-based techniques, we're doing magnetic resonance elastography also cT1 corrected fibro inflammation imaging. The most important aspect is to really study what is the mechanism of action of lanifibranor on insulin sensitivity. Among the many pathways that we think play an important role insulin resistance is probably the one that is universal even if you are lean and have NASH, you're insulin resistant and one that is actionable in this case, with an insulin sensitizer like lanifibranor. So we're going to be looking at this very, very carefully, looking at what is the impact of lanifibranor on adipose tissue, muscle and liver. We're going to look at key pathway in the liver, which is the novel lipogenesis, and this is using very careful studies. And we look -- we're doing a low and high dose insulin infusion to see the impact of lanifibranor at the different tissue levels. This is important, of course, we're also going to be looking at glycemic control, biomarkers and different kinds of adipose tissue, metabolism, biomarkers of liver fibrosis. But again, our #1 target will be to understand the effect on insulin sensitivity and the cardiometabolic profile. Next, please. So the key thing, just to put this into perspective, there has been no other study in the field of NASH that has looked at this as carefully. We have done this before and published with pioglitazone in a couple of our clinical trials. But this is key because many times, drugs are developed based on mechanisms of action studied in rodents and other animal models. But very few times, there is a good proof-of-target engagement in NASH trials other than surrogate markers. Instead here, we're going to have direct measures of insulin sensitivity to really understand the underlying mechanism of lanifibranor. You can see there a little bit easier to see the study design, this 24-week treatment in which the 34 patients studied have been used estimating the results of the NATIVE study. And again, the primary endpoint is liver fat, but again, in relationship to changes in adipose tissue as a main target. But again, PPAR gamma also by studies we have done in the field of diabetes and humans and animal studies, we know that there are direct mechanisms of mitochondrial function, mitochondrial biogenesis. We know that another important step is that PPAR gamma agonism doubles or triples the levels of adiponectin. Other compounds sometimes says there's been a 20% increase in adiponectin, but that's usually not clinically relevant. Adiponectin levels are about 1/3 of what they should be in normal or patient with NASH and only PPAR gamma agonism can double or triple the level that Adiponectin in humans. Muscle is also an important pathway because insulin resistance in liver and muscle also promote the development of diabetes. People as was very nicely summarized before prediabetes is a key feature, if you noticed from the native database among those without diabetes. 1/3 had prediabetes, PPAR gamma agonist like pioglitazone reduced the progression from prediabetes to diabetes by about 70%, 80%. And the other important feature is people with prediabetes have 2 or 3x higher rates of cardiovascular disease and of course, higher rates of progression to NASH. So a drug that can work on the specific people with prediabetes is a critical feature. And we believe that lanifibranor will perform very well in the patients with prediabetes. The secondary endpoints are quite obvious there, the usual ones. And as a study update, we have -- we will have the publication ready in the third quarter of next year. We are hoping to finish recruitment in December. We have -- we identified more than 110 patients. We had several ways of COVID that affected us significantly. The last year, 8 of the 9 patients that were in the trial were discontinued. One patient developed COVID but fully recovered and was discharge fully recovered from the hospital. But we are very excited about this. We have already 22 of the patients and for the controls -- healthy controls studied, and we have another 7 that are already at different stages in the study. And so we are pretty excited about finishing the study and being the first-in-class to really, at a human level, explain the mechanism of action. What I think has been the most successful drug to date in terms of the outcomes that were presented earlier in terms of resolution of NASH and reversal of fibrosis. So with that, I think we're going to -- I'm going to finish my presentation and happy to address any questions from the audience.

So I think, I'm up. Next slide.

So I think Michelle got disconnected. So we're calling her back. [Technical Difficulty]

Okay. I'm sorry. technical issues. But as my previous speakers gave a very nice background, especially it's nice to follow Dr. Cusi where he talked about the connection between NASH and Type 2 diabetes. And a large portion of patients with Type 2 diabetes in NASH have typical features of metabolic syndrome. NASH really is, as you've heard, a multisystem disease where -- it's part of the metabolic syndrome, including abdominal obesity, dyslipidemia, hypertension and insulin resistance. The vast majority of all cases of diabetes is Type 2 diabetes. And there's an increasing prevalence with about almost 0.5 billion of people affected worldwide. In the Type 2 diabetes patients, about over 1/3 of them have NASH. And so that's 37.3%, and that's giving us roughly about 172 million people with NASH and Type 2 diabetes in the world. Insulin resistance is the key pathophysiologic event leading to the clinical manifestation of both the NASH and Type 2 diabetes. Therapeutic compounds that address the upstream metabolic and immune-mediated pathways of NASH are also expected to be beneficial for Type 2 diabetes. And there's a rationale to assess the combination therapy with drugs that have a complementary mechanisms of action in the complex disease pathophysiology of patients with NASH who also have Type 2 diabetes. Next slide. And so as you've heard, the lanifibranor is a balanced pan-PPAR agonist. It has been shown to improve insulin sensitivity, decreased macrophage activation, liver fibrosis and inflammation, improves lipid and glucose metabolism. So sort of addresses multiple mechanisms in NASH. Empagliflozin is an SGLT2 inhibitor that reduces the proximal tubule reabsorption of sodium and glucose, has been shown to improve A1c, body weight and fat mass, insulin sensitivity and fluid overload. So this is the rationale for our proof-of-concept study using the combination of these 2 medications based on their mechanism of action. Next slide. So using drug combinations to target multiple aspects of the metabolic syndrome has the potential to address the clinical outcomes in both type 2 diabetes and NASH. And as Dr. Afdhal alluded to, really the clinical outcomes and improvement in showing that clinical outcomes will be what will result in the final approval. Complex NASH pathophysiology requires targeting multiple mechanisms. And there's potential for additive effects using the 2 medications. While there's data to support that lanifibranor is related to -- the weight gain related to lanifibranor is due to redistribution toward a more metabolically healthy fat profile, it can still be undesirable for patients to have weight gain. So combining this with an SGLT2 inhibitor may help mitigate lanifibranor-related weight increase, and that's one of the rationale for this combination. This combination study can assess potential additive effects on metabolic and noninvasive liver parameters. We will be measuring reverse steatosis inflammation and fibrosis using the liver multi-scan, and that A1c is a gold standard biomarker for glycemic control. And it also predicts the severity of the necroinflammation and fibrosis associated with NASH. Next slide. So we are proposing this proof-of-concept study, which is a double-blind comparison of lanifibranor versus placebo which will allow controlled assessment of body composition changes using MRI. We will also have an open-label arm of this combination of lanifibranor and empagliflozin to allow for proof-of-concept data to be developed on the use of this combination. Our primary outcome measure will be the A1c change. But we are also measuring MRI-based imaging using the liver multiscan to collect noninvasive data on hepatic fat, inflammation and fibrosis. We're looking at glycemic and lipid parameters, inflammatory markers and changes in body fat composition. And obviously, we will also be looking at safety, body weight, PK and other biomarkers. Next slide. So in summary, this combination is an attractive combination to studying patients with NASH and Type 2 diabetes. The LEGEND trial will develop important proof-of-concept data on the combination, including data on metabolic function, body composition and liver parameters as well as safety. And for the metabolic functions, we'll be looking at disease pathways across the spectrum from lipid and glucose metabolism to fibrosis. Empagliflozin acts upstream on metabolic pathways, which may work synergistically with lanifibranor. A1c in addition to being the gold standard for glycemic control also predicts the severity of ballooning hepatocytes and liver fibrosis. So based on the mechanism of action and available data from pioglitazone in combination with several SGLT2 inhibitors, the weight-reducing effect of the SGLT2 inhibitor may balance out the weight gain observed with lanifibranor. There is data to support that lanifibranor induces a fat rate distribution, favoring subcutaneous fat that is more metabolically healthy. And for the liver parameters, we're going to be looking at the impact of the combination on noninvasive markers of NASH and fibrosis. So there will not be biopsy needed, liver steatosis, inflammation fibrosis will be assessed via the liver multiscan. And we're also going to be looking at the safety profile of the combination. Thank you.

Thank you. I think with that, we are done with all the presentation, the operator, if you can give the procedure to start the Q&A session.

[Operator Instructions] And your first question comes from the line of Zegbeh Jallah from ROTH Capital Partners.

I think for me, one of the key questions that I wanted to ask was, just about how one is thinking about NASH, in general. I think one of the key overhangs on the stock is just historically the affiliates that we've seen in NASH. And so maybe Dr. Cusi or Dr. Afdhal could probably talk about some of the advances that have made our understanding of the disease a lot better or understanding about the targets, like you noted at being multifactorial or systemic and why lanifibranor does kind of tackle that relative to some of the drugs that have seen some failures in the past. So just kind of putting that into perspective, I think, would be helpful for the audience. And then I have a follow-up.

So maybe I'll start on the issue of the endpoints and the mechanism of action of lanifibranor. So NASH has been bedeviled by endpoints to some degree. And those endpoints predominantly are histological. Mechanistically, if you think about the histologies that are supposed to be addressed by -- for approval lanifibranor's mechanism of action really hits along all of the different pathways that are involved in both resolution of NASH and also improvements in fibrosis. I also think there's a potential for some of its alternative effects on fibrosis and endothelial cell function to help in terms of the long-term outcomes, which we'll need for final approval. So mechanistically, it's very good. And I totally understand the issue that many other drugs have had difficulty meeting these endpoints. But the endpoints themselves are actually difficult endpoints to hit. And as the only drug that's done that in a relatively large Phase II, it gives us a little bit of a feeling that this may well be the correct pathway. To combine it with other drugs is also of interest because, again, the more suppression of the mechanistic pathways you have, the more likely you are to have resolution of injury. Perhaps not so much for progression of liver disease, but for resolution, I think that's very important. And I think Ken can address the metabolic pathways of why we like the PPAR pathways, if you want to, Ken.

Thanks, Nez. Yes, so this is complex. I mean, we have limited information of the mechanisms of action in human. So traditionally and still today, people have tried to conceptualize treatment as metabolic drugs that treat say, factors that promote ketosis as a triggering event that downstream activates inflammation, and fibrosis to direct anti-fibrotic agents. And again, if you want to think -- it does make complete sense that the first attempts were to work on drugs that would work on inflammation or fibrosis directly based on animal studies. However, animal studies are in perfect models. And as you know, those attempts have, in general been, unsuccessful. So until we understand more what are the mechanisms in human, it seems that an approach that targets excess adiposity by any mechanism that you promote weight loss or that change the biology of fat. So what you are doing with lanifibranor is taking an individual is extremely abnormal adipose tissue that is causing major metabolic derangement and converting that person in a metabolically lean, healthy individuals. That is why our experience in the past with some PPAR gamma with some ALP activity like pioglitazone not only improve the liver but reduced cardiovascular disease. Now in lanifibranor, we see that there's an addition of PPAR delta component that may add the additional anti-inflammatory effect that we're seeing. And probably additional effect on fibrosis. So it is not unexpected that reversing that unfavorable environment at an upstream level and also some direct mechanisms that are difficult to prove in humans have led to these results. So I would be wary of compounds that promote target one pathway in the liver or one inflammatory pathway or on anti-fibrotic step. Because in the metabolic abnormality seen in our patients with NASH, I would anticipate that they're not going to be very successful.

And I think that's very helpful also in terms of separating data that's to come from other programs and then having investors look at that and then think that, that could be the same outcome for an either positive or negative? And then the second question that I have here, another overhang, and I'm sure you guys have read this question multiple times. But I was just wondering, how important is a noninvasive test going to be to adoption of lanifibranor, is eventually approved? And then how far are we from actually having noninvasive approaches?

So that's a phenomenally important question. And how important a noninvasive test? Incredibly important. Which is why every company that's involved in developing NASH therapeutics is also investing significantly in the NITs. In addition, the various European and U.S. consortium like NIMBLE are absolutely focused on the use of NITs. What you probably don't realize is that NITs is the current standard of care for the evaluation of patients with NASH. So the NIT, such as FibroScan, Velacur and other imaging criteria MR-based criteria plus the serum tests are all used by clinicians to evaluate the initial patient with NASH to make the determination of their standard of disease. So they are already in clinical practice. What is critical and I think well demonstrated by the lanifibranor study comparing liver biopsy steatosis to CAP is that for the uptake of these drugs, it's going to be important to be able to measure effectiveness in a noninvasive fashion. It's going to be important, both for the clinician to use these drugs to see that they're effective. But also it's going to be important for the payers in terms of reimbursement strategies for what could be an expensive overall program just because of the simple size of the NASH population. So NITs are critical, and everybody has recognized that. And how close are we? I would say we're pretty close. We're certainly using them on a daily basis for a diagnostic test for making the diagnosis of NASH in a positive fashion. And I would say we're fairly close in using them to look at improvements that we see with various therapeutics that we're using in clinical practice. So I'm upbeat on NITs. What is harder to do is to get the regulatory authorities to agree that NITs can be used as an endpoint for that early Subpart H approval. That's a little more of a complicated issue at the moment.

This is Jörn Schattenberg. I'm just going to follow up quickly on this comment, which are right on target. But I think we're making good progress to also link the NITs to outcome, which is essential to the acceptance of the regulatory to actually look at NIT changes as a primary endpoint. We're looking at a lot of correlation of NIT to histology in these trials. But the research consultants that have been mentioned and its LITMUS in Europe and NIMBLE in the U.S. We actually have a long history of patients that we follow with NITs and we'll know what the outcome is. And I'd like to direct you to the paper in the New England Journal that was published by the NASH CRN and the [indiscernible] first author. We know the endpoints and liver events already. And if you link that to the NITs, we are very close to understand what the relevant changes mean for our patients.

As your next question comes from the line of Ed Arce from H.C. Wainwright.

Really appreciate all of the detail here in these presentations. So I have a few questions. Firstly, on -- and this is for management firstly. You mentioned that the biopsies would be read digitally. So the question is, are these biopsies for the NATiV3 study all going to be digitized? Are there some traditional glass slices or both? And how is that going to be assessed for the primary endpoint? And then in a related question, just your thoughts, in general, about supplementing traditional slides with AI-type machine learning technologies.

A good question for Michael, I think, because you're totally into this question about AI and the biopsy process.

Yes. Thanks for the question. So I think there are 2 components here. One is the digitalizing of the biopsies instead of using the classic glass slices. All biopsies are digitalized and the pathologists read them on the computer screen. But there are pathologists-read biopsy specimens. So it's the procedure of making the biopsy available to the pathologist that is digitalized in this case, and that's accepted by the FDA. So that's what we are currently doing. But essentially, for NATiV3, the primary efficacy endpoint, for the surrogate endpoint is based on reading by human pathologists in this case, by 2 or 3 human pathologists, right? So that has not changed. What is different from digitalizing of the images themselves is the reading of the biopsy by a computer program, whether we call it machine reading, compute reading or artificial intelligence. That depends a lot of the kind of software and programs that are used to being developed under a couple of companies that are at different stages of progress in this field. We work with them. And the idea is that these programs can support the human pathologists, data on that from a couple of companies that are advanced in this field. So it helps the human pathologist to be more consistent in his or her reading because the program can in an easier way, look at the entire biopsy or to take certain changes that difference between F2 and F3. That is essentially support of the human pathologists by software program. That's something that we are looking into in order to further increase, I would say, the reliability of histology as a primary efficacy endpoint. The next step would be that the histology is entirely read by computer program. That's not something that we're pursuing right now and the FDA has made clear, that's also something that, at this point, would not accept as data for submission. So what we are looking to is at how a program, a well-developed program can help the pathologist to reach the biopsy specimens.

Yes. Yes, Dr. Cooreman, that's helpful. And next question is related to the first abstract that Dr. Afdhal mentioned, and this is related -- the work related to the CAP cutoffs and how that's correlated to histology. I recognize that FibroScan is probably the most widely available and used in clinical practice, but of course, in liver fat MRI-PDFF is the gold standard. And I'm just wondering, and this is open perhaps to any of the KOLs on the call. Your thoughts around the myriad of different niches available, of course, in fibrosis, you have imaging like MRI -- excuse me, MRE and VCTE, but you also have serum labs like ELF and FIB-4 and PRO-C3. Some of these are more widely available than others. Some of these are proprietary. And so I'm wondering how you see the use of this as we get the first few drugs approved for NASH.

So I think people use what they have. So this was very true for hepatitis C when we were initially trying to get approval to use the expensive DAAs for treatment of hepatitis C and payers asked for evidence of the presence of cirrhosis. And people used FIB-4, people used APRI scores, people used other biomarker scores such as fiber test and for people who have FiberScan use FiberScan. So I think, essentially, they will use what's available. One of the problems which you've highlighted is that there are a plethora of choices. But those choices are good in some way because not every country and not every place has access to the same technologies and the same blood tests. I really think that if you look just this month, the Europeans really put out a very good paper on the current guidelines for the use of noninvasive tests. And I think that what will happen is that people will use what is available to them. That's my real belief. Is one better than the other? When you look at the all the diagnosis and the way they're utilized, they're pretty close. They're pretty close. And in clinical practice, availability really trumps a lot of other issues when it comes to tests that are minimally differentiated. That's my perspective, but I'm happy to hear somebody else's.

A quick follow-up comment, I'm Schattenberg. I think Nez, again, covered everything that's said. And it depends on the setting, so the context of use, I think, in primary care and diabetes clinics you will see more blood-based markers. And then if you move to GI or more specialized, at least, in Europe, there will be more imaging be utilized, again, as Professor Afdhal said, based on what's available.

And I agree, and I think one other thing would be the cost as well of the test there.

Right, right. I asked just because, of course, there's a lot of studies ongoing and some more recent data that's begun to be published and a lot of focus on the differential effects and comparing different studies, whether one or the other has better positive or negative predictive value and I think at the end of the day, with all of the different choices, as you said, is largely around cost and availability.

Go ahead, Nez.

Go ahead, Ken. Go ahead. No, no, you go ahead. Ken, you go ahead.

No, a brief comment. I mean, the short answer is we don't have a great test for a follow-up of these patients in the clinic, that was where you are heading to. In the research setting, I think additional failures have been observed in this meeting like with aldafermin I would be cautious in interpreting studies only on the reductions on liver fat by MR imaging for example, it's aldafermin the reduction in 80% of patients had reductions in liver fat and the average reduction was 59%, but only 22% had improvement on NASH resolution with no worsening or fibrosis. So we are still struggling a little bit in this field with that. And for the time being for the clinical trials, I think the liver biopsy, still with all its imperfections and debate, remains the gold standard for the clinical trial. So I think liver fat is an overall average niche when it goes in the right direction, but you need to think what is a mechanism of action of the drug and what histology results that still with all the pros and cons is the bottom line. And that's very exciting about lanifibranor that we have hardcore results that are very, very encouraging moving forward.

I appreciate that. So I just wanted to ask you then, if I may, a quick question around the LEGEND study, the combination of lani and the SGLT2 primary endpoint there is HbA1, which is, as you mentioned, the gold standard for glycemic control. I believe there was some effect of that shown by lani in the NATIVE study, perhaps not earth shattering, but there was some beneficial effect, I believe. So the question is by adding the SGLT2 in this study, what are the other additive or synergistic outcomes you're hoping to see beyond just mitigating the weight gain from lani.

This is Ken. I'll take as first approach to this, as an endocrinologist, this is our bread and butter. So there are many aspects, a, we know from the diabetes field that adding SGLT2 to any other drug, and there are studies also adding it to pioglitazone like that have been published. You have a robust reduction in A1c. And you also improve the cardiometabolic profile. I think that we have done studies with SGLT2 inhibitors and the improvement from insensitivity in some cases. But uniformly, they reduced liver fat compared to placebo by an additional 20%. So we still don't know what it would do at the level of the liver and then in terms of histology. We think that, again, by promoting some weight loss. And I would have to say that adding a PPAR gamma, for example, in the past, pioglitazone, for example, empagliflozin or canagliflozin leads to net weight loss I think that, that will lead to additional histological benefit. But more importantly, SGLT2 inhibitors have fantastic effects on reducing liver -- reducing adipose tissue depots, improving cardiac function, reducing renal progression of nephropathy in diabetes and reversing the cardiometabolic problems of these patients. So I think that lanifibranor on its own plus one of our rising stars in the diabetes field, makes a lot of sense. And remember that most patients were match were by of cardiovascular disease. So this is an extremely attractive combination of my view.

That's great. And if I may just squeeze in one last question. This is for management. Just getting your thoughts on perhaps any interim or preliminary data readouts that may lead to impacting the value of the shares, given the long 3-year wait for the pivotal registrational data in the second half of '24.

Yes. Thank you, Ed. So I think the main inflection point, of course, would be in '24 with the lanifibranor trial, but as Professor Cusi explained and also Professor Lai showed these 2 study we're conducting in lanifibranor patients and the combination with SGLT2 will certainly provide value, additional derisking to the program. So we really see those are very impactful events. And then we should not forget that in Inventiva we have a pipeline, there is a lot of value created by our team besides of lani, and we are extremely excited by what we have seen with Resmetirom with AbbVie. As we know, we have Phase IIb starting momentarily, and the data will be available in Q1 '23 in patients with psoriasis. And when you look at the developing psoriasis, you can expect the Phase III starting immediately afterwards with another milestone. So I really think that [indiscernible] will also provide inflection point to Inventiva and impactful events that the investors and analysts can look at.

And your next question comes from the line of Jean-Jacques Le Fur from Bryan Garnier.

I have 3 questions actually. The first one on LEGEND and the follow-on question on the primary endpoint and having chosen HbA1c. Why this as a primary point and not a more traditional NASH endpoint since the key indication or the indication for lanifibranor will be NASH and not diabetes. So and with a more traditional NASH endpoint, it would have been a good way to confirm the NATIVE finding. So is it because you wanted to avoid invasive tests. So that's my first question. The second question on NATIVE is why did you choose the 800-milligram and not the 1,200 milligram or both, like in NATiV3. Since in NATIVE, the 800-milligram did not meet the primary endpoint over 24 weeks. So I understood that it could reach primary endpoint more -- in more than 24 weeks, but LEGEND is also 24 weeks. And my last question is for the audience, I would say, is why do you think Semaglutide did not have effect on fibrosis since it has had a strong effect on the NASH resolution? And I always heard from KOLs or during Congress at ESL or AASLD, that NASH resolution should lead with time to fibrosis improvement. So is it just a question of treatment duration, for example, more than this 72 weeks? Or is it a question of mechanism of action?

This is Michael Cooreman. I can address the first 2 parts of your question. Thanks for that. So the reason why we chose HbA1c is it is proof-of-concept study. And for a proof-of-concept study, you don't necessarily -- you don't need to have the same endpoints as primary efficacy endpoints that you would choose for study that is more directly aimed at confirming or registration. In addition to that, if you look at the biology of NASH and Type 2 diabetes, there was a lot of commonalities, and HbA1c is clearly also in the pathophysiological path of NASH as been shown. It is related to the underlying metabolic dysfunctions, and so in resistance. And it is related to NASH in its activity and progression. So in that sense, it is an established endpoint in Type 2 diabetes, but it is a biologically plausible endpoint in NASH as well. And certainly, therefore, suited for a proof-of-concept approach. In addition to convey the question you have, how do you get more information specific for NASH, and it's conventional thinking. We do look at more NASH-specific endpoints, as we are now in secondary endpoints, including imaging notice scan MRI and a number of biologic blood tests of metabolism. So this is all covered in that, I believe. Why the 800 milligram? If you look at -- you're right, you're absolutely right that if you look at fibrosis endpoint histologically, 800 milligrams is less specification than 1,200. And I think that has to do in the current Phase III study will show that, but fibrosis histologically has a lag time. And so it's assumed that over time, the effect of 800-milligram may be similar than 1,200 that remains to be seen in the NATiV3 study, but what it is based on is if you look at the metabolic markets like lipid profile, effects on lipid profiles, et cetera, and including HbA1c, where lanifibranor has actually a very clear effect, the effect of lanifibranor 800-milligram and 1,200 milligram at 6 months is about the same. So that's the reason why in this proof-of-concept study the 800-milligram was chosen. And I hope I addressed the first 2 parts of your question.

Your next question comes from the line of...

Sorry, [indiscernible], I don't know if anybody from our KOL panel address that one, it was an interesting question.

It's an interesting and tough one. This is Jörn. I'm just going to make a quick comment. Maybe someone else wants to follow up. So the one aspect you can say is what's been studied in the trials and for Semaglutide, but also in a previous smaller Phase II study, the liraglutide study, there was no significant effect seen on fibrosis improvement, but seen on NASH resolution. And both trials had quite a high placebo response rate, 33% of fibrosis improvement in the Semaglutide at 72 weeks. And numerically higher in the 0.04 Semaglutide arm, but not statistically significant. What does that mean? It means that, that endpoint was achieved. That's a clear-cut answer. I think in real life, that placebo rate will not be seen. And I think that over time, you'll see that improvement of fibrosis when you lose weight. The other part of the -- the other side of the coin is that taking those 2 trials together, I also mentioned the liraglutide, the anti-fibrotic effect is not as strong as seen with the GLP-1s. That's my take of the data, and I'm happy to hear if anybody else has a thought on that.

And our next question comes from the line of Lucy Codrington from Jefferies.

I just got a few left. Just regarding the NASH field, I just wondered whether you had any updated thoughts on the FGF21 analogs, given the Phase IIb data for Bristol at AASLD and what you think that could be -- whether there could be implications for other FGF21 in development? Then for the Phase III, we discussed already the kind of time to the final data. I was just wondering whether how many DSMB safety reviews will be taking place and what -- where we can disclose what time points they will be happening. And therefore, whether that can give some assurance in terms of safety, at least throughout the trial. And then sorry if I missed this because my line is not very good, but in the LEGEND trial, can you just -- so again, why the combination trial is open label and not blinded like the other?

Any volunteer to try to answer if there is any readout from the BMS FGF21 trial to other development, specifically the NGM Bio's?

So I guess, Lucy, your question is too difficult...

This is Jörn, again. Sorry, I'll be happy to answer the FGF, but maybe rephrase quickly. I missed part of the first. So maybe rephrase the question on the FGFs.

Yes, I think the -- Lucy...

Yes. Just your thoughts on the updated -- the Bristol data that was at AASLD and whether that has read across for the class as a whole, I guess, and therefore, the other products in development.

Well, that's difficult. Well, what we've seen is some negative trials in the FGF arena. And I think Nez mentioned that there is effect on hepatic steatosis that do not necessarily translates into the effects of fibrosis improvement. And now there is plenty of biological plausibility to study that. But based on the data that's been recently presented, these effects on NITs do not necessarily directly translate at the time point study. There's some issues that you can -- making a 24-week trial, for example, with the aldafermin and looking at fibrosis and the variability of histology that added to that. And but I would say, yes, that treatment class has fallen behind a little bit based on these negative results.

This is Ken Cusi. Also, sorry, I was having a communication problem. So Yes. I think you're talking specifically for the aldafermin study, their Phase IIb program. And then they had these 3 doses. FGF21 and republished this is increase in people with advanced NASH and more so if they have fibrosis. So there seems to be -- the biology FGF21 is poorly understood in humans. It's a hormone that you see creating states of starvation or metabolic stress, which makes sense why it would be elevated in NASH. And now you're giving more FGF21 to overcome that. That's like insulin therapy in diabetes, your insulin resistance giving more insulin. That approach may not be the most -- and again, there are many different FGF21s. But it might be fraught with an ability to maybe reduce somehow liver fat, although the results don't -- are not consistent with the biopsy results reported, right? In which the change in their primary endpoint was at one or greater stage improvement in fibrosis without working with mass or NASH improvement without worsening of fibrosis, which was between 24% to 30% when in placebo was 14%. But when you take the traditional endpoint like NASH resolution without worsening fibrosis was only 8% at the highest against 6% in placebo. So it failed. I think the challenge is, again, translating just changes in fact to a downstream effect. And also, there is potential with the class with off-target effects on the cardiovascular system or increasing cortisol levels as shown with some FGF21s at the higher doses. So I think it is -- it's a biology that's incompletely understood that can have some long-term off-target effects and unfortunately, very disappointing also in terms of safety, about 50% or more of people had GI side effects that happened at all doses and injection site reactions. And again, very costly, I expect, to produce. So disappointing, and again, I would be cautious with that approach in general, moving forward.

And Michael, do you want to say a couple of words about the DSMB and why one of the open labels with impact in empagliflozin.

Yes. So the open label -- the choice of open label for the empagliflozin is primarily technical in nature, the challenges we will have to make the -- double-blind with regard to empagliflozin. And given the fact that we are looking at a proof-of-concept study that will basically tell us what the benefit of this combination is to make decisions on further steps. This appears to us to be an adequate approach at this point in time. With regard to the DSMB, they will meet every 6 months. And of course, as needed, in between data what require it. We have an ongoing real-time safety monitoring, of course, which is done by the medical monitors. And we have an established pharmacovigilance DSMB-dependent data safety monitoring board comes together and will review the unblinded data at 6 months. And yes, that will indeed provide us more information as the study goes on. So I hope that addresses your question.

And your next question comes from the line of Tarun Soni from Guggenheim Securities.

So my first question is to Dr. Afdhal. You mentioned that Semaglutide has shown kind of great data on the NASH resolution but may not be on fibrosis endpoint. So wanted to know, but they have kind of shown great weight loss with [indiscernible] of around 15% in the non-diabetes population. So I wanted to know what's the value proposition of lanifibranor? Do you think it would be used more as an induction therapy where it kind of improves fibrosis? And then patients, especially for the F2, F3 stage patients, they are switched over to more metabolic drugs, which has benefits of the weight loss.

This is Ken. Let me just -- there are many, many aspects to that question, excellent points. I would say that with the results of the NATIVE study, a little bit that distinction between metabolic and anti-fibrotic drugs is diluting a bit because a drug traditionally viewed as metabolic has had now the best results on fibrosis. So that's one concept. The second is that we are going to be using a lot of combination therapy in the same way we do to treat diabetes, to treat hypertension, et cetera. And I think the third point is that payers are going to be more excited to use drugs that have multiple benefits that are, in other words, more cost effective. And among the many NASH drugs, I mean, clearly, lanifibranor stands out. It has the ability to reverse insulin resistance, lower glucose in people with diabetes or prediabetes. Long-term studies may show cardiovascular disease improvement. Again, that will take another kind of study and the liver histological benefits. Now again, I mean, I see lanifibranor like the starting drug and combined with an SGLT2 inhibitor and with Semaglutide. Remember that there's a lot still any of the drugs that have been successful so far, still have a lot of people that would need to be treated additionally. So I do see as a very exciting approach in the future combining lanifibranor with Semaglutide. And definitely, we'll see the effects on SGLT2 inhibitors. But this is going to be a combination therapy field. Now in the United States, where I work, I work in Florida, the cost of the major drawback of GLP-1 receptor agonist is something that doesn't depend on the drug. It's the cost. So they cost several hundred dollars. It's sometimes $1,000 or more a month depending on the dose, if you don't have insurance. So that has been the limiting factor. And again, we're still a long way to how lanifibranor will be marketed. But again, to answer to your question, I think that they are going to work both and haven't added to the fact GLP-1 receptor agonist and lanifibranor, both work by different pathways. So you reduce the mass of adipose tissue, you prevent weight regain and you prove the quality of adipose tissue and insulin sensitivity in liver and muscle with the histological effects seen in NATIVE. So I do think that this is going to be really probably the approach. And if you add the benefits of fibrosis hinted by Semaglutide and those in NATIVE with a longer duration of treatment, I think we will be at a point where the majority of people will be having a reversal of fibrosis and definitely halting progression of disease.

Got it. So just as a follow-up, the LEGEND trial may have kind of may mitigate the risk of the weight gain. But how are you thinking about [indiscernible] population, which may be obese, a lot of the NASH patients would be obese in general. So how are you thinking of the -- using lanifibranor there? Is that [indiscernible] there? Or any color on that?

Yes, that's a great question. And again, there is a lot of confusion around the issue of weight gain because from -- since I'm in medical school and since you open any magazine, weight gain is associated with more cardiovascular harm and increased cardiovascular disease and more diabetes. It's extremely important that you understand that the weight gain with pioglitazone is associated -- and with lanifibranor -- with pioglitazone is just because we're using it for 20 years. But now even with the pan-PPAR, we expect greater metabolic and liver benefits. What you're going to see is quite the opposite. So with pioglitazone you gain 3% or 4% of body weight, but you have a 15%, 20% reduction in cardiovascular disease, 80% reduction in progression from prediabetes to diabetes. Increases in HDL, reductions in triglycerides, except everything that you really would like a drug to do. So the weight gain is an important thing, but also remember that in clinical trials, you're not actively doing a multidisciplinary approach to prevent that weight gain. You keep them everybody on an advice that is ethically necessary, but you're not promoting weight loss. So in real life, with weight loss programs embedded in diabetes care, that is -- can be largely prevented. And as you're going to probably see from the literature, when you combine with an SGLT2, you have net weight loss at least with pioglitazone, and we will see with lanifibranor. So this is the issue. So you have a weight gain that you don't want, don't get me wrong, but that will prevent the progression to cirrhosis cure -- stop NASH in about 2/3 of the patients. And again, I believe that in the future, as we learn to use lanifibranor, we will find the correct approach to prevent weight gain and combine it with other drugs that are going to further enhance the liver and cardiometabolic benefits. So the weight gain is undesirable, but it's associated with everything that you see with weight loss and more. So again, a little bit confusing, but I think that over time, these concepts will become more clear as you see less people having NASH on these drugs and less people having fibrosis.

And just my final question. Dr. Afdhal mentioned during his section that the conditional approval as listed or based on a lot of surrogate endpoints, a lot of these drugs may hit that -- hit those surrogate endpoints, especially the NASH resolution without worsening of fibrosis. So what do you think that for the final approval that which mechanism of action may falter that they may not able to show? And what is that particular clinical meaningful benefit endpoint that you would be leaned on?

So maybe I can give a first answer and colleagues can add to this. The surrogate endpoint for NASH is the basis for accelerated approval by the FDA and conditional approval for the European Union has defined its histology at this point in time. And it's either a resolution of NASH without worsening of fibrosis or the other way around, improvement of fibrosis without having reaching a NASH resolution. So both are acceptable. In the case of lanifibranor, we have actually met both of these criteria to have both -- to meet both NASH resolution and improvement of fibrosis. That's the surrogate endpoint, and surrogate means that there's accepted knowledge that this endpoint predicts clinical outcome benefits. So the clinical outcome in the case of NASH is related mainly to the liver outcomes. And as you know, and it was also mentioned in the discussion, patients with NASH also have cardiovascular disease and Type 2 diabetes and roughly half of them will die of cardiovascular complications and the other half of liver-related complications, that's a simplification, but that's about how it is. So to get full approval for NASH, the outcome benefit on the liver-specific events are what matter. And in this case, the outcome that we have is based on the progression of the liver disease to cirrhosis, which is considered to be a clinically relevant outcome, or if cirrhosis has developed, decompensation of cirrhosis, which is measured by the occurrence of situs and ciliopathy or variceal bleeding, bleeding from upper gastrointestinal viruses or progression to viruses that need to be treated, or liver transplantation that can occur earlier, for example, if liver cancer develops, or cause mortality. So the combination of these endpoints constitute a clinical benefit with relation to the NASH-specific liver outcomes to get full approval.

Just to follow up quickly. Jörn Schattenberg. Remember, I presented the data on the combined endpoint, combined surrogate endpoint for accelerated approval the -- achieving both NASH resolution and fibrosis improvement in the same patient. And from a clinician's perspective, I would think these patients will show benefit earlier compared to patients that just show one improvement of benefit. And looking back to the GLP-1 question earlier, I think that there's a heads-up for this class of drugs, the PPARs that shows a higher amount of achieving both these simultaneously.

No question at this time. Please continue.

Well, then I would like to conclude first, I would like to thank the expert panel that has joined us that has been extremely interesting and lively discussion. Of course, thank all of the participants and looking at the level of participation, it has been very high. So that is extremely motivating for all of us. And of course, I will give you a rendezvous for the next event. We keep on doing this type of events because it proves very helpful for us, but also and passing -- disseminating the very solid data we continue to produce with lanifibranor. So thank you very much for attending. And for us, in Europe, have an excellent weekend. And for all of you in the U.S., we wish you a good afternoon of work. And then all of us, enjoy a nice weekend, and see you very soon. Thank you, and goodbye.

And this concludes today's conference call. Thank you for participating. You may now disconnect.