Okay, why don't we kick things off? Hi everyone, I'm Mark Pruzanski, I'm the Chairman of the Board of Inventiva and welcome to our investor event. We're going to be telling you today about the next and hopefully best in category oral therapy to get to patients with MASH, lanifibranor. We're going to be making forward-looking statements. Here's the agenda. It's going to be pretty packed and I'm going to get out of your way and introduce you to Andrew in a minute, followed by three well-known key opinion leading hepatologists in the MASH space. We will have a panel discussion with some of the senior management team and time for Q&A at the end. I've been involved with Inventiva for the better part of a year and it's been a momentous year. All of you know that we just about a year ago raised a $400+ million pipe, which positioned the company very well with respect to the enrollment of the global phase III NATiV3 trial. We double clicked to accelerate enrollment and over-enrolled the study, which we announced in April of this year. In the last few months we've been working hard to strengthen the management team. Over the summer we announced the addition of Jason Campagna. Many of you know him, he worked with me at Intercept as our Chief Medical Officer there, knows the space extremely well and we are very pleased to welcome him as the CMO and President of R&D. Also, Martine Zimmermann, who's here, was a longtime board member at Inventiva and most recently was Head of Global Regulatory Affairs at Ipsen, where she helped to shepherd two liver drugs, including elafibranor, a PPAR agonist for the treatment of PBC. She knows the liver disease space very, very well and FDA, the liver review division, and other regulatory authorities of course. Just a week ago we were thrilled to introduce our new CEO, Andrew Obenshain, who many of you know. Most recently he was the CEO at bluebird. He has extensive global biopharma experience, a number of leadership positions, especially in the commercial side. He'll be leading the company going forward as we set the stage to bring lanifibranor to market. Andrew? Thank you. Mark. Whoa. Sorry. Welcome to everyone in the room. Welcome to everyone online to or listen to the recording later on. As Mark said, I'm Andrew Obenshain. I've been with Inventiva for a total of six days. There's probably people in the room that know NASH or MASH even better than I do. I have six days of knowledge that I would like to share with you. The first thing I want to do is thank the team at Inventiva for the work over the last 12 years. Since I come in as a new CEO, inheriting a fantastic platform for the future. We've enrolled, fully enrolled, a phase III trial as of April. That phase III trial was designed on positive data from a phase II-B that had some, you know, set the standard for, I would say, for the efficacy in an oral in the MASH space. We have an asset in lanifibranor that really has the potential to make a difference for patients in a really large and growing market in MASH. I couldn't be more excited to take over at this point to take Inventiva from a development stage company into a commercial stage company, which is something I've done before, been through a number of launches, and I'm really excited to do it here as well. I'd like to, maybe to start off, what I'm going to do is I'm going to cover a couple topics. I'm going to give a little bit of an overview of MASH. I think many of you are familiar with that. I'm going to talk about how that MASH space is developing over time, where lanifibranor fits into it, and what the future is for Inventiva. For those, most of you know that MASH is a very, it's a liver disease. It is progressive. It starts off with, you know, it starts off with fatty liver, leads, inflammation followed by liver damage. It is the number one cause of liver transplant in women in the U.S. It's number two overall. Despite that, despite the severity of the disease, it remains incredibly underdiagnosed. Of the 18 million patients in the U.S., only 10% of those patients are diagnosed right now. Even if we go even further and say, how many of those are under treated care and specifically focusing on the F2 and F3 patients, which is what we're enrolling on a clinical trial, what will be the commercial target? There's 367,000, it's a very precise number, 367,000 patients under treated care right now in the U.S. I've done a lot of launches into markets that are underdeveloped and usually they get to do a lot of market development to actually grow that number. However, that number, that 367,000, is 70% higher than it was even four years ago. This market is developing already. Why is that? MASH is a subsegment of the metabolic space. Like the entire metabolic space, there has been a tremendous amount of innovation, a tremendous amount of investment in this area, MASH not excluded. We've had two new products come to market in the last couple years in MASH, which has really prompted the development of this market as well. There's a lot more coming. However, even with two products on the market, almost nine out of ten physicians say that there's still a need for more efficacious products and specifically products that target the liver. This is where lanifibranor comes in. We believe that we have a therapy that is uniquely positioned to deliver on the physician and the patient needs. Let me actually start with the patient. This is a simple product for patients. This is an oral once a day, therapy with manageable safety and tolerability profile. If we look at our phase II-B data, it's a product that works, it has potential best in class oral efficacy. We showed an 18% improvement in fibrosis in just six months. That efficacy is based on a unique mechanism of action in the market. This is a pan-PPAR agonist and it was actually designed specifically for MASH. It works on both the liver with direct fibrosis, directly on fibrosis in the liver, and also has extrahepatic benefits in cardiovascular markers as well. We believe that we have the therapy that really can make a difference for patients in MASH. Now, what's next for Inventiva? Right. I'm standing here in front of you as a new CEO. You've just heard that we've brought on some new management recently as well. That is to prepare for what we have as real milestones coming up in the next two years. We are super focused for the next year on delivering the clinical data, the top line results in the second half of 2026, and then launching this therapy in 2028. I feel very privileged to have come into a company that has had such a wonderful asset developed. I feel privileged to be able to bring my experience in launching therapies both in Europe and in the U.S. to Inventiva. I think that we have a very bright future as a company. I'm going to get off the stage in terms of the background, actually hand you to the experts that can tell you much, much more about MASH. I would like to hand it over next to Dr. William Alazawi. Excuse me. He's going to bring us through pan-PPAR in MASH. I think I need that actually, so leave it on the podium. There we are. Okay. Yes, I'm William Alazawi. I'm a Professor of Hepatology in London. It's a real pleasure to be with you here in New York City today. I'm very excited to talk to you about PPARs, PPAR agonists, and how those mechanisms link into steat, hepatitis, and fibrosis. Andrew's already touched on this, and I'm sure I don't need to tell this audience that metabolic dysfunction-associated steatotic liver disease is a spectrum of disease entities that starts with the accumulation of steatosis or fat in the liver. A proportion of those people will go on to develop steatohepatitis, which is the inflammatory, progressive form. When that fails to resolve, you get fibrosis, or scar tissue being deposited in the liver a little bit more, fibrosis is a bit more again, and patients can progress to cirrhosis. That increases the risk of developing liver cancer or liver failure requiring transplantation. You only need to look at just how common this condition is amongst people living with type 2 diabetes or with obesity to really hammer home the point that this is a metabolic condition. At its heart, that metabolic condition is associated with liver disease, as we've already seen, but also increases the risk of cardiometabolic comorbidity or mortality also. What this graph is data that supports what we've known for a long time, which is that if you take the fingers of one hand and tot up the number of cardiometabolic risk factors the patient has got, then that indicates that the patient's going to run into trouble. If you look at what's underpinning those cardiometabolic traits, those are all closely linked to insulin resistance. That's a really important driver of this disease. We can't get away from the fact that the obesogenic diet and the effect that that has on the gut, the obesogenic environment, the societal factors in which this disease develops, physical activity, or lack thereof, all play a role. If you ask how much of that dietary composition is actually translated into fat in the liver, it's not that much. The vast majority of the fat that we see in the liver is a direct consequence of insulin resistance. Insulin resistance in the liver means that there's too much glucose flying around. Despite that, the liver is making new glucose, it's breaking down glycogen to make even more of that glucose pulling also. That's called De novo lipogenesis, which is also driven that way. That means there's new fat being made in liver cells. In addition, over in the adipose tissue, insulin is supposed to stop fat being broken down. A failure to respond to insulin means that there's excess fat delivery to the liver where it's stored and manifests as steatohepatitis. Meanwhile, in the pancreas, the beta cells are working super, super hard to make lots and lots of insulin and that's a problem. The muscles, which should be spending energy like it's going out of fashion, like wasteful teenagers if you like, are not doing what they need to be doing either. The lipid-loaded hepatocyte is not a happy hepatocyte. It activates reactive oxygen species, so oxidative stress activates inflammatory pathways that lead to liver cell damage, infiltration of inflammatory cells, and activation of resident inflammatory cells. This cascade eventually leads to the activation of stellate cells that lay down fibrosis and scar tissue in the liver. This orchestra of tissues and of cells within the liver that are driving the disease are coordinated or conducted by nuclear receptors. Prominent among those nuclear receptors is the PPAR family. Those PPARs affect lots of different roles. If you start with a PPAR alpha isoform, this is the one that's most expressed in the liver. This is the PPAR that, as the liver disease progresses, you get less and less amounts of it expressed anyway. Steatohepatitis and fibrosis are both associated with low levels of this PPAR alpha. It maintains healthy carbohydrate and fat metabolism, turns on fatty acid oxidation, the burning of fat out of the liver cell. It also has effects in the adipose tissue as well, where it's doing the same sort of thing. The beta delta subunit has got lots of effects across fatty acid oxidation, but really excitingly has an anti-inflammatory effect on those infiltrating immune cells and also suppresses the fibrosis-producing cells. Finally, PPAR gamma is the isoform that's also involved in maintaining healthy adipose function. Fat tissue biology is maintained by PPAR gamma. It also insulin-sensitizes, so it reverses some of that insulin resistance that we've got. That adipose biology is really important because there's a redistribution of weight from the unhealthy visceral adipose tissue through to the subcutaneous adipose tissue, perhaps speaking a little bit to the weight queries that have been raised. We've known about PPARs for a long time and we've known that they're really critical in metabolic diseases. In the early 2010s we had the PIVENS study and Professor Sanyal, who's going to follow me, was the lead author on that New England Journal paper and that proved the concept that modulation of this class of nuclear receptors could affect steatohepatitis. There was significant improvement in steatohepatitis. Despite the fact that there was no effect on fibrosis, the drug was prominent and recommended in various guidelines around the world. The field didn't stop there. There was work around the receptor understanding, more around that, understanding more about developing drugs that could activate those receptors, such that now already in routine clinical practice we've got PPAR agonists being used for liver disease. That brings us to lanifibranor, which is, as we've heard already from Andrew, is a pan-PPAR agonist. It's different, it's not a glitazone. It is a small molecule, which means it can be taken orally, it doesn't need to be injected, it induces different cofactors and it can be taken once a day. There are two different doses being worked up at the moment. The graph on the left is in pharmacology that just demonstrates that it is acting across all three of those PPAR subunits. That's concept, that's mechanism and sort of theorizing as to what may be going on. Actually, when you give the drug in, here is an experimental medicine setting. This is a very carefully constructed study where a small number of people were given either lanifibranor or placebo and then fairly sophisticated metabolic parameters were assessed. You can see over there on the left-hand side in the graphical abstract that lanifibranor led to a reduction. Intrahepatic triglycerides reduced, reduced insulin resistance. Adipose tissue insulin resistance went down as well and the muscles also responded. I'll draw your attention to this adiponectin increase by twofold. We'll come back to that in a moment. In the native, the phase II-B trial that we've just heard about, we're going to hear more about in more detail in a moment. There was a reduction in fasting glucose, reduction in triglycerides, and an increase in the good cholesterol, HDL cholesterol, all speaking to a wider metabolic benefit in addition to the headline liver results that we see. When we think about inflammation, systemic inflammation, ferritin going down, highly sensitive CRP, all of relevance to cardiometabolic diseases improving, and adiponectin going up as well. Adiponectin is an adipokine, that means it is made by adipose tissue and it's involved in insulin resistance and sensitization, but it's also anti-inflammatory. I think that makes for a very fascinating readout. The other thing to consider, and I'm sure you are all aware of this, is that this is not happening in a vacuum. Patients, when they arrive with a diagnosis, albeit they may be underdiagnosed when they arrive with that diagnosis, may already be on medicines for their cardiometabolic comorbidities, so GLP-1 incretin use or SGLT2s. The evidence base for these medicines is broad across that metabolic spectrum. With respect to response in terms of liver disease, the doses that they may be on may differ, adherence may differ, and reimbursement issues. Certainly where I work, I work in the United Kingdom, you know, access to these medicines is not as widespread as one would expect based on their indication profile. Updated guidance, for example, in type 2 diabetes would suggest that these drugs should be used earlier. In fact, you might almost call them sort of first and a half line after metformin if you really read between the lines of the ADA guidance. That means that patients with MASH may be on drugs that have an effect at diagnosis. When we think about what a drug might do, what drug we might use, we need to think about how we partner with that. Could I imagine a synergy between, let's say, a pan-PPAR like lanifibranor and a GLP-1 backbone? The answer is probably yes, because that synergy would look good in terms of improvement in HbA1c, insulin sensitization, and lipid profile. You've got the weight loss independent effects of the PPAR, together with the weight loss mediated benefit of the GLP-1. You've got improved dyslipidemia and triglyceride levels, which has got a cardiovascular benefit as well. I've mentioned the adiponectin. In summary, what I think I've shown you is that lanifibranor, through its mechanism of action, acting across all the PPARs, improves insulin sensitivity. I hope I've made the link between improving insulin sensitivity, the mechanisms of disease, and what outcomes we want in our patients. Thank you very much indeed for listening. What I'm going to do now is hand over to Professor Sanyal, who's going to talk to us about the clinical data. Professor Sanyal, thank you. We heard a lot about the basic mechanistic rationale for using pan-PPARs. We move on to now looking at the clinical trial data. My name is Arun Sanyal and as noted over here, I'm the Co-PI for the NATiV3 trial. The clinical foundation for where we are today started with this NATiV trial, which was a phase II-B trial, which is a very classic phase II-B trial. Remember, this trial started many years ago and the world has sort of evolved since then. It was a straightforward two doses of lanifibranor vs placebo, biopsy at the beginning, biopsy at the end. What was remarkable about this was two or three things. One, that it was less than stage four or five, so excluded cirrhotics. There were some people with stage one disease. Number two, it was a 24-week study, so it was a relatively short study. We were looking at the two classic endpoints. One is resolution of MASH without worsening of fibrosis. The other one was improvement in fibrosis without worsening of MASH. I'm going to show you the data over here, but also showing some of the comparable data from some of the other molecules that are currently under development. What I'll point out to you over here is not to necessarily obsess about any single number, but what it shows over here. These studies are of different sample sizes, you will see, and they're also very importantly of different durations. The inclusion criteria are not exactly the same. I think obsessing about individual numbers is probably not the best way, but it gives you a gesture. The goal of phase II-B is to give you enough confidence to go into phase III and to design your phase III program for success. What you see over here, this was the first molecule that actually hit both endpoints, which was a combination of MASH resolution and fibrosis improvement. There's an AND up there, and it was the first one with a 7% in placebo, 31% at the higher dose of lani. The comparable numbers are shown for the other molecules that are over here. If you break it down into the two individual components, what you see is that these are the data for fibrosis improvement. A lot of people obsess about fibrosis improvement because fibrosis tells you about proximity to cirrhosis. Cirrhosis is when you have clinical outcomes. Fibrosis improvement gives you greater confidence that you are actually going to slow down or reverse the progression towards cirrhosis. Here again, 24% vs 42%, almost a doubling compared to the placebo arm for lanifibranor. Comparable data are shown for some of the other molecules that are currently under investigation. When you look at MASH resolution, invariably for most drugs targeting the underlying root cause, the MASH resolution numbers are a little bit higher than the fibrosis because you first have to basically put the fire out, that is the MASH, and then that translates into fibrosis improvement. It follows sequentially. In these short term studies, remember, this is only 24 weeks, only six months, which at the time was thought, really, how could you even show that? At the time these studies were being designed, it was felt that it takes 2-5 years to see fibrosis to shift. There was this trial, the FLINT trial, other trials that showed that it could be moved relatively faster. Over here we are seeing a very robust benefit both in terms of MASH resolution and fibrosis improvement. While all this was going on, the world keeps moving and our large population of patients with MASH continue to age. With the aging, we are seeing more patients with diabetes. There's a global trend that within the MASH population, the proportion of people with diabetes keeps increasing, the proportion of people with more advanced fibrosis keeps increasing. This is sort of the aging of the cohort effect. We've previously shown, these are data from the NASH CRN that Daniel Huang showed, that even early on, within 2-3 years, you're beginning to see a little separation, that diabetic patients tend to progress more than the non-diabetic patients. What you see on the other side, on your right hand side, is that lanifibranor in phase II-B nicely reduced A1C over and on top of any background therapies that the patients received. This gives us a lot of reassurance that we're not only treating the liver disease, but all of the metabolic dysfunction around the liver that is also driving liver disease. Remember, these are competing threats to life. In the long term, at least as physicians, we are very interested in making sure all the threats to life are taken care of. When you actually take a look back then into the phase II-B data and look at all these endpoints in our diabetic population to really see are these people well served with this molecule, what you see again compared to, you have all the endpoints listed over here. We'll go from top to bottom. Resolution of MASH and improvement in fibrosis, if you look at the 800 mg, clearly it works somewhere for these different endpoints between 3 and 7.5 to 8-fold jump in the response rate, and then a little incremental jump over to the 1200 mg dose. What it shows is whether you talk about resolution of MASH, resolution of MASH and improvement in fibrosis, and then particularly in the lower two sets of data where you look at the F2, F3 population, remember this is our target population. Once you get to F2, your overall risk of mortality and your liver-related event starts going up, which is why from F2 onwards we call it clinically significant fibrosis, because that's when people start having outcomes in those populations. You see these retained benefits. Even in a higher risk diabetic population with F2, F3s, you are seeing that the benefits are actually retained. To continue on this sort of conversation about the overarching benefits beyond these liver-related endpoints, what you see on the four quadrants in each of these, you see actually improvement in liver enzymes, which is of course a classic way of looking at liver numbers. You do see, I think Bill showed the improvement in HDL cholesterol and triglycerides. It's relatively flat on the LDL, and then an improvement in A1C and then markers of insulin resistance, both liver, whole body, muscle. Sort of a really nice profile of metabolic benefit. In those days we were very concerned, and especially with a short study, whether histologic assessment, which carries some noise, might mislead us. We wanted reassurance that we wanted some biochemical markers linked to disease development and disease progression that would say, you know, this is really, we're looking at real data. We had some fibrogenic markers. Pro-C3 is a marker of fibrogenesis as opposed to fibrosis alone, and then we have markers of apoptosis, which is CK18, some inflammatory markers, and compared to placebo, as you can see, lanifibranor had a beneficial effect on these, again telling us that these histologic changes that we saw, that this actually, there's real biology behind it. This just gives us reassurance. Of course, efficacy is one side of the story. The other side is tolerability, always. When you look at this, you can see overall in the phase II-B, there's really no signal that really dramatically jumped out. I will point out to you there were a couple of things, a little bit, few patients with anemia, very easily manageable, and nobody who actually had to really stop because of any of this. Otherwise, there was really nothing that jumped out. In terms of tolerability, most patients took the medicine and were able to handle it quite well. I will also point out that small amount of weight gain that was noted. It's part of the PPAR gamma profile, and it ranged between 5 lbs and 10 lbs, sort of the average for those. It was a small number of patients. It was 10% of these patients. That's actually the weight gain as the number of patients or percent of patients who experienced weight gain as opposed to amount of weight gain. The question is, if they do gain some weight, is that a bad thing for these patients? What we see over here, it's a lot of data over here. I'll walk you through it a little slowly. What we've done is in the lanifibranor arm, broken it down by those who had stable weight, moderate weight gain, or those who had more than 5% weight gain. For the placebo arm, there are two. The dark one, which is stable weight, and the light set of data, which is those who had weight gain. What you are actually seeing over here, number one, is that regardless of weight gain, the HOMA-IR, which is a marker of insulin resistance, the triglyceride level, the ApoB, which is a cardiovascular ApoC, these are cardiovascular risk factors. They are liver enzymes. This is the liver fat with the FibroScan and the C-reactive protein all moving in the right direction. They're still becoming metabolically more healthy. They're less metabolically inflamed than, you know, despite that weight gain. Now look at the placebo data on the other side over here, and you're seeing all the numbers going in the opposite direction. A little bit of weight gain in the placebo arm had a much different biochemical and physiologic impact than in the lanifibranor arm. This again points out that, yes, you do get some weight gain, but the patient is still getting a lot of metabolic benefit in this context. That has to be placed in context as we think about these drug therapies. Together, all of this provided the basis for the development of the NATiV3 or our phase III program, which, as you heard, is now fully enrolled. We're now eagerly waiting to get it to the finish line. Essentially, you have the main cohort which has about 1,000 patients. We are recapitulating the same population, recapitulating the same design. We expect to recapitulate the results of what we saw in the phase II-B study. You're seeing a non-cirrhotic F2/F3 fibrosis, 72 weeks. Those who sort of screen failed, many of these people had F1- F4, they're going into this exploratory cohort with 400 patients who will also get randomized. At the end of 72 weeks, there is a possibility for this 48-week extension. The key readout is going to be at that 72-week mark, but then there is a 48-week extension where those who were previously on placebo will get randomized to 800 mg or 1200 mg and the rest who are on 800 mg, 1200 mg will stay in their original dose frame. The primary endpoint histologic is this composite endpoint of MASH resolution and at least one stage fibrosis improvement. The key secondary endpoint, of course, are the usual ones of MASH resolution and fibrosis improved. Those who are on GLP-1 agonists for more than three months on a stable dose and meet the eligibility criteria will be allowed in. This is all in the statistical power with a large number of patients that we have to be able to clearly demonstrate the histological benefits of lanifibranor. The baseline demographics that can be shared is sort of, you can see it's about 58% female. We are seeing the data for NATiV3 vs NATiV side by side and you can see very comparable. We're basically recapitulating our phase II-B study population, very similar to many other phase II-B, phase III programs, nothing unusual. We will have more F3s in NATiV3 simply because in the first one we had 20% stage 1 patients. Now we don't have stage 1 patients in the phase III because that's not the target population. It's stage 2, stage 3. Those get replaced by the more advanced. You could argue that bridging fibrosis or stage 3 is really the sweet spot in MASH where you can still turn the ship around relatively easily and they are at clearly increased risk of outcomes for sure. This is their liver disease profile. This speaks to the increase in the F3 proportion that we expect to see. You're seeing again very similar LSM, SCAP, FIB-4, ELF, AST, ALT, all the usual liver-related parameters. We're really recapitulating our phase II-B program. Our co-medication profile: the majority of our patients are not on SGLT2, they're about 10%, and so far pretty low numbers with SGLT2 and GLP-1 receptor agonists. We're getting about 10%, 14% in that, about 14% were on GLP-1s previously. If you take 1,000 patients, we're very well positioned to actually be able to even see what the incremental gain over in this particular population would be. With the caveat these are people who are on GLP-1 and still met eligibility criteria after a period of time of GLP-1. It's not all GLP, but it's a select population on GLPs. What I think I've shown you here is that the baseline characteristics for the NATiV3 and NATiV2 are quite comparable. The design, of course, is virtually identical. There's a greater representation of patients with type 2 diabetes, and we have more F3s, but there's a strong efficacy signal in diabetic patients in phase II-B with fibrosis improvement and MASH resolution that were a little bit higher in type 2 than in non-diabetic patients. The numbers are provided over here. These numbers are placebo-corrected, by the way, and then NATiV3. Therefore, I think we're well positioned to, again, as I mentioned, look at also the incremental gain over background GLP-1 kind of therapies. I think we can say that with this differentiated pan-PPAR mechanism that Bill very eloquently walked us through, this puts us in a very good place. We're looking forward to getting this trial, NATiV3, finished and hope to present those data in a year, year and a half, year's time. Next, I think now we've gone through the trial data and I'll hand over to Dr. Nid Afdhal, who's going to walk us through sort of his real-world experience. We are taking you all the way from basic mechanisms through the trial data to what actually happens in the real world. Nid? Thanks, Arun. Good afternoon everybody. I'm Nid Afdhal. I'm a hepatologist. I have a longstanding interest in liver fibrosis across multiple diseases and I am also a practicing clinician with a very large practice of patients with all sorts of liver diseases, including MASLD and MASH. We've heard from the last two speakers very eloquently the pathophysiological profile of how a pan-PPAR can work. Incredibly important because it's targeting all of the key components that lead to disease progression. It's targeting inflammation, it's targeting apoptosis, it's targeting the fibrotic mechanism through the inflammatory and apoptotic pathways. We've heard of the really outstanding results that were seen in the initial phase II-B trial for a short duration of treatment. Our expectation, and it's just an expectation because clinical trials have to complete, is that we're going to see a significant response in terms of the results of the NATiV study, and that that response will give us another therapeutic option. Why is that important? As I go through what's happening in the real world, what you're going to see is that no new treatment comes out in a vacuum. It comes out in what is actually happening in practice. Where does that treatment fit in, and what role can that treatment play, and how can it be optimally utilized to benefit our patients? I hope I'm going to show you some of that because I think we're excited about treatments with new mechanisms of action. If we look at what we have had, and we still have it today, and this is actually probably the slide that indicates what we spend most of our time talking to people about, which is lifestyle modification. We want people to change their lifestyles. We want caloric reduction, intake. We like some of the fancy diets that are out there, like the Mediterranean diet, the low carb diets and stuff. We want to promote weight loss. This five years ago was done through conversations. Now it's done through modifications that take place with incretin use. We get a lot more weight loss. We promote exercise. Why? Because exercise improves insulin resistance. It affects the basic mechanism of disease. It has muscle utilizing carbohydrates, and it has muscle improving hepatic health. These are still very, very strong there. We have the bugbear in the room, which is alcohol. It's very important to realize that many, many of the patients that progress their disease are not heavy alcoholics, but they drink alcohol and they have a component of what we call MET ALD, which is metabolic alcoholic liver disease. The combination of the two and alcohol cessation becomes very important. It's a key factor when we think about some of the agents that we're using today, because some of those agents actually take away both the cravings for alcohol. They also make patients less likely to drink as much as they were in the past. I'm thinking of the incretins in general. Weight loss works, but it's hard to get it. All right? It's hard to get it. Prior to the GLP-1 agonists and the incretin families, we really weren't seeing a lot of weight loss. If you look at some of the older data and the older literature, which was biopsy controlled, what they showed was that weight loss is associated with lots and lots of the histological benefits that take place when you treat people and try to reverse MASH. You actually can end up with fibrosis regression when you have significant amounts of weight loss in the 10% range. Not everybody will have fibrosis regression. Overall, that's very, very important. You can look at it another way, and you can look at it according to bariatric surgery. In bariatric surgery, you promote significant weight loss. You also get metabolic changes that take place. Not everybody benefits from the weight loss. It's somewhere around 40% will have reversal of fibrosis with the weight loss that comes from bariatric surgery. Weight loss per se is very important, but it's not enough, all right? It's not correcting all of the problems that we have to deal with. Now we have two drugs, all right? We have choice. Choice is always very good. We can use a drug individually or we can use drugs in combination because a lot of treatment of complex diseases requires multiple drug use. We've done all of the initial, you know, be a good boy, don't drink alcohol, lose weight, do all these cool things, and most people haven't done it. Now we're going to go to what we have available to us. I've put this up as a way, and this is a personal opinion, as a way that we look at the two choices we have between the various families of incretins and resmetirom. As you know, both agents are pretty good at MASH resolution. These are placebo-adjusted numbers, which means this is the difference from the clinical trials of those on the drug versus those on placebo. You can see that MASH resolution is pretty good. Then we look at fibrosis improvement. You would have to say this is modest, all right? This is fibrosis improvement from the phase III trials of 72 weeks of treatment. Remember, the data that Arun showed you was better at only 24 weeks of treatment. The longer you treat people, the more resolution it's possible to get from fibrosis. Fibrosis resolution takes that key word of time. This is a modest improvement that we see in fibrosis across these drugs. They have both certainly got other benefits. They both have some degree of benefits on type 2 diabetes and cardiometabolic benefits. That is where the GLP-1 agonists really strike out strong. You're all well aware of this, that there's significant improvements that take place in all of these parameters of cardiometabolic health. We want to point out that we're treating a patient, a person. What do most people with MASH die from? They die from cardiometabolic disease, all right? That's what they die from. They have heart attacks, they have cerebrovascular events, they get progressive renal failure. You have to consider the improvement of cardiometabolic disease as a key factor of treating a patient. That's why we like what we see in the cardiometabolic profile of the pan-PPAR agonists like lanifibranor. We see good cardiometabolic benefits across both diabetes and across cardiovascular risk factors. There comes the component of ease of use. Ease of use is a very, very important component when physicians make choices of what to use. All right, if you work like I do in a major liver center, in a major university, in a big, big hospital, you have something that a lot of people don't have, and that's resources. You have really good resources. I have nurses, I have PharmDs, I have nurse practitioners, all of whom are being trained to be experts in liver and cardiometabolic health. They can help us with all issues that we face. Titration of GLP-1 agonists, tolerability in dealing with the side effects, which is relatively straightforward, patient-related concerns, and the high discontinuation rates that we hear about for GLP-1 agonists don't happen as frequently as you think. When patients are managed appropriately, our retention rate is about 85% at one year. That means that we keep patients on treatment, especially if you're seeing the cardiometabolic benefits. Having said that, resmetirom is a phenomenally easy treatment to use. The side effects are relatively easy to deal with, the GI side effects, and very well tolerated by the majority of patients. Let's look at how we've been doing over the last year. This is a snapshot of some data on our patients from maybe a month ago. This just looks at the patients that we have and what they're on. I'm putting this up because I want you to understand that the real world is different from the clinical trial world and it's different from the FDA approved world. All right? It's the real world. It's when you're faced with a patient, you have to decide what to do. Let's start off by looking at who we're treating. If you look at the disease stage, these drugs are approved for F2, F3 fibrosis. This data is only about patients who are started on treatment in the MASH and hepatology clinics. These are not diabetics like Arun mentioned that come in already on an incretin. These are people that we have decided we want to treat because they have features to suggest cardiometabolic disease and liver disease. You can see that a significant proportion are F0- F1 and a significant proportion are F4 or cirrhotic. That's not what we should be treating, but it's the patient that we're treating and they have reasons for us to treat them. F2, F3 account for about a third. When you contrast that with resmetirom, much more focused utilization, predominantly in the F2, F3 population. Different practices go in different ways. Biopsy has disappeared from armamentarium in clinical practice to a great degree. The majority of these patients are staged based on something like FibroScan elastography, which we use basically as our go-to test for staging. What is approved recently for the treatment of MASH is obviously Wegovy. The reality is that we treat them with a whole variety of different GLP-1s. Why? The why is because we can't control what GLP-1 we can get for an individual patient. We have no ability. We can't say, well, we absolutely must have X because different payers have different preferential GLP-1s. Our decision is to treat the patient with a GLP-1 for their liver and cardiometabolic benefits. We will use whatever we can get. Therefore, you can see that there's a broad range of utilization of these drugs in our patient population. More interestingly is how is resmetirom used? A lot of the time the patients that we see, about half of them already come in on a GLP-1 and they come in on the GLP-1 and they have evidence to suggest that they already have ongoing and continuing MASH. They have high FibroScan scores. We're worried about them. They have abnormal liver function tests, many of them are not on the optimal dose of GLP-1. We will up the dose of the GLP-1. A lot of those patients go on combination therapy. I think when you talk to people that are in big centers, you'll realize that about 40%- 50% of our patients that are on resmetirom are on it on top of a GLP-1, which is very important because that may look like what the future in the therapeutic space may be as we get to 2028 and these newer, more potent, we hope, drugs like lanifibranor get approved. It's a process. You have to go through a fairly big process to get this. You have to diagnose and stage the liver diseases as appropriate. You need to have a lot of support to get them, particularly for the GLP-1. There are differences in different areas of the country as to the ease of access to these drugs. Massachusetts, where I work, is relatively good in terms of allowing us to prescribe these things. We have been also, recently since the approval, able to get, with the specific diagnosis of MASH, GLP-1s approved for the treatment of MASH. We've also got it approved for the treatment of sleep apnea. Everybody with MASH has sleep apnea. If we have difficulty getting it approved for diabetes, do we just say, oh, it's for sleep apnea? At the end of the day, we always want to treat our patients. The question becomes, and this is an important question because nobody has answered this question yet, this paradigm will change over time. More people will enter the treatment pathway for both of these drugs with MASH as the primary indication. What we haven't seen to date specifically is what is success? We haven't been asked by payers yet, what is the success of your drug? How do you know that it's working? We need to develop, and there are some guidelines, although those guidelines are very nonspecific. We have to develop individually what we believe is evidence of good success. When we put people on these drugs, what we're looking for is a stepwise improvement. We're looking for the first step on either of these drugs as improvement in steatosis. These drugs melt fat out of the liver. You can look at this based on the clinical trials, based on the MR data that shows that they melt out fat. You can lose 60%- 70% of the hepatic fat fairly quickly. Our first step at six months is has the CAP score and elastography gone down? Is the fat improved? The second step at 12 months is how is the fibrosis doing? Is it stable? Has it gone up? Preferably, has it gone down? As long as there's stability in that score, we're also very, very comfortable to say we're having success because, again, resolution of fibrosis takes time. The MASH world is a very, very interesting world because it's not just liver disease, it's cardiometabolic disease, where the liver is also one of the major players. We don't follow the guidelines simply because, you know, in reality you're dealing with patients. A lot of the incretin use that's being used is expanded outside of some of the guidelines that are there for MASH drugs alone. When you look at the diagnostics that are being used in the real world, it's all over the place and it's very uncommon, clear how people stage the liver disease to say it's F2 or F3. Those staging things that we use today are also not foolproof. A lot of the decision analysis to treat somebody with MASH is based on clinical risk factor profile, ALT levels, FibroScan scores, etc. You try to compile all those together and determine whether you're going to treat somebody. What that means is that you're under treating some people and you're probably over treating some people, but at the same rate with such a huge population, it really is a lot of people that are out there. You need a lot of resources to use incretins. I think that at the end of the day, incretin use is something now with the new indication that we're going to see more and more of our liver and GI colleagues, but mostly our liver colleagues, begin to use more and more of these. I imagine in 2028, a great proportion of the people that we see are going to be already on baseline treatment with an incretin for its other cardiometabolic, etc things. Resmetirom use is simple and it's being prescribed and it's doing well in F2, F3 patients in terms of its utilization. You have to say that overall effectiveness is basically how effective it is in clinical practice. We don't know yet from real-world data, but both agents are relatively underwhelming. It hasn't hit the 20% mark rate in clinical trials. In the real world, in the majority of cases, true clinical effectiveness is worse than the efficacy that you see in clinical trials. What that actually means is that you're going to see all these people on GLP-1 agonists and 80% of them probably are not responding adequately in terms of their response from the liver point of view, although they may be responding well from the cardiometabolic risk factors. That secondary benefit of the cardiometabolic benefit, I think, is what's going to drive its use in patients with MASH. Where will we be in two years' time in 2028, 2.5 years' time when we begin to see some of the newer, clearly more potent agents from phase II coming out and available for use? We'll have a lot of patients, and as Arun pointed out very nicely, the number of patients actually just keeps going up and the number of patients with complications, including diabetes, keeps going up. We're going to need better antifibrotic agents. We're going to need agents that can push that envelope up. 25% is really, really good. 30% above placebo is outstanding in terms of what you would expect at this stage. We're going to be seeing these drugs being used on top of the majority of patients who are on GLP-1 agonists. The world and opportunities in MASH are going to be very different in 2028. We're going to have background therapeutics. We p robably have data on some of the early combination therapies, but we're going to have a space in which more potent, more effective agents that have both anti-fibrotic, anti-inflammatory, anti-apoptotic, and cardiometabolic effects like lanifibranor are going to be really revealing effective agents to add in and to treat patients with MASH and MASLD. Thank you for listening to my opinion, not fact. Do we have. I'd like to ask the three physicians and Henry, whom we haven't met yet, but we will, why don't we come on up and populate the chair. Thank you. Henry up, the room. Do I have a mic? My name is Henry Chang and thank you. My name is Henry Chang. I'm the Executive Director of the Fatty Liver Foundation, which is a patient advocacy organization established in 2019 by Wayne Eskridge. I think some of you may know Wayne, who's a MASH patient, and I'm based here in New York City. Really delighted to represent the patient perspective in this discussion. Thanks, Henry. I want to thank the physicians, Dr. Sanyal, Afdhal, and Alazawi. Your passion is clear for the field and for the work, and we're grateful for your time here today. I'm going to open with a briefing yet, get into a quick, an important Q and A here with the panel. When I first met Wayne Eskridge, back when he was starting the Fatty Liver Foundation, his story was very clear. He was basically living a life in Idaho, I think retired and happy, just moved out there with his wife Rosemary, and he went in for a routine laparoscopic gallbladder procedure. They popped in the camera and what they found was nodular cirrhosis due to NASH. That story in 2015 would make us think, wow, that's terrible, right? No one knows anything about this disease. That can't happen anymore. Now it's 2025, right? Prior to coming to Inventiva a few months ago, I was at a small startup in Boston and I had a colleague there whose husband, middle 50s, healthy, energetic, young children, went in for a routine procedure and it's 2024. He walked in and he was determined to have cirrhosis due to NASH, completely asymptomatic and completely undiagnosed. When Nid was mentioning that he lives in a world in which people come in and they sort of have all these cardiometabolic problems and they're not being adequately diagnosed, and we look at the world today and you heard all of the physicians say we have more work to do. I just wanted to ground it in a real story that we have more work to do and that whatever Wayne Eskridge did back in the late 2010s to kind of get the Fatty Liver Foundation up and going, we're not done yet. With that, I'd like to open for the first question. I want to go back to Dr. Sanyal, but I want to note Dr. Sanyal talked about numbers, right? He was looking. You were looking at the graphs and you said, you know, sort of don't get bent out of shape or wound up around a given number. On the other hand, Nid had just talked about that. He called some of the data that he was looking at modest, his decision. He put out this sort of 20% threshold. We also know, as all of you have said, that this is about outcomes. In the end, liver-related and cardiovascular outcomes will ultimately drive this field. The open question, starting with you, Arun, is how are we supposed to think about all of this? I think I still have the microphone on, so thanks. I think this is a really important point. When we think about looking at these numbers and outcomes, the first thing to keep in mind is this is context specific. If you had a disease that would kill you 100% within the next six weeks, if you had a 1% improvement, I think you would try and take that, right. It is really context specific. Here we are talking about a disease which is a chronic disease, runs its course over 20 years or so, and there may be some people who are rapid progressors, but that's another conversation. Over here, to assess benefit in the long term compared to the natural history itself, which waxes and wanes, it is a very heterogeneous disorder. I think I agree with Nid, about a 20% placebo-corrected benefit gives you reassurance that this is enough to say, yes, we have something that works because there's also noise around each of these numbers because different studies have different results. There are confidence bands around the natural course of the disease and the trajectory of the disease. Until we have a number of these studies that have completed their outcomes, gone all the way to outcomes and read out the results, we will not be able to actually say what this means in terms of real hard outcomes, which is ultimately where the rubber meets the road. These surrogate endpoints that we use, whether it's histology or NITs, these are road stops along the way. We're making a best guess over here along the way based on these. Although it is not entirely a guess, it is based on all of these NITs. Other markers have data to support that, yes, when you see these changes, it's likely that these will translate into clinical benefit. William, I'd like to go to you on this point. I want to sort of stay in the depth here. Paul Angulo's paper was what, 11 years ago now that said it's all about fibrosis. When you opened with your talk, you spent a fair bit of time talking about the cardiometabolic elements here, particularly the role of insulin resistance and the role of adiponectin, the adipose tissue itself, in driving the disease. How do we reconcile this? You got fibrosis on the one hand, which everybody agrees is important. We just have two physicians up there said 20% looks like it's a reasonable benchmark. You spent a lot of time talking about the metabolic drivers. How do we balance that? Thank you. I mean, I think to keep it really simple, if you've got two cars driving down the motorway or freeway, the one that's going to get to its destination first is the one that has traveled the furthest, not the one that is revving its engine the loudest. The engine had to get it there in the first place. If you don't think about what's happening in terms of where the drive is coming from, you're not going to be able, as Professor Sanyal said, to turn out the fire. That's really what you need to. Be able to do. I think, yes, absolutely. You know, we don't want liver disease to progress. We measure that progression based on fibrosis. We know that if you've got more fibrosis, you're more likely to run into trouble sooner. That doesn't take away from the fact that actually what you really want to be seeing is an ending of the disease process itself. If I want to use another analogy, then think about viral hepatitis. Actually, the treatment for hepatitis C, the thing that's really made that difference, the reason why the transplantation rates are as they are now in terms of they've plummeted, is not because medicines to treat viral hepatitis reverse fibrosis, it's because they take away the primary injury. I think that's what we need to understand. What does it raise in Nid and Henry? Coming to you both. Henry, I want to start with you. This is complicated, right? How do patients understand any of these dynamics, and if they do, what matters to them? If they don't, what do we need to do to make that better? Absolutely. One thing I wanted to mention is that the Fatty Liver Foundation, we've been running an annual national survey. It's called the State of Steatotic Liver Care in America. We'll be presenting some data at the liver meeting. This is a survey based on a sample size, about 1,000 diagnosed adults in the U.S., and what's clear is that people really, what really values for the patient is whether a treatment affects their day to day lives. You know, whether that treatment reduces fatigue, reduces hospitalization rate, improves cardiometabolic health. That's what really matters to the patient at the end of the day. When we talk about the oral therapy that has the potential to shut down those drivers of disease activity that doctors sent out mentioned, that's what really resonates with the patients and the providers. Great answer. Nid, I saw you nod your head when Henry mentioned that. You obviously spent a lot of time talking the real world, right? Not the FDA world, not clinical trial world. What were you thinking when you were nodding your head? I think Henry's totally right. Your patients come in with symptoms. Sometimes those symptoms are often fatigue, they're often sleep disturbances, their anxiety related to having this diagnosis, and anxiety related to cardiometabolic disease, their diabetes and obesity. The reality is that every time you show them an improvement in something, you reinforce to them dramatically what benefits they're getting. Whether that improvement is normalization of their ALT, whether it's reduction in their CAP score, showing their steatosis in their liver is improving, and whether, as my friend Dr. Younossi has done in Washington, you show quality of life improvements, as Henry said, in daily functioning. These things all stress why patients want to be treated. Quite honestly, most of those benefits, a lot of those lifestyle benefits are coming from utilization of the incretin class of family. Fibrosis is something that they worry about, but it's less important to an individual patient than the daily factors of living support to us. I would make the comment that there is no liver disease, none at all, in which you are. When you can stop the mechanism of injury like a drug like lanifibranor does with stopping inflammation, stopping apoptosis, improving all of the lipid parameters. There is no liver disease in which fibrosis cannot be reversed so long as it's not fully established, irreversible cirrhosis. Every liver disease that we treat, we can reverse fibrosis in. The biggest driver of the reversal of fibrosis is control the disease and give it enough time. That's it. It's true for every single one. William, I saw you nodding your head too, and I want to stay here for a moment because when Nid gave his talk, he said that many of the GLP-1 agonist patients sort of come in needing additional therapy. The point that despite the fact that they're on GLP-1s, he just said again, but I'm sticking with the real-world here. Both you and Arun talked a lot about the extra and the intrahepatic sort of targets that are needed to address the disease. Can we lean into that a little bit more? Right. How does that look in the real world? What is it that we need to address exactly? It's less about lanifibranor and more about the diversity of the mechanism that we may need to come to bear on the problem. You know, we have three patients who come to clinic over the next five years. One might have a cardiovascular outcome, which might be the terminal event. Another one may have a liver outcome, you know, so somebody may have a stroke, you know. I think it's really, and I think Nid touched on it a little bit, that this is a very interesting disease in the sense that it takes us liver doctors away from what we know, which is very focused on the liver, to back to internal medicine, because now we also have to look at these competing risks to life. The person who has bad MASH also has got likelihood of having diabetes, heart disease, vascular disease, risk of non-hepatic cancers, all of the above. We have to make this assessment to help the patient. We need to address the totality of the threats to the patient. Some of these, we may say the primary care physician, you take care of it. Increasingly, as we understand this common biology that connects a lot of these conditions, we are becoming the caretakers for these patients, because frequently what happens in the real world is that as soon as a patient is identified to have liver disease, their primary care physician gets a little nervous about managing all of their different drugs because of the liver disease. Essentially, we become their quote, unquote doctor, you know, managing literally all aspects of their care. In that setting, it is really important that we not only address the liver disease, but also these other comorbidities that are threats to life by attacking the core root problem, which is linked to insulin resistance and the state of what we call metabo inflammation. William, you're nodding there. Please go ahead. It's obviously very dangerous to nod. You get picked on. Because I pay attention to it. Yes. I totally agree. One of the privileges I have in my role is I look after the diabetes and the obesity departments as well. I'm learning from my colleagues that this is not new in that we have got different drugs that can do different things. For the right patient, one makes the selection that addresses the unmet needs in that individual there in front of you. Our cardiologists are very comfortable choosing the best beta blocker in combination with the best antihypertensive, choosing the right lipid lowering medication. We simply need to recognize that can happen in a hepatology clinic just as well as it can happen in a cardiology clinic. To your original point about intra versus extrahepatic, ultimately, I don't think the patient in front of me necessarily is too concerned what the MOA is, what silo we decide to put the medicine in, does it work, does it achieve what it needs to achieve, is it a tolerable pill burden, is it something that the side effect profile is compatible with everything else that's going on. That's the reality in which we prescribe. I think that's what Nid, you've described really elegantly, is actually even down to the fact that you'll use whichever incretin you're allowed to use, that we individualize to the patient in front of us. Having something in the back pocket in the armamentarium that starts to address the underlying insulin resistance, I still think most people would agree mechanistically that is the main driver for progressive liver disease. Henry, does that match with what patients want? I mean, this sort of diversity of options? Do they want their doctors to come in and say, look, I have this new magic drug. It could be a GLP-1 agonist, it could be any other drug that's going to be a. Do they just want the doctor to tell them take this, should be fine? How do patients think about this? I think most patients really don't pay too much attention on the mechanism or action. As William mentioned, every patient really wants to know, can they stay on this treatment? Right. Ultimately, we talked about oral once daily treatment that doesn't trigger significant GI issues and injection fatigue, especially for those patients who can't tolerate GLP-1. This is where convenience is often underestimated in evaluation modeling, and patients ultimately are seeking simplicity and tolerability. That's what's really served as the bridge between commercial success and clinical success and commercial success. We've come back down, right again to the real world. We were talking earlier, some of the folks up there and myself, but Nid was not there. As an anesthesiologist, you learn one lesson early on. If the drug doesn't go in the body, nobody goes to sleep. It's very straightforward. What Henry is just saying is that patients just want a drug, if I'm interpreting it right, that they can take and that they know they can keep taking it because if they don't, things don't work out. Nid, coming back to you here, right in the real world, how important will that be? You sort of said at the end of your talk, in the world of 2028, you know, looking forward two years, how important will that kind of adherence challenge be to the future? It is always going to be a challenge based on two things, the ease of use. Injectables are more complicated than oral agents, obviously, even though the injectables are not that difficult and once a week is not that onerous, especially since many patients are diabetic and taking lots of medicines. Obviously, the side effect profile is the other one and their management of whatever side effect profile is out there. It is very difficult for me to have an issue with a lot of the treatments that we use because I know that we have a lot of support in our system that helps the patient get through it. I grew up in the world of high dose daily interferon therapy. If you grew up in that world, you know what side effects are and you know how difficult it is to keep people on treatment. I find that. Will an oral GLP-1 come out? Hopefully. If it does, that may be a really good thing in combination with other agents that are more liver targeted. Will we get combination GLP-1s with other mechanistic drugs in one shot? What are we thinking of? We are thinking of maybe a GLP-1 plus an FGF21 as a one shot therapeutic. Will that come out in the next three to five years? Maybe. At the end of the day, no matter what you do, Henry is totally right. You have to treat the person. If that person cannot take a GLP-1, it is useless. It is completely useless. You have to think of something else. That is the reality of where we live. This will be the final question. I'm going to give each of the panelists an opportunity to respond. I'm just generalizing the same question, though. Nid, you just said this is where I think the world might look like in 2028. I want to go back to something Andrew, a new CEO, said at the very beginning of this. He said, how interesting, right, that this market, how it's developed so quickly. Just four years ago, we've nearly, you know, we've 50% or more growth in the awareness of actual diagnosed patients. The base was pretty big. I think we showed 18 million people to something around 400,000. Now back to the group evolving landscape. William, it was in your deck, that beautiful slide, you know, metabolic landscape evolving. Now to each of you, maybe just starting with William, where will we be in 2028, do you think? It depends which healthcare system you're talking about, okay, and that's half joking but half real in the sense that depends on how these medicines land and how systems allow us to use them. Where will we be? I think we will have a better understanding of how a general metabolic health service looks like. I think physicians will be more acknowledging of the need to be holistic. That sort of liver on legs that you were describing will be a thing of the past. I think physicians will be better positioned because there will be medicines that are licensed for the treatment as there are now coming in my territory. I think that will drive recognition because it's not okay to ignore somebody's ALT, their FibroScan score, if there's actually a medicine that could be used for that. I think physician practice will change to recognize those more and I think we will be starting to get real-world evidence exactly as you present today. You know, those sorts of early nuggets of information are super important and they will craft our thinking around this. The more things we've got in the cupboard that we can use, the more rich our offering to our patients will be. Arun? I think it's always a little dangerous to try and predict the future. Fortunately for you, this is only webcast. No one will know. Yeah. I think the way I'm thinking about this is a few. A couple of thoughts to build on what I agree with everything Will just said. I think the future is going to be more holistic, more integrated. Already we're seeing in the larger medical centers a move towards these metabolic health programs, bringing cardiology, liver, everybody together. You're going to see more integration. Integration number two, my sense is that the GLP-1 agonists, because of the widespread benefits around so many different facets of metabolic ill health, are going to be part of the background and the future is going to be additional organ-based therapies layered on top of that. It may be that in that kind of setting a combination of an oral GLP-1 agonist plus something else, whether it's lanifibranor or something else, could be a base on which other things could be layered on. These are all open with question marks around them with more organ-focused therapies for those who have more severe individual end organ disease. I think at the end, again, the more choices there are, I think we're going to move towards prevention and also instead of waiting for organs to become terribly sick and then try and get small incremental gains at great cost, move towards prevention. That's sort of the way I see this whole metabolic health space evolving, but the more there will be a bigger portfolio of options. Given the heterogeneity of the disease, there are trade-offs. As Nid said, there's no free ride. Some people may have to deal with nausea and say I can handle this but I will take this, this is my, I'm willing to take this poison. Some people will say I may gain a little weight but I'm getting the same benefits and I don't want to feel nauseous and I'll take the other option. I think having more options is great for patients and great for physicians in order to be able to take care of our day-to-day business. Henry, you're going to get the last word from the panel. It's not a shock, right, that the doctors have this all planned out? Of course, it's straightforward. You think the patients will be along. For this journey, too. I'm completely aligned with what Arun just said, I think the future certainly is very bright. We're looking at the expansion of the armamentarium in the fight against MASH. What we see in the last couple of years is that there's more awareness around the need to detect this condition early, and there's certainly a number of industry-sponsored disease state awareness campaigns that are making meaningful impact, getting more and more people paying attention to this condition, getting their healthcare providers engaged. We're quite hopeful that the percentage that's been shown earlier, that 10% being diagnosed, can only continue to expand with the expansion of available treatment in the coming years. I want to thank the panelists for the genuinely good dialogue. I enjoyed it. I'm sorry for watching you all nod, but it was great for me. I think we're going to finish with the panel, and I have a wrap up for Andy. Thank you, Pascaline, for helping with that. Good. Thank you everyone. I think it's bring it over. What we're going to do is. We're going to bring up everyone for a Q and A. Before I do that, I wanted to just summarize what we've heard today. Number one, treatments have been approved but unmet medical need persists for liver-directed therapies. I think we've heard that loud and clear. Two, lanifibranor, oral liver-targeted drug candidate, addresses both intrahepatic liver and extrahepatic metabolic cardiovascular components of MASH within six months. I think this is one of the key differentiators for lanifibranor. It's also the direct antifibrotic effects but also acting on the entire body. Our trial is fully recruited, phase III. That trial design has been informed by a positive readout of a phase II-B study. We're now focused and structured on being able to execute the delivery of the top-line data as soon as the second half of 2026. With that, I'd like to invite up the panel. Mark, come on up. And Jason. We're just going to take Q and A. What? And Martine. Where's Martine? Yeah, yeah. Without microphones and the physicians as well. Please take off your mic. So. All right, just give a second. Pascaline, are you passing around the mics? Okay, we're going to Pascaline in the back there. She's going to have a mic and she's going to choose people to do the questions first. So. Go ahead and state your name and affiliation. Let's start with Seamus and then go to Yasmin. Hi, Seamus Fernandez from Guggenheim Security. Just a couple of questions. Maybe we'll start with the panelists first. You know, the availability of resmetirom vs t he opportunity for lanifibranor. I think we had Dr. Afdhal provide some thoughts early on, but wanted to get a sense of the development of the market as you see. With the availability of resmetirom, how has the endocrinologist actually started to? Integrate with the hepatologist, and how much has the availability of that product changed the ability to catalyze forward movement, and how much more room do you think there is to go? Yeah, go ahead. Yeah, Nid and Arun, I think. Yeah. I'll take the last part of the question first. There's lots of room for growth and improvement. The reason being there's still a lot of non-responders both to resmetirom and to GLP-1 agonists, you know, as the PI for the ESSENCE trial as well. Clearly it's better than doing nothing, but there's a lot more room to grow. If I again pull on the hepatitis C analogies, this is somewhere like the Peginterferon days. We are not in the daily interferon. We've moved to the Peginterferon. I'm dating myself for those of you who remember those days. We're midway in this journey and I think there's lots of room. Endocrinologists are slowly coming around. They're lagged behind a little bit for a variety of reasons and I can only hypothesize why that might be so. I think Rezdiffra was developed in the liver space, so I think it's largely lack of awareness, lack of familiarity. Of course, because it's a thyroid pathway, they might have their own biases about how thyroid functions work. The whole Rezdiffra development came from the liver community, so obviously the liver community has embraced it with both arms and all of us are, I think, using it on an everyday basis. In general, experience is good, but there's lots of room for growth. I'm going to start off with saying, where will we be in 2028? I'm going to be on a beach having a very nice long drink because I should be retired by then. Where this space will be is it will evolve out of the hands of hepatology alone, out of the hands of gastroenterology and into the hands of many, many other specialties that are involved in cardiometabolic disease. I said this was going to happen with hepatitis C, nobody believed me. It absolutely happened. It will happen with this disease state as well. The reason it will is that there are so many patients that need to be treated. That treatment, as it becomes more simplistic, which I believe it will, with introduction of some of the more novel and oral therapies, is going to be taken up by people interested in cardiometabolic health. Right now, Rezdiffra is the go-to drug for gastroenterologists. Why? It is because it's much easier to give. They have a lot of patients they followed for years with MASH. They've got an oral agent, it's easy to use and they want to use it. They've got these patients they haven't treated in the past. That paradigm's going to change as awareness goes up, as other specialties get involved. I see this as, like Arun Sanyal said, we're going to have cardiometabolic units that deal with the whole patient and all the different aspects. I'm very excited if endocrinology gets involved. I'm very excited if internal medicine and family practice get involved, which I think they will eventually. Just one follow up question. As you think about the importance of bone health in these patients, patients as they progress, we have some questions that have been raised around other potential targets in the space. How much does that matter. In your evaluation of the patient? Obviously targeting the liver, but in terms of introducing a new therapy to F2, F3, how much might that weigh into your decision process? If you know, again, FGF21, we saw some interesting, maybe not the best i mpact on potential impact on bone. Questions there and just wondering how you think about sequencing therapy given some of those impacts. We need to see more of the actual data on bone health. To start off with, we basically got a snapshot of a negative effect on osteopenia at a fairly high rate and a fairly big decline over a short period of time. We really need to know more about the patients, who they were and where they go. Bones and liver disease go hand in hand. Bones are important to people who have advanced liver disease. Osteopenia from liver disease is incredibly common. Acceleration of that can lead to very bad outcomes. All of us have PBC patients that have died post fractures, post really simple things that happen from their osteopenia. We need more clarity and we need more knowledge and it is a negative side effect that we need to understand a little bit better. I just don't think we know enough about it. Yeah, I'd just add to that that it's only in the elderly patients. In the average middle-aged patient or a young patient, it really doesn't configure that much into our clinical decision making. In the older patient where there's this whole concept of frailty, increased risk of fractures, they have bone density studies done as part of their medical assessment. It has nothing to do with their liver disease anyways. In those, I think we work with the primary care physicians to try and maintain bone health as best as possible. That's standard of care. We're used to it too, by the way. I mean, don't think that for us it's nothing big. I mean, look at what happened with tenofovir and the two different forms and all the bone health stuff in HPV. We're used to it, but we need more information. I don't think we got enough information yet on it. Right, yes. Yasmeen, thank you for the great presentation. My God, what an awesome panel. Right? A decade of work in MASH, two approved therapies, two questions. Two and a half decades. Yeah, that's right, two questions. I think maybe we'll go with the easy question at the end. One question is that I think was very clear is that fibrosis gets better over time. NATiV2 is a 24-week time point. NATiV3 is 72 weeks. Given the depth of data that we have had over many years, how do we think about deepening of a fibrosis response on the lanifibranor arm? Also, how does that change in the placebo arm? If you could talk about that. The second question is, it was very nice to correlate weight gain with improvement in metabolic parameters, which I think a lot of investors are missing. We also know that the weight gain occurs within the first six months and it plateaus. Maybe it'd be good to understand the biological rationale for the plateauing effect. I'll ask Mark my easy one at the end. Maybe start with Will for the first time. Part of that. Can I push you in? Sorry, I was thinking about the second part. The first part of your question. Go there next. No, that's fine. The first question was? How does fibrosis. Should change from the week 24, 70? The answer is we don't actually know. I think what would make logical sense is that if you have improved insulin sensitivity, if you've activated tissues to keep burning out the fat from the liver, one would anticipate that if you saw a signal, you wouldn't then see a reversal, number one, because that's happened with other agents that have fallen by the wayside. Next thing to say is that not progressing is really important for the patient. I said it earlier. You don't need your liver to look amazing. You need not to get to advanced fibrosis and cancer risk. Over time, yes, indeed, I think that we would want to start to see improvements and see the fibrosis get better. We also know that the earlier the fibrosis is, the more likely it is to melt away. Nid told us that. If we're not treating too far down the line, then I think we should be seeing those improvements. We need to see. I think what we learned from the efruxifermin story is that, yes, you saw a certain degree of improvement at week 36 or 32, whatever that first time point was, but then we went to week 96. This is a remarkable jump. There are clearly people who are late fibrosis responders, if I may use that word, as opposed to the early fibrosis responders. I don't think we have a lot of data yet to understand the biology. I can hypothesize that there are people who have NASH resolution at week 24 or 36 who have not yet shown fibrosis improvement. That's the population that if you keep that NASH, the fibrosis benefit will catch up, which is why you have to treat the root cause. It comes back to what we were talking about again and again, about treating the root cause and the underlying disease to improve the fibrosis. You know, liver biopsy sucks. All right. In simple terms, it is a test that has so much variability in it across all liver diseases, and so there is an error there. You asked a question that prevention of progression, what's going to happen to placebo? 96 weeks, and certainly 72 weeks is long enough to see a significant proportion of placebo patients worsen. There should be more worsening than that was present at the 24 weeks. Data is always presented on the primary endpoint predominantly, which is reversal. In fact, progression is equally, if not more important. The FDA in phase III studies doesn't like you to present who progressed to cirrhosis. Why? Because they want to use that as an endpoint for the long term outcomes. Bad. That's really bad. Because there's a proportion of those F3s on placebo that progress and we're not giving that data. That's a bad thing. The most important thing to look at, which actually Arun Sanyal pointed out so beautifully, is that all the biomarkers, which are far more active than liver biopsy, are telling you what's happening in a patient with lanifibranor. In the phase II-B, all the biomarkers, every single one, moved in the right direction. When you see that, you know that the activity is there to prevent disease progression. I always look. Everybody looks at the number at the endpoint. I always look at the biomarkers because they're actually telling me what is dynamic. The liver is a dynamic organ. It's always in the phase of having fibrogenesis and fibrosis regression. You want to speculate? If at 24 weeks you see 18% fibrosis improvement, you could see significantly more, clinically significantly more, at that stage at 72 weeks. Sorry. All right. We had a question about the mechanism of weight gain. William, maybe back to you on that one. Do you want to actually, maybe, we'll go to our Medical Director here, Jason. Sure. If you were to ask any general practitioner what happens to a diabetic when you get them better controlled on insulin, the answer would be they gain weight. Answer number one: the weight gain is a pharmacodynamic marker of lanifibranor's efficacy, period, full stop. As insulin sensitization improves, glycemic handling improves. The best controlled diabetics are often the ones with weight problems. The inverse of that from just living in the world today in America, the Atkins diet is all about depriving your body of insulin and you lose weight under those circumstances. Step one, insulin sensitization drives weight gain. Step two is, as Arun mentioned very clearly, he asked the right question in the talk. What does this mean for the efficacy of a therapeutic? It depends on the therapeutic. If you live in a world and you gain weight, we showed very clearly with our placebo data, you're going to have worse disease. On the other hand, the GLP-1 agonists have clearly showed weight does matter. As we also know, it's not enough. What we find with lanifibranor is that it's the one thing that cuts cleanly through both problems. If you gain weight on lanifibranor, your efficacy is not only in evidence, it's actually better than patients who don't gain weight. It's an unusual circumstance in which we find ourselves today where we all acknowledge that weight matters. In MASH, on the other hand, in the case of lanifibranor, it is the one exception to that rule or maybe said differently, weight does matter, but not in the way that we've generally been simplifying it. Is that fair? Anything more to add? Yeah, just add one thing because as you mentioned, the apparent plateau effect with lanifibranor that was observed in the phase II-B study in contrast to PPAR gamma drug like pioglitazone. Right? If you remember the Piven study, you saw linear weight gain right through the two-year study phase. The hypothesis there, this is a pan-PPAR agonist, right. So it's probably PPAR delta, we think that's contributing to that. It's important also to remember, as Jason just mentioned, this is healthy weight gain, and as we've seen in combination with SGLT2 inhibitors and also with PIO in combination with GLP-1s, can be likely completely abrogated in combination on top of a GLP-1. Thanks. Ritu Baral TD Cowen. Actually, one of my questions is a follow-up to that. In the many investor conversations we've had about that weight issue, I wanted to ask the doctors, you know, where's that inflection point for you guys as far as that weight gain? When in your mind do you say up until this, obviously it's a function, it's an on-target effect of this mechanism, but beyond it now we're a little worried, like where is that line in the sand? I have a follow-up on secondary endpoints. Yeah. Why don't we go to the physicians first, and then we're going to go to our patient advocate as well. You know, because we know it's relatively so-called good weight gain, you could set your mind a number where you'll say, you know, if the patient gets a 3 kg weight gain, I can literally live with that. The real question is, what can the patient live with? All right. That's the real question. That requires education, that requires a discussion about, look, there may be a 2 kg- 3 kg weight gain and that's okay, because that's good weight. You know, we will look at that in context to the other parameters that show that the medication is working. That's a key conversation. I mean, if somebody gained 5 kg or 6 kg, I would be worried. I would be like, you know, this is probably going to give them a lot of problem. They actually don't like the edema as much as they don't like the weight gain. You know, when you talk to the patients, they don't like the edema. Nobody likes fat ankles. Yeah, I think it's very individual patient specific. Some patients will, you know, handle it quite well and some are less tolerant of the weight gain. Somewhere in the 5 lbs- 10 lbs is something that most patients can live with, depending on, of course, where you start. For the lean patient with MASH, it could be a different conversation. Again, you have to be careful that if you see a lot of excess weight gain, then is there something else going on, you know, in the issues about edema, heart failure? This is a population at high risk for all of the above. We see it in our placebo arms in every study as well. So. I think it requires clinical evaluation, but 5- 10 is sort of in general range. Henry, do you want to? Yeah, just. Just building on what Arun mentioned. It's very patient specific. There are individual patients among our membership who are more interested in weight loss. The primary driver for why patients get on treatment is the fear of dying from cardiovascular disease. If you can show them while on treatment that your cardiometabolic and liver metabolic are all moving in the right direction, that's really how most patients define treatment success. My second question actually goes to. Ritu. Can I add one sentence to that? That is the three Cs that patients we talk about. One is cardiovascular, one is cirrhosis, one is cancer. The fibrosis stage, all of this, they're not interested, they don't, I don't get it. They get cirrhosis. I don't drink, am I going to die? Cirrhosis everybody gets. Nobody wants either of the three Cs, so it's really about that at the end of the day. To that point, what is folded into NATiV3 to compete with that evidence of metabolic benefit and those markers along the same parameters that, you know, we had this discussion about GLP-1s, they help this and they help that, they help insulin sensitivity across tissues. What is the NATiV3 trial going to generate to help start that part of the discussion? Because one of the important parts of our model for lanifibranor is this idea of patients come in, they're on low dose GLP-1 and then you have something like lani. Do you add a lani or do you try to titrate up and deal with those potential side effect issues, like what's actually easier even from an endo? What is that? What are the secondary endpoints that address that cardiovascular, maybe cancer is too long, but that part of the reach for GLP-1 first argument? I can start. I'll then pass it on to Jason to really provide a lot of detail. I think from a high level you have to remember the timeframe over which these outcomes occur. Within the 72-week timeframe, unless you have 8,000, 10,000 patients, you'd probably not see a cardiovascular outcome signal. You look at surrogates like improvement in lipid profile, markers of vascular inflammation, you know, CRP, those kind of things. These are standard classical portfolio of markers that are linked to cardiovascular risk. That for sure would all be included. From that you sort of draw the lines to connect the dots, if you will, to sort of impute a metabolic health benefit in the long term. Hopefully there'll be larger data sets that will actually show real numbers for metabolic health outcome benefit. I'll pass this on to Jason to provide more details about specifics. Yeah, I think the details actually Arun gave a perfect framework and it's very simple. Call it XYZ axis, X axis drug work that you hit the primary and the key secondary endpoints. Axis number two, when you look at are there non-invasive technology data to support those histologic endpoints just like we showed in NATiV2, that could be FibroScan, other Pro-C3, a diversity of those to give confidence that the drug works. X and Y are all about this drug work. Z, are those cardiometabolic components, are they tracking in the right direction? You take those data sets and you just cut them in quartiles or thirds. Is it the same in people that have no weight change, modest weight gain, and more extreme weight gain? We believe that those, that core XYZ cut in that way, will give providers enough data to have the conversation that the physicians just said. I would go back to the physicians. The question is, is that right? We think it is based on the phase II-B data. That's why we built the study that way. That's all that providers would need. I believe that we're aligned on that. It's a good come to Jesus moment because we're all here talking about it now. Could NATiV3 generate the sort of data that would let you in your head comp adding lanifibranor versus titrating up a GLP-1 agonist? It will? I actually think it will because you'll have patients coming out of that, that you'll see better control of all the various cardiovascular. You'll see improvements in hemoglobin A1c. Most of the people that we see that are already on low dose of the incretins and therefore diabetes-related issues will see improvements in the factors that were mentioned in terms of CRP, lipid profile, fasting glucose. They're measuring everything. I think that there will be enough to say, oh, look at this, these are all positive cardiometabolic events. I don't need to take the risk of titrating that patient's GLP-1 up to full dose and risking him having bad side effects or whatever. I can just add on top for both the cardiometabolic benefit and the liver benefit. I could consider just straightforwardly adding lanifibranor to the current dose of GLP-1. You don't have to titrate it up. I can add two more points to that. One is that at an individual patient in the real world you always have to do this balance between side effects, tolerability, and benefit. You may get to a certain point. We do this all the time when we are using Rezdiffra. Patient says, doc, I can, I'm managing with 0.5 mg or 1 mg of, you know, semaglutide. I don't want to be more nauseous, you know, and you say, you've been on it for a year and your liver stiffness is still 16 or 15, you know, so then we add Rezdiffra. I think something like this will happen. Remember the second point is 14% of NATiV3 has GLP-1 in the background. We will be able to show also what the benefit level in that subpopulation is and whether it's comparable to those who are GLP-1 naive coming into the study and whether there's incremental gain. In parallel, the ESSENCE trial is still ongoing and the ESSENCE trial by 2028 or 2029, you know, at some point in that general around 2029, we will have sort of five-year outcomes data as well. You'll be able to get at full dose semaglutide what the profile looks like, people getting diabetic dose GLP-1, and then add lanifibranor, what does that look like? We'll have a lot of options based on tolerability and this whole conversation about how do I maximize benefit while maintaining tolerability at an individual patient level. Hi, Edward Nash from Canaccord. I want to ask about compensated cirrhotic, so if you are F4 and you, let's say, if you look at Dr. Afdhal's slide and you start with the FGF21, would you now consider, because I know we hear a lot about everyone's now used to the needles, we'll just wait longer, it's not a problem, we'll keep them on the therapy even if they move back to, say, becoming F3. Do you see yourselves now moving away from the FGF21 after the patient is kind of pulled away from being compensated, sort of like to say bridging and then moving to something like lanifibranor? Would that be the next likely option given the cardiometabolic effect? Just a second question while I have you, we hear a lot about obviously combining with GLP-1 agonists, which for obvious reasons, but are there any other mechanisms out there that seem to make a lot of sense? We see that a FAST inhibitor is now going to be combined with resmetirom to look at in clinical development. Is there anything that you see that lanifibranor would be appealing potentially mechanistically to? Combine with two good questions. We're going to answer them. I'm going to challenge my panelists to be relatively summarized in the responses, just so we can move to more questions as well. I just want to open on the cirrhotic question and then turn it over to the doc. We have to be clear on just one thing given the forum we're in right now. What's on the table for lanifibranor, which is the same on the table for the Madrigal Therapeutics. This is an approval in F2, F3, non-cirrhotic MASH. I think what the world holds for the future of cirrhotic MASH is sort of being informed real time. The comment from Inventiva's perspective is that cirrhosis is more than an anatomic description as an F4. There's a physiologic component to cirrhosis, which is really critical to understand. Inventiva will have more to say about how we're thinking about that next year. For today, everything we're talking about is our view of lanifibranor as an F2, F3 treatment option. I want to make sure that we're clear on that. We're not at all talking about F4. That being said, the doctors can talk about anything they would like. William, you were about to say something? I was going to actually echo that to say that there isn't anything licensed at the moment. What I would say is that again, if we draw from other liver disease areas, I don't think anyone would be bold enough to think that once the patient's gone from having circles on their biopsy, if they have one, to having just shy of a circle on their biopsy means that there is a major change in how you need to follow them, how you need to treat them, how intensive you need to be. I think that actually what I would advocate for is treatment at F2/F3 to prevent progression to cirrhosis, because that's the real opportunity, opportunity cost. That's the point at which you could then say over to your family physician to continue that medicine. I think that's where I'd like to direct that. In terms of your specific question, could you imagine pulling a drug and then adding in another? That could well be the case. That could well be the case. I think we need to see what the data look like. We also need to understand the protoplasm. What is the patient actually like? So far we've been talking about people living with MASH. Actually, there are many, many people living with different MASHs. I think as we do more on the basic science side, we start to understand that better as well. I think this is a real sort of work in evolution. I think that, you know, once a patient is cirrhotic, I think their risks will be they'll stay with them for a while. Certainly, yeah. The only additional thing I would say is that there's a lot of opportunity for innovation in this area with respect to fibrosis regression induction and fibrosis regression maintenance. Hi. Thanks, Annabel Samimy at Stifel. We've heard now several times that you want to get to the root of the problem. It seems that lanifibranor truly is getting to the root of the metabolic problem with MASH. Outside of the F2, F3 sweet spot that you're all talking about, given that you are getting at the source of disease, how do you plan on leveraging the F1 and F4 data that you might be collecting from NATiV? Could this give you possibly broader opportunity? I'm going to pass that question to Jason. Thank you, Andrew. Good question. F1, I think the physician said earlier on the panel that we're going, it's a prediction, but the prediction would be that we're moving into preventative posture in the future and less treatment oriented. Still very treatment oriented, but more preventative. F1s really have a role there to play. Many years ago, when Intercept had approached FDA, there was an exploratory cohort in the phase III pivotal trial at that time that was larger than, I think, the NATiV2 clinical trial was, like, 287 patients, if I remember right. That was the largest cohort of F1 data that had ever been assembled. FDA in that era was not interested. I don't think that's the case anymore. I think they're much more interested in understanding more about that F1. We're interested as well on cirrhosis. My only point here is just echoing what Arun had said. We have an exploratory cohort in NATiV We have about 75- 100 patients approximately that will likely be cirrhotic that we'll have an opportunity to look at. It's our view that these cardiometabolic drivers matter to outcomes. Because if you look at MASH, if you're fortunate, maybe I'll say it this way, if you're fortunate enough to survive a cardiovascular event, then you'll ultimately die of a liver related event with MASH cirrhosis. You have to pay attention to both. This idea that you construct a trial that filters out for cardiovascular events so you have this pure look at the liver related events looks good on paper, but NID said earlier that's not the real world. That's the world of a clinical trial or FDA. In the real world, the patients that come to your office with natural cirrhosis will have a much higher risk of cardiovascular death first before they get to the liver. We're very interested in that. Martine? Yeah. What I just wanted to say is that the pivotal trial, the NATiV3, as you know, is constructed with a primary endpoint and a population that is described in the priority protocol. Right. We are targeting F3, F4, but yes, in the exploratory cohort, we have the other two groups and pair rules. FDA, it's not the real world data, but we have to present data in what we put in the protocol. Right. Which is the targeted population. Of course, we will also describe the patients in the exploratory cohort and make the link. The statistical analysis plan that is validated by an agency before you submit a new, you all know, has to target the population that you enroll and the primary endpoint that you measure. The world is evolving and some colleagues here discussed their experience in the past, but we see over the last couple of years now FDA being more open to look at what's happening more holistically, if we can say, in the patients that are not exactly the same patients as the ones that you have in your targeted population, the population from the protocol. I'm very encouraged, actually. Yeah. Just one final point on that. Important to remember though, that in that exploratory cohort of F1s and F4s, we're not looking at histology, they're not being repeat biopsied. We will, of course, have safety in NITs and all of that as part of the broader data set. It is also important to remember in the real world, as has been said, many patients identified who are appropriate for therapy are not biopsied typically. Right. They're selected based on NITs. It'll be good to have the reassurance of the additional safety and non-invasive efficacy data across the broader spectrum of disease. Okay. If I can maybe ask a slightly more granular question and maybe a little bit more loaded for the physicians. Obviously, the MASH market is extremely heterogeneous. How do you think the market's going to be segmented if you've got 80% of the population that has type 2 diabetes? That seems like it would be perfect for lanifibranor. Maybe you can see where FGF21s fit in for a very severe patient who might be tipping into cirrhosis. Where would that leave resmetirom? That's, yes, liver targeted, but it doesn't have that much efficacy and it doesn't have any impact on the metabolic markers or some of the other markers that you deem very important. Just your view about that. I would not take such a pessimistic view of resmetirom. Yes, I think all our patients are either prediabetic or they're diabetic because they're all insulin resistant. There's a good rationale for a drug like a GLP-1 agonist or lanifibranor or anything affecting metabolic insulin resistance. Having said that, I think there are clearly people who are fibrosis non-responders to all of these individual drugs. There's going to be lots of room. When people don't respond to one, they can be put on another. There may be other patients who may not tolerate one drug versus another, and then you have to switch drugs around. It's not that different than in hypertension when you start with lisinopril and then you get this little dry hacking cough and then you have to switch to something else. You go to losartan and then your creatinine goes up and then you switch to something else. You go to a calcium channel blocker and your feet swell up and then you keep bouncing around. Now I'm just telling my own story over here. I think having multiple short set goal is good for the patients and resmetirom clearly does work. Their actual real-world data that was presented at EASL looked really, really good as well. I would not discount drugs like that. I think FGF21s probably will have a much bigger role for those who already have very advanced fibrosis. In terms of fibrosis benefit, especially the data in the cirrhotic population, I think looks very, very exciting. I wonder if Ned, do you agree? You know, resmetirom has a place, it's not going anywhere. It's a very solid drug and it does have some metabolic benefits. I don't see an. I think what will happen is it's too difficult to say that we're going to segment the population based on certain parameters or certain patient clinical characteristics. That's really, really complex. In a disease that's so common, it's extremely, extremely difficult. I think that what we're going to do is we're going to use some very common and easily definable clinical parameters to determine what's best on an individualized basis. I think that the good clinical trials will help us understand what is best for the individual patient as they analyze their data. I think the good clinical trials, and I hope Arun 's trial is a good clinical trial, will enable us to actually determine what is success. To me, the biggest issue is not worrying about how many choices I have. It's worrying about making the right choice for the right patient and knowing that I'm actually succeeding in what my goals are for that patient. If we can get that out of any clinical trial, it's a winner. Will go to our next question here. Yeah. Hi. Ananda Ghosh from H.C. Wainwright. Just wanted to tell that it was a fantastic set of panelists and learned a lot. One of the questions I had was that when we look at the lanifibranor story over the past two, three hours. There are a couple of things which kind of stood out: insulin sensitization, glycemic control, fibrosis improvement. Weight gain, which is metabolically active now, having this set of protein profile. Assuming that the NATiV3 does replicate several aspects of these observations, how do you think that lanifibranor should position itself, given the learnings from Rezdiffra or GLP-1 agonists' approach to educate the physicians and payers with respect to the market? Actually, I'm looking at our physicians for that. Where do you think it fits into care? I think it's a very interesting position, isn't it? The question is, where do you start? Your patient doesn't start afresh. That choice is not really up to you to make that call because the patient walks into your room with all of that backstory there. They may already be on a GLP-1 agonist, they may already have seen somebody who's decided to put them on various other medications. They may have tried certain things. They may have come to you differently. I think where to position it is an understanding of the disease process. What we need to be doing as physicians, we need to make sure that we're well educated enough. We need to make sure that we've got the environment right for the patients and that we need to understand what the different mechanisms of action are. Now, in a sort of a blank territory like the U.K., we're preparing for that as specialist societies, and we're interacting with our primary care colleagues, our endocrine colleagues, colleagues getting ready, watching what's happening here in the U.S. very carefully and then borrowing the learnings. I think the key there is to understand what's happening in your patient, what their drug history is and then understanding this is where the role is. Yeah, you're right, you've enumerated all the different reasons why one would consider this medicine. As colleagues have said, all the other medicines have got their things too. Consider as well, you've got to. Fix it for the patient in front of them. Your question was semi, where should they position this? That's not a physician choice as to where a company positions a drug. If you look at it from the point of view of who is going to be excited specifically by this mechanism of action, where it goes, look at our endocrinologists, educate them on MASH even more and they're pretty well educated. Educate them even more on MASH. They're using 6 million patients on pioglitazone, they know PPARs, they like PPARs, and they're going to get a pan-PPAR with a better profile of activity and they're going to have lots and lots of patients with MASH and they know the cardiometabolic status of these patients very well. I think they are a population that, you know, I would be very excited to see from my own point of view getting involved in MASH. At the end of the day when we're all talking about all this, him and me and William as well are real card-carrying hepatologists. We deal with transplant, bleeding, liver failure, all of this stuff. What do we really want? I want nothing but cirrhosis in my clinic. I love cirrhosis, all right? I like dealing with it, I like taking care of patients with it. Quite honestly, if every F2, F3 patient with MASH was taken care of by my endocrine or primary care colleagues and they looked at them from a holistic patient point of view, I'm a happy man. I'll just take my million cirrhotics and deal with that. Sorry, just to add to that, let's remember that Novo and now Madrigal will be out there educating the endos to care about these patients more and more. That's great for us, right? Assuming we get lanifibranor launched in the early 2028 timeframe, we'll have the stage set for what is, I think, truly driven, differentiated about this profile. Let's remember that the type 2 diabetic with advanced fibrosis due to MASH, as the physicians mentioned earlier, is the toughest to treat, most at-risk patient. Starting with the fact that GLP-1 agonists, a lot of these patients will be on GLP-1 agonists, they're resistant to weight loss, which is what indirectly leads to benefit on the liver side. Really, adding lanifibranor to a patient like that I think is the sweet, sweet spot. Of course, the drug's more broadly efficacious based on the phase II-B data, but that's where the benefit, risk, the value prop for this drug is strongest. Got it. Very quickly, you know, a follow up. Question on the similar lines is that as lanifibranor comes out in 2028, you know, and given the biopsy noise. The shift in the FibroScanning, the real. real-world practice, how do you see lani kind of utilizes these non-visible tools shaping adoption and reimbursement? I mean I can't imagine that you're going to have medicine-specific criteria for treatment at a macro-l evel in a disease that is looked after by so many different people. I think our understanding of what the non-invasives mean is growing, our confidence with what success, Ned, you mentioned that what that looks like is growing, and I think we as a field will understand that if you meet a certain threshold of eligibility to treat, then I think we'll end up treating. I don't think as physicians I don't want to see, you need a FibroScan score of X in order to have this medicine, but it's X3 if you're going to have that medicine. The payers might use that as a tap for on and off, but we would be advocating strongly against that. I think it's about finding those individuals who need to be treated. Just as a follow-on to Nid, what we really want is for all those cirrhotics not to become cirrhotic. We'd love to trim down our practices and consider that everybody who care takes turns up with that cirrhosis or decompensation or cancer was actually a failure of prevention in the first place. I mean that's the real goal. There are specific companies that have created barriers to the utilization of drugs without a doubt in the liver space. The one you think about most was when the true DAAs came out for viral hepatitis C, the payers insisted on a FibroScan score of 15 or above. We had patients that we clearly knew were very advanced fibrosis and cirrhosis who, you know, I used to send off to eat a cheeseburger and then I would scan them and they would always have a FibroScan score of greater than 15 because a cheeseburger increases your liver stiffness quite significantly. I actually ended up being investigated by the state of California. These are things that, you know, I care for patients and you gotta do what's right. We're probably close to closing here, but I want to go back to the key question that we asked on Inventiva. What we heard at Inventiva from the panelists today are that the field needs four things at the time of lanifibranor coming to market. They need a drug that's patient friendly and offers simplicity. They need a drug that addresses the metabolic drivers of the disease around insulin resistance, glycemic control. They need a drug that gets at fibrosis because that is still the number one marker and predictor of long term survivability. If you ignore the underlying drivers of the liver disorder, the inflammation, the hepatocellular injury, that fibrosis benefit will be short lived. We think that the way that the NATiV3 study is designed and the data we've delivered on NATiV, if we hit on those, we have a vote and we have an opportunity to play in that market. That's how we're approaching it. One more question, and then two more questions, I think we'll wrap it up. W e're a little bit over. I'll keep it short, I promise. Rami Katkhuda, LifeSci Capital. Maybe a question for you, Jason. I guess you mentioned 14% of patients came in with a concomitant GLP-1 use. Given that it's a 72-week study. How are those patients handled if they come off kind of GLP-1 agonists during the course that I of NATiV3? For any concomitant medication in the trial or new starts, they're all protocol specified. I don't know that we're prepared today to get into that level of detail, but a patient that begins on a treatment option called, in this case, GLP-1, that stops that GLP-1, they're appropriately flagged and they're managed in our analysis plan, our statistical analysis plan, in a way that allows us to sort of impute what their data would have been. In that case, we would be sort of penalized, you can think about it, because we would have lost some efficacy. That will all be specified in our statistical analysis plan. Anything more to add there? Okay, great, thank you. Antonio Arce West Park Capital. Thanks for squeezing me in. I just want to add my thanks for putting this panel together, well timed about a year before readout. I have a couple, well actually I'll just keep with one question given the time, and this is for the KOLs on the panel. Kind of putting you on the spot here. I'm just thinking about, you know, as you look across the landscape, really, you've got two drugs that target F2, F3, are oral, and are liver directed, and that's Rezdiffra and lani. So kind of just focusing on those two, how do you see that? What do you see as the strongest product differentiation on lani in particular, as you think about perhaps switching from Rezdiffra to lani upon approval. Any volunteers yet? I think the word switching is a very, very early, early word. I don't think that you're going to switch anybody because you think one drug is necessarily at this point when we don't know what the response rate is to lani that we're going to be thinking about switching. What I am going to be doing is looking at people who are failing to respond and may already be on a GLP-1 agonist and Rezdiffra and putting them on lani. I think what we've heard today from everybody starting off with the mechanism of action and stuff is that most of us as physicians like the metabolic profile and the cardiometabolic benefits of lani significantly. Perhaps in new patients, lani might be a first choice in comparison to what we're seeing with Rezdiffra. Rezdiffra has three more years to generate more data, which it will take to, and I have an incredibly open mind as to, you know, what the space is going to look like in 2028. Until I know what that space looks like, I'm going to leave myself very open to what I have as a choice to use. Yeah, I'd like to add, so the way I look at it is that when the, I agree that if my patient's doing well, I'm not switching anything. If they are a non-responder, this gives me another option. One thing that I would also think about is the different lipid profile changes on Rezdiffra vs lani. So, lani drops the triglyceride, lani improves HDL, but Rezdiffra drops LDL cholesterol. For specific patients who are very high, say you have a coronary calcium score of 80 and have a strong family history and on high dose statin, your LDL is still 105. I may use a drug which will give me still the liver benefit, but at the same time reduce LDL without having to put them on a PCSK9, you know, to not—so, you know, there are nuances to that, but other than that I fully agree with everything Nid just said. I don't think we should think of this disease area as that wonderfully different to other cardiometabolic disease areas. I think the analogy's been used by all of us of hypertension, and I think that's a very good way of looking at this. Different drugs, different classes, different efficacies across different receptors, all acceptable. All that does is it allows us to have a smorgasbord. It's not the case that every time a new antihypertensive comes out, we all about face and change our patients. That's for me, not a bad analogy and probably not a bad framework for the evolution of the treatment landscape. I think that brings us to the end of our time. Thank you everyone for attending today and letting us run over a little bit. I want to thank our panelists as well, and our physicians and our patient advocate for being here as well. Thank you. Thanks everyone.