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

Good day, and thank you for standing by. Welcome to the results of LEGEND Phase II combination trial with lanifibranor and Empagliflozin in patients with metabolic dysfunction associated steatohepatitis and type 2 diabetes conference call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Frederic Cren, CEO of Inventiva. Please go ahead.

Thank you, and welcome, everybody, very pleased to host this conference on the LEGEND webcast and on also an update on the lani development program in NASH. As usual, we will be making forward-looking statements. So please look at our regulatory filings that are available on our website. We have fully packed agenda today. I'll make some introductory comments, and then I'll pass to Michael, our CMO, to present the LEGEND results, a study that you've seen last night with our press release that met all of its objectives, in particular, by demonstrating that the moderate weight gain that had been seen in some patients in the Phase IIb NATIVE can be mitigated by associating lani with Empagliflozin. We also have the pleasure today to have guest speaker, first, Professor Harrison that will present some very interesting data on lani and the benefit of the hepatic and metabolic side of this drug. And then will present some data already show that EASL23 on the vascular benefit lanifibranor and then other conclusion, I'll present the results -- some of the results of the survey we did with payers and prescribers in the U.S. And as usual, we will end up with a Q&A session. Just a very quick update on NATIVE 3. You know that mid-February, we made the choice to pull screening. It's Luckily, following the approval by the U.S. and Canada central IRB early March and earlier than expected, we restarted screening following the implementation of the DSMB recommendation in the protocol in the ICF and of the regulatory document until now screen has resumed. As you can see in the slide, we have now more than 7030 patients that have been randomized in the main core. That's more than 70% of the target. And we have 400 patients in screening, concerning the exploratory core, we have already achieved more than 90% of our target, including approximately 30% with [indiscernible] fibrosis and we continue to target the last patient first visit for the first semester of '24. That's a very quick and positive update on NATIVE 3. And now let me turn to Michael for the presentation of the LEGEND data.

Thank you, Frederic, and good afternoon and good morning, everybody, on the call. If you go to Slide #6. There is a very strong rationale to combine lanifibranor with an SGLT2 inhibitor in patients with MASH or NASH, and that is what we set out to study in this Phase II proof-of-concept study in LEGEND. For one lanifibranor [indiscernible] agonist, and as such, it has an effect on insulin sensitivity, which is an upstream mechanism of NASH and also type 2 diabetes, lipid and glucose metabolism, inflammation, and also liver tissue injury, which is MASH or NASH activity and fibrosis that has been shown in the Phase II study NATIVE and also in a smaller study, we conducted with [indiscernible] specifically on the metabolic benefits of lanifibranor. Empagliflozin is an SGLT2 inhibitor and as such, it is a reuptake inhibitor of glucose in the renal tubule. It's an approved drug for type 2 diabetes. It improves glycemia control as insulin sensitivity and it also has a such diuretic effect and has some weight reducing effect. Therefore, the combination of lanifibranor with Empagliflozin may add additional metabolic benefits to patients who have NASH and certainly also those to have NASH and type 2 diabetes. But as I mentioned and as you know, some patients on lanifibranor have modest weight gain. And although this weight gain is different, from the weight gain you see as a result of poor lifestyle, the way [indiscernible] metabolically healthy. But it may still be an issue for some patients. And in this study, we evaluated what the effect will be if you combine lanifibranor with Empagliflozin with the hypothesis that this weight increase could be neutralized -- could be addressed. Go to the next slide. This is the study design. There are 3 arms, 1 arm was placebo, 1 arm lanifibranor at a dose of 800 milligrams and those are [indiscernible] and the third arm was the combination with Empagliflozin, which is the low dose of the approved medication for type 2 diabetes 10 milligram. Treatment duration was 6 months, 24 weeks with 4 weeks of follow-up. And the patients who are enrolled in the study had to have NASH diagnosed histologically with a certain degree of disease activity NASH 4 or more or diagnosed with MRI based on Iron corrected Tier 1 of more than 875 milliseconds, which is now to correlate with a degree of steatohepatitis and fibrosis or patients who had a somewhat lesser degree of disease activity, but had a certain minimum amount of liver fat measured with MRI-PDFF or 10% or more. Also, the inclusion criteria with regard to NASH, they had to have diagnosed type 2 diabetes and had to be poorly controlled measured with HbA1c between 7% and 10%. And the primary efficacy endpoint, which was used to calculate the minimum sample size that would be needed to show and a meaningful effect was based on the reduction of HbA1c that we knew from the native study. So the primary outcome is a reduction of HbA1c at 6 months of treatment. And of course, we had a lot of secondary outcome, efficacy outcomes, related to insulin resistance, hepatic steatosis measured with MRI, liver injury markers, aminotransferases, lipid markers. And then the question on what happens to body weight? What happens to body fat composition? And there is of particular interest as it is known that subcutaneous fat is typically more metabolically healthy, more insulin sensitive than visceral fat. And also evaluation of noninvasive liver markers and, of course, safety and tolerability. We did a prespecified interim analysis, and what we present here, when 50% of the patients had completed the 24-week treatment period. Some of the patients are prematurely discontinued. So 50% of the patients randomized and treated. If you go to the next slide, that is the patient disposition of the full analysis set, 32 patients were randomized and treated, 12 patients in the 800-milligram lanifibranor arm. All these patients completed the 24 weeks of treatment, 10 patients in the combination of lanifibranor and Empagliflozin. All these patients also completed the 24 weeks of treatment and 10 patients in the placebo arm. In this arm, 510 patients were completed the 24-week treatment and 5 discontinued prematurely because of either withdrawal by the patient lost to follow up or noncompliant with study drug. If you go to the next slide, the basic demographics of the patients who were included in this study actually were rather typical for patients, as you would expect, patients who have metabolic syndrome who have both MASH and type 2 diabetes. So they have an average age during the mid-50s to 60% ratio female versus male, which we also see in other NASH studies. The [indiscernible] are overweight here with an average weight of between 90 and 100 kilograms. BMI is high, above 30 in all patients. HbA1c between 7 and 8.2. They have high insulin levels, as you would expect, and insulin resistance based on HOMA. Their HDL cholesterol is on the low side, as you would also expect in this patient population, you will see the LDL-cholesterol values. And then with regard to the corrected T1 for MRI multiscan, MRI values well above the 875 mili second inclusion criteria. Hepatic Steatosis patients were -- as you see on average between 17% and 19.7%, so high fat content. Aminotransferases also expected in this patient population was not too high, might be elevated on average, and they had these patients also have low adiponectin values, which is a marker of poor cardiometabolic health and it's also an important mediator of the effect of lanifibranor, specifically through its [indiscernible] pathways. If you go to the next slide, this is the slide that shows the primary efficacy endpoint, was met statistically significant reduction in HbA1c at week 24 in the lanifibranor alone and also in the combination, and you see the effect already at week 24. And if you look on the right side, in the completer's population, the percentage of patients who have an HbA1c lower than -- less than 6.5, which is a very good response, of course. You see that doesn't occur in the placebo arm, but more than 50% of the patients in both arms on active lanifibranor and lanifibranor with Empa reached that end point and also the absolute decrease of HbA1c of 1% or more at the end of treatment, high values in the active arms, majority of patients reach that. You don't see that, of course, in the placebo arm. So this was known from NATIVE, a very good response on the -- on HbA1c and glycemia control with lanifibranor and also with the combination that is new. If you go to Slide 11, these are markers related to insulin sensitivity. You see a nice decrease of insulin on the left side in the vast population. That's the mean absolute change from baseline to week 24. And you see on the right side also that insulin resistance HOMA basically remains unchanged in placebo treated patients while it reduces nicely in the patients who are active and also on lanifibranor with the combination. Slide #12, then shows the effect on the aminotransferases. As you see on the left for ALT and the first population on the right for AST, the values do not change through treatment in the placebo arm, but you see a rapid decrease starting at week 4, actually with both lanifibranor alone and with the combination treatment, also consistent for lanifibranor with [indiscernible] early response on aminotransferases. Slide #13, shows a nice decrease in hepatic steatosis. You see on the left, the liver fat measured with MRI PDFF. The decrease in -- the relative decrease in the active arms and both active arms compared to placebo, you see no change in the placebo arm. And on the right side, you see the individual values where you can in fact, see that the decreases -- the relative changes in decreases in hepatic steatosis occur in the patients who are on lanifibranor or lanifibranor with Empagliflozin. Hepatic steatosis is of course, also a cardiometabolic health marker. And in such -- as such, this funding is very relevant for the cardiometabolic benefits of lanifibranor and the combination as well. Bottom right, the table shows some categorical values bid percentage of patients who reached a reduction of 30% or more on MRI-PDFF and you don't see that with placebo, but the vast majority of the patients in the active groups reach that or an absolute reduction of 5% or more. Again, no such effects were seen with placebo but high values are seen with both active groups. The next slide is really new data because we have not shown results, with multiscan MRI before. You see here that on the left side, the changes in CET1, which is a marker for steatohepatitis inflammation, specifically on fibrosis, absolute change in milliseconds from baseline to week 24 with both active arms, not with placebo. And then on the right side, if you look at the categorically, the percentage of patients who have 80 milliseconds or more improvement with CET1. You don't see that with placebo, and you see that a substantial proportion of patients in the active arm reached that goal. And it has been shown in a number of papers that if you have that threshold or improvement of CET1 that actually corresponds or predict well histological response with regard to natural solution and with regard to fibrosis. So this is an important benchmark to show effect of the treatment after 6 months in this case. Slide #15 shows the effect on other metabolic markers. In this case, HDLC also consistent with what we've shown in NATIVE, you see an increase in HDLC, HDL cholesterol -- the good cholesterol in other words, with both active arms. You don't see that in placebo and adiponectin, which is an important marker of target interaction for lanifibranor, of course, but also a marker of cardiometabolic health and also a very important mediator of insulin sensitivity. We see consistent again with what we've previously shown an increase in adiponectin, this is here a fold change from baseline of roughly 3%, which is a significant increase in adiponectin. The next slide and the next 2 slides are really coming to the most, I think, enthusiastic and data that we have from the LEGEND study, confirming that our objectives were fully met when we set out to study the benefits of the combination. Here, you see the evolution of weight in the 3 arms. And also, again, consistent with what we know you see some weight gain in the patients, who are on lanifibranor alone. And here, you see the median -- the average values, of course. And what is shown is the relative change from baseline with 24%, 3.6% increase from baseline on average in lanifibranor alone. And -- but you can also see, of course, that when patients have lanifibranor and Empagliflozin, that is the dotted green line that the weight gain is entirely neutralized and is the same as with -- the weight evolution is the same as with placebo. So this is a clear demonstration that when you combine lanifibranor with Empagliflozin that the weight gain can be entirely addressed. And I point out again that the weight gain with lanifibranor is metabolically healthy. It is essentially different from weight gain that results from poor diet and nutrition. It is not a medical issue as such, but it may be a concern for some patients. And here, I think we show that it can be addressed with a combination that makes a lot of sense in itself already. And then the next slide is closely related to this to the metabolic health of Adipose tissue. Adipose is not the same with [indiscernible] tissue. It depends very much on the metabolic status and on the distribution and on average, you see that subcutaneous fat is more insulin sensitive and metabolically healthy than visceral fat, which typically is actually insulin resistant and has a lot of pro-inflammatory effects. Together, combined with the data that we have shown at lanifibranor is a very potent insulin sensitizer. This is I would say, a very consistent set of data showing that the metabolic health induced by lanifibranor is relevant also with regard to the effects on weight. What you see here on this slide is the ratio measured with MRI on visceral Adipose tissue versus subcutaneous Adipose tissue shifts with lanifibranor alone and with the combination to the benefits of subcutaneous Adipose tissue, while you see the opposite with placebo. There you have a shift towards more digital Adipose tissue in this study. In other words, the shift with lanifibranor and with the combination towards metabolically healthy insulin-sensitive Adipose tissue. And that's a very important message. This last slide is on the safety and tolerability. There were in the combination and lanifibranor alone appears very safe. There is not really much of a difference between the 3 arms; placebo, lanifibranor and the combination treatment. The only thing to mention are anemia, which was supported in 1 patient in the placebo arm and 2 in lanifibranor. The anemia as defined as a hemoglobin level below the lower level of the reference range, so not a symptomatic anemia and the same for hypoglycemia, which was reported in 1 patient on placebo and 1 patient in the combination arm, again, measured as the cost levels below the lower level of the reference range, not symptomatic and not requiring treatment. And 1 patient in the combination arm had peripheral edema, which was also changed and did not require treatment. So no other findings to mention with regard to the safety findings, and then I'll go to the last slide, which are the conclusions, which I'll go through. So this LEGEND Phase II study has met the primary efficacy endpoint, which was based on the reduction of HbA1c. The endpoint was met for both lanifibranor alone and for the combination of lanifibranor and Empagliflozin. And the combination of lanifibranor with Empagliflozin addresses and neutralizes the weight gain, the metabolically healthy weight gain, that is seen in some patients who have lanifibranor alone. Both lanifibranor and the combination of lanifibranor with Empagliflozin induced a redistribution of Adipose tissue from visceral to subcutaneous Adipose tissue together with the improved insulin sensitivity. This is a consistent message that with lanifibranor treatment, Adipose tisssue becomes more healthy and metabolically insulin sensitive. Lanifibranor improved markers of cardiometabolic health and the effect size appears to be further improved when lanifibranor is combined with Empagliflozin. The sample size is such that we can -- we have to be cautious about to what extent the combination has as it is effect or more of an effect, but I think there's trends towards -- there's still improvement of the metabolic effects, as you would expect, when you combine 2 compounds that are complementary to each other's mechanism of action. And the last point, lanifibranor alone and the combination of lamofibranor and Empagliflozin appear to be safe and well tolerated. So that's it from my side. And I think I'll pass on now to Stephen to talk about the cardiometabolic health.

Yes. Thank you, Michael. It's good to be here today, and I think that's terrific data that you just presented from LEGEND. I just wanted to take a brief moment and dive into metabolic dysfunction associated steatohepatitis and really highlight a couple salient foundational features of this disease. And I think this slide does a great job of explaining it. So there's metabolic stress that occurs. This can occur from substrate overload, unhealthy diet, lack of physical activity, genetic influences, microbiome. We know that it really is a plethora of different insults and factors that drive underlying metabolic stress. But at the end of the day, what does this metabolic stress do? Well, it induces systemic insulin resistance. And that really is the core or the root of the problem relative to this disease. And we see that there are a couple of organs that are preferentially impacted by insulin resistance. And you see those listed here, skeletal muscle, adipose tissue and liver. And so it's important to understand that in the setting of metabolic stress and insulin resistance that adipose tissue cannot function properly. It has an inability to hold on to fatty acids. So these fatty acids get released into circulation. You're taking up in the portal vein and ultimately, the liver now has to deal with these free fatty acids. And there are a couple of different ways that it can deal with them. It can terrify them to triglycerides. It can burn them through beta oxidation where it can repackage them in the form of VLDL and ship them out of the liver. Inevitably, in about 25% of patients with fatty liver, the liver is unable to appropriately deal with these excess fatty acids, and these fatty acids are very toxic. And what we see here is toxic lipids that are in the form of oxidized phospholipids, ceramides and Diacylglycerols that lead to upregulation of proinflammatory cytokines, immune cell dysfunction and ultimately, stellate cell activation. Along the way, mitochondria become dysfunctional something called endoplasmic reticulum stress builds up, and there's an inability to appropriately manage the fact that's in the liver. Now additionally, because of excess substrate overload, the liver is put into a situation where it also drives de novo lipogenesis. We see multiple drugs being developed now that inhibit de novo lipogenesis. So we know this also plays a role and skeletal muscle on the left also becomes dysfunctional as illustrated. So this really is a multifaceted problem. And the good news about lanifibranor is it tackles many of these issues as was mentioned by Michael, and I'll go to in a minute. So the next slide just speaks a little bit to the Phase II data that was already published. I just wanted to bring this back to life for a moment and focus on a couple of things. The primary endpoint was a decrease of at least 2 points in the SAF activity score with no worsening of fibrosis. And when you look at the 2 doses versus placebo, we see the high dose was highly significant, 49% versus 27% for placebo or a 22% placebo-corrected number. Looking down at resolution of NASH with no worsening of fibrosis, we know that is 1 of the FDA endpoints for accelerated approval. Both doses were significant relative to placebo. And then looking at improvement of fibrosis by at least 1 stage with no worsening of NASH, again, significant for high dose, 42% versus 24% for placebo. Importantly, it's also good to look at both of these endpoints in the same patient. So resolution of NASH and improvement of fibrosis occurred in 31% of high-dose, 21% of low dose and 7% of placebo or a 24% treatment effect delta, and then finally, a decrease of at least 2 points of the NAFLD activity score and no worsening of fibrosis occurred in twice as many patients on high dose versus placebo, 64% versus 32%. Now just again to highlight data that has been previously published by 1 of the other presenters today, Sven Francque, who will speak after me. Looking at following on some of the data that Michael mentioned with hemoglobin A1c HOMA-IR insulin, you see 3 different bars representing 3 different bar graphs. So with HbA1c on the left, we see least square mean absolute change in percentage from baseline to week 24 and the numbers here are very impressive. So placebo, there's no change to slight worsening, and you see a dose response, 0.38 and 0.41 change that is significant for both doses relative to placebo. Now in the middle, looking at HOMA-IR, we see again a significant change relative to placebo, that also is clinically meaningful with around of 5 change in Homa-IR. And then finally, for insulin on the right, again, very nice changes, very nice drops and absolute change from baseline for both doses relative to placebo. So what does this mean when we begin to think about dysfunctional adipose tissue. Well, what's been shown previously by Michael at EASL 2022 was that there are weight changes in patients with NASH in the Phase II NATIVE trial treated with lanifibranor and placebo. And we see here around 33% of patients on lanifibranor have a weight increase superior to 5% and on the right, you can see the correlatory changes in placebo with around 6% of patients or 4 patients having greater than 5% weight and this actually is important because it speaks to the mechanism of action of the drug and it speaks to the patient becoming more metabolically healthy and reconstituting the health of the adipose tissue and subsequent insulin sensitivity as I would like to show on the subsequent slides. So here, we see insulin sensitivity expressed as fast in HOMA and mean absolute change at week 24 from baseline. In those people with stable weight in the dark green and in the light green weight gain of 2.5% to 5%. And then finally, in the right-hand green bar, where it's minus 8.2%, that is the change in patients who have the biggest weight gain of 5%. So this illustrates very nicely that as patients have gained weight, they've actually improved their insulin sensitivity juxtaposed against the placebo patients that gained weight and they actually worsened insulin sensitivity speaking to the fact that these patients are improving their metabolic health. Now how does this translate into inflammation? And we look at ALT to assess that in our patients. And again, each of these slides are illustrated in the same way. So on the left is the 3 bars for lanifibranor and on the right in the gray and black are placebo illustrated with stable weight gain of 2.5% to 5% in the center and weight gain of greater than 5% on the right. And you can see again that it doesn't matter if the patients gained weight or not as they all have had significant improvement in ALT. And I'd say significant here to mean clinically significant change. Now on placebo, there's actually worsening, again, consistent with the fact that these people are worsening insulin resistance, as I showed you on the previous slide, they're also worsening their inflammation in the 12 patients that had at least 5% weight gain on placebo. So what does this mean to triglycerides and lipoproteins? On the right, we can see the change here at 24 weeks from baseline and millimoles per liter. It's about the same, whether or not you lost weight or you gained weight with lanifibranor, there was improvement in all 3 groups and slight worsening to no change in those patients that were on placebo where they gained weight. Ultimately, LDL levels do not change, but HDL level improve in patients treated with lanifibranor independent of weight change. Now I want to talk briefly about circulating atherogenic lipoprotein ApoC3 and Apo B -- these decrease in patients treated with lanifibranor independent of weight change, but increase in placebo-treated patients. So similar to what I've shown you on the prior slides, the 3 lanifibranor categories I illustrate on the left, stable weight, modest weight gain -- minimal weight gain of 2.5% to 5% and weight gain greater than 5%, all are improving ApoC3 values from 7.3 to 10.7, the placebo as they gain weight, they actually worsened ApoC3 here. And on the right, you see again a dose responsive change in lanifibranor, the more weight that's gained, the lower the Apo B as opposed to no change or a slight change with placebo. Now I think another important biomarker that we don't talk a lot about in the NASH field is highly sensitive CRP. Highly sensitive CRP is linked and synced to atherogenic disease and CV risk -- and we know that relative changes in hs-CRP have actually been shown to be linked to improvement in CV risk. And so historically, we've seen that lanifibranor has had a significant reduction in hs-CRP. And here, you see that this reduction is independent of weight change, and that's not the case with placebo and I illustrate this in 2 ways, absolute change on the left and relative change on the right. I like the relative change on the right better because this is what is linked to something that I can relate to CV risk reduction. And you see this ranging from 21% change in those with stable weight. And in those that have 2% to 5%, it's a 61% reduction greater than 5%, 41% -- both of those numbers are very impressive, no change with placebo. And then when we look at liver steatosis, we see that it improves in patients treated with lanifibranor, again, independent of weight change, but it's worsening in placebo patients. So here's just another illustration of the fact that as there is weight gain in some patients, these patients clearly are improving their metabolic health. In this case, illustrated by the in the continuous attenuation parameter or CAP, which is a measure of fat on fibroscan, I'm sorry -- controlled attenuation parameter. And here, what we see on the left is a range of reduction from 4 to almost 15 points relative to the different weight categories for lanifibranor versus a worsening of CAP in those patients that have gained weight in placebo. Again, suggesting that there is liver fat content reduction even in those people gaining weight on lanifibranor. And as would be expected with weight gain and placebo, there is worsening of liver fat. So in conclusion, I'd like to make 3 main points: First of all, lanifibranor has a therapeutic effect on the broad spectrum of disease biology in patients with metabolic associated steatohepatitis. There's also significant effects on cardiometabolic and hepatic [indiscernible] what we've illustrated today is improvements in insulin sensitivity, reduction in insulin resistance, improvements in lipoprotein metabolism, improvements in glycemic control, reduction in systemic inflammation highlighting that hs-CRP reduction. There's also improvements in hepatic steatosis, measures of liver tissue injury and liver fibrosis as well. The second main point I want to make is this broad efficacy from upstream insulin resistance to downstream fibrosis reflects the balanced activation of all 3 PPAR receptors that are unique to this particular compound. And finally, the cardiometabolic and hepatic benefits with lani are independent of weight gains seen in some patients and known to be related to PPAR-gamma-induced maturation of adipose tissue. Thank you.

Thank you, Stephen. Now we move to the presentation from Sven. Sven the floor is yours.

Thank you very much [indiscernible]

It's really hard to hear you probably need to mute your computer -- there's a big echo.

[ Technical Difficulty ]

No, not really.

[ Technical Difficulty ].

Unfortunately, we still cannot hear you. I propose I'll go to my slides. While the operator tries to solve your echo problem. If that's okay. So let's move to the conclusion and the survey we conducted -- so we did actually 2 surveys, 1 with U.S. payers and then we did a prescriber survey in the U.S. among 100 prescribers 50% approximately being a pathologist treating NASH patients and the remaining being evenly distributed between gastroenterologists and endocrinologists. You've seen this slide, it's quite interesting. So we are really first to payers. What matters to them? And I would really shine out it was the fact that -- what really matters to payers is really to have a drug that can improve fibrosis. And on this parameter lani was really very well perceived and with a stronger profiles and Resmetirom and semaglutide. We also, at the time, discussed about pricing. We tested the [indiscernible] pricing, approximately $50,000 a year, and we did not get pushback actually price that was accepted by payers, as I think is reflected by the recent announcement made by [indiscernible] on their pricing. On the right, we have the prescriber perception of the key attributes. So we listed here the 6 key attributes of that were perceived as key in a drug in NASH. And you can see that on all 6 of them, lan is extremely well positioned. And so we really believe we have a drug that will be highly prescribed. We then looked at how lani is perceived versus other oral drugs and then especially Resmetirom. And we're really pleased to see that both in the diabetic population and as well in the predebt population, the benefit of lanifibranor are perceived more highly than Resmetirom with actually a statistical difference. Of course, combination, we know in NASH will be used given the complexity of this disease. So we tested the possibility to combine lani with a GLP-1, specifically at the time semaglutide. And there too, the combination was extremely well perceived suggesting potential or a perception of synergies from the survey prescriber of the combination of lani with GLP-1 with the possibility to enhance the GLP-1 benefit. On the weight gain, and this was before the data coming from the LEGEND study. We tested both the 2, 3 kilos that we have seen with lani with payers, and we did not get any pushback actually this moderate weight increase was accepted or not viewed as an issue by payers. And when we got the same question to prescriber, large majority, you see some figures here. Actually, I would say that they would prescribe lani even if with this modest weight gain that the benefit clearly are superior to this modest weight gain. And also in terms of drawbacks, you can see that though that were listed as key by the prescriber and not present with lanifibranor. And then on the bottom right, I'd just highlight a couple of figures that appear to us, extremely important. The first is that that really appears it's really important, the fact that we need a drug that have a low discontinuation rate, and this is clearly present with landing in the Phase IIb, we only had 7% of dropout, contrary to other drugs in development. And in terms of another key benefit of the approach is that the fact that 80% of the prescribers see or administration are the key benefits and that again is a key benefit that we have. And so out of that, we transform or translate into prescription. We see that among the physicians that we have served they think that approximately 30% of the script for patients with MASH will be with lani. And very importantly, when we go and we go into the detail, we see that the 30% is more or less constant across the F2 and F3 patients across prediabetic and diabetic patients and also does not change among BMI groups suggesting once again that these 2 or 3 kilos weight gain that we've seen with lani can be managed by prescriber. So these were really the key highlights of this survey. And now let's see if we have -- we can go back to Sven and see if the audio is better. Sven, can you try.

Can you hear me now?

Yes, perfectly. Great.

So I don't know what happened [indiscernible] -- so talking about [indiscernible] effects of lanifibranor, it's important to highlight that the liver [ Technical Difficulty ].

Sven, I'm really sorry, but the technique is not with us today, and we really cannot hear you anymore. So unfortunately, we'll have to keep your presentation and move directly to Q&A. I'm really sorry for that. We try to rerecord your part and post it on the website later. So with that, maybe operator, you can explain out to ask the question.

[Operator Instructions] Our first question comes from the line of Edward Nash from Canaccord Genuity.

Thanks everyone, and congratulations really terrific data. I guess the first question I have is to management is just kind of what were the thoughts, 800-milligram and 1,200 milligrams in the NATIVE study performed quite well. I just wanted to kind of understand why you went forward with 800-milligram for the LEGEND trial as opposed to 1,200 milligrams.

I'll try to give it an answer. And then if I'm incomplete, Michael, please, come in. We look at the 800 milligrams first because when we look at the metabolic improvement that we have seen in the Phase IIb, the 800 milligrams was really competitive, close to be at par with the 1,200 milligrams. And so we felt that dose would be sufficient to achieve the objective that we were targeting with LEGEND. Of course, meeting the primary endpoint, but once again showing that the combination could mitigate the weight increase while retaining all the benefits of lani.

No. I think what Frederic said is completely right. So the 800-milligram actually on cardiometabolic or metabolic immune markers had the same degree of efficacy as a 1,200 milligram. And that's the main rationale really also in a small study, of course, if you would have good dose of lanifibranor would have impact on the sample size. But the main reason was that we are -- we know from the NATIVE study that of cardio metabolic markers, 800-milligram is doing the same as 1,200 milligram.

Great. That's very helpful. And then just one other question I have in for Dr. Harrison. Dr. Harrison, now that we've gotten Resmetirom approved. Just wanted to understand with lanifibranor, do you see lanifibranor as being a potential combo therapy there as well with Resmetirom -- or do you see lani as being really kind of its own different backbone therapy depending on what the physician is really looking to achieve in their MASH patients?

Yes, I think that's a terrific question. It's one we're all kind of working through now. I would say, based on the Phase II data, certainly based on the data we went through today, there are some key differences between the 2 therapies. And just looking at this from a metabolic perspective, the benefit on hemoglobin A1c and some sensitivity certainly is something that stands out for lani. And so I do think as we move into the area where potentially both oral therapies are available. Again, these are liver-directed therapies, right? So we're not necessarily thinking about GLP-1-based therapy here. I think what we're targeting are those with some degree of fibrosis, particularly F2 or greater, as currently we see in the NATIVE III trial where we're enrolling a large number of patients for accelerated approval. And I think here, it's going to be important to see what the results of the Phase III are relative to NASH resolution and fibrosis improvement. Assuming it's similar to what we saw in the Phase II or even better, I do think that combination therapy would be something we would want to look at because either -- I mentioned this today in a lecture where a combo therapy is ultimately going to be where we want to be to try to achieve NASH resolution and fibrosis improvement in the majority of our patients. But if I had to start with one, I had a diabetic patient with F2 disease. Certainly, I would look at lanifibranor or F3 disease, I would look at lanifibranor as a first-line agent if both were approved for the same indication and the safety and tolerability profile remain what it is today.

We'll now move on to our next question. Our next question comes from the line of Seamus Fernandez from Guggenheim Securities Research.

So one question that we've gotten from investors is why there wasn't a control arm with SGLT2 in this study. And perhaps you could just kind of metric for us how an SGLT2 might have performed on its own in a similar patient population. Just to kind of metric, the sort of placebo comparison there and to clear that up as a question. Second, Frederic, I was hoping that you might give us a little bit of an update on the Phase III program and baseline characteristics as well as baseline medications. If you can't do that today, is that something that you plan to announce in the -- when the patient population is fully recruited. There's obviously a lot of interest in the underlying use of SGLT2s in the study as well as the underlying use of GLP-1s. And then just as a final question, is there an opportunity for an interim look at a group of patients who have completed the full sort of 12 months rather than going through the entire study population. I know that there are statistical penalties associated with that. So just interested to know if there is an opportunity for an interim look at the Phase III study.

Michael, do you want to take the first question, then I'll take the one on the baseline characteristic. All right, Michael. I think you're on mute.

So I'm not on mute, but I didn't hear everything. But -- so the first question was whether -- [indiscernible] Empagliflozin alone and that's, of course, a very good question. It would have been an additional piece of information, of course. At some point, we had to make a decision about how large the study would be and what our main questions were that we would want to address? And the main questions were, does the addition of Empagliflozin to lanifibranor have a benefit? Both with regard to further improvement of cardiometabolic marker -- metabolic immune markers for those patients who may benefit from that and specifically also for those patients who have a concern with weight gain that you see in some of them, can that be addressed with Empagliflozin? And such studies were -- similar studies were done actually for [indiscernible] agonist with actually 4 of the SGLT2 inhibitors that are available in the market, including Empagliflozin. And so we know from those studies that you do have an additional benefit on the cardiometabolic markets and that weight increase can be addressed. So that was the, I would say, the background information that we had -- and of course, if you look at the effects on Empagliflozin or other SGLT2 inhibitors alone, they are very well established with regard to their efficacy in the type 2 diabetes indication. On NASH/MASH, they probably have an effect mainly on upstream markets, but not so much on the more downstream markers of the liver manifestations of NASH. So at the end, we decided not to do an Empagliflozin arm alone even though that would have been, of course, additional information of interest because it was not pertinent to the key questions we wanted to address for this study. So that's on the first question. I think Frederic you said, you want to take the...

Yes, on the baseline characteristic. So Seamus, yes, we will, once we reach last patient first visit, we will publish the baseline characteristic. As we did early in the summer, when we reached 500, 600 patients, we did an analysis of the baseline characteristic. We don't think they will evolve significantly. They are in line with our expectation, similar to the one of the Phase IIb, which is not a surprise because the screening criteria have not changed. We continue to look for patients that are F2/F3 with a high level of inflammation and ballooning using SAF Score like we did in the Phase IIb. The main difference that we noted, there was a higher percentage of patients with type 2 diabetes, 60% in the Phase III versus 40%, which we don't view as an issue to the contrary when we did some analysis in the Phase IIb in the patient with type 2 diabetes, the responder rates are similar, actually slightly higher than in the general population. And then to your question about the GLP-1 and SGLT2, we have approximately 17% of patients that are randomized that are under GLP-1. And on GLP-2 inhibitor is close to 10%. No interim look. So it's a Phase IIb, Phase III placebo-controlled. We will not look at efficacy data before the top line data.

Okay. Great. And then maybe just a question for Dr. Harrison. Dr. Harrison, I'm sure you're very familiar with the data on SGLT2s that has been sort of explored whether it be with MRI-PDFF or in sort of similar Phase II programs. Just hoping you could kind of offer us a little bit of the baseline of what you would have expected with an SGLT2 alone in a similar patient population. And separately, as it relates to Resmetirom, if could you just help us understand the population that you think is most appropriate for use of Resmetirom and perhaps how the lanifibranor opportunity compares in your mind?

Yes. The SGLT2 inhibitor story is -- I mean people have dabbled in it. I studied the Licogliflozin, which is an SGLT1/2 inhibitor published that data. And there have been small data sets looking at other SGLT2 inhibitors like Empagliflozin. But I think at the end of the day, we don't have any histopathology data with that. So we really just can look at ALT and MRI-PDFF. From my memory, I want to say that there was a modest reduction in liver fat, but nothing that was -- that stood out as being impressive. I think probably -- again, I don't want to come up with a number. I just think maybe keeping it broad strokes. The data doesn't suggest a huge reduction in MRI-PDFF with SGLT2 inhibitors alone. And right, this is the first data where we've looked at a liver-directed therapy like lanifibranor in combination. And I think the data are actually quite impressive. In addition to the mitigating the weight gain, I think the impacts on insulin sensitivity and overall reduction in cT1, for instance, are impressive in addition to the MRI-PDFF change. Real quickly on the Resmetirom. This is an evolving area. I mean, my goodness, we only are 5 days into FDA approval, and working out who is going to be a good candidate for therapy is something that we're aggressively working through. The win, and I say this categorically a huge win is no liver biopsy requirement for treatment. And that opens up the whole NIT field in a way that has never been thought of before. I mean, certainly, we thought about what if? But now it's here. And so I think we're going to have to very carefully look at what constitutes consistent with F2/F3 disease. And we talked about that again today at the meeting that I'm at. And I think we're going to look at the guidance documents that have been published and that are out there. And we're going to look at the MAESTRO-NASH data, look at their baseline characteristics, understanding that we used FibroScan and AST values as prescreen screening tools for that trial. And we'll look at those numbers and provide some guidance in the coming time on what those numbers might be for treatment. And again, part of it is going to be up to the payers as well and what their expectations are. And hopefully, we can provide some guidance to them. Thank you.

Our next question comes from the line of Annabel Samimy from Stifel.

Again, congratulations on the very consistent data. So maybe one for Dr. Harrison. Given the weight gain issue, weight gain still seems to be issued for lani alone. And appreciating that it's more metabolically healthy weight gain. Does this suggest that you think lani should be used only in combination with something like SGLT2 or SGLT1. And do you think when you are assessing patients for treatment that you'll be thinking more about the type 2 diabetic patients as those were most appropriate for treatment, or do you think that you would be using it across the spectrum of patients given the important benefit on the metabolic markers across the entire population. So maybe you can respond to that first. And I have a couple of follow-ups.

Yes. I mean I think, again, it's early to be thinking about necessarily where we would use this particular drug knowing we don't have Phase III results yet. But if we were to make an assumption that the Phase III results mirrored what we saw in the Phase II trial, then I think we can make some comments. So number one, diabetic patients have more advanced disease, diabetic patients progress more quickly. And so there is an urgent need to manage those patients. And we need to manage the patient, not be organ. And so in managing the patient, one of the tenets of diabetic management is glycemic control. And if I've got a drug that improves glycemic control, that's oral that's once a day, that's built for the long haul and that has histopathologic benefit as well as lipoprotein benefit, and then that's something that becomes very attractive. Now where that fits in the armamentarium of diabetic management is yet to be determined diabetologists look at things from how it changes outcomes. And certainly, we don't have an outcome study yet that's read out. And so I think -- we have to look at this from that perspective, from an endocrine perspective and then from a liver perspective. So if as a liver doctor, I look at lani and it's met its Phase II accelerated approval endpoint on both NASH resolution and fibrosis improvement. And we see insulin-sensitivity benefit reduction in HbA1c and lipoprotein benefit and it's well tolerated. Despite the modest weight gain that's seen, it becomes a very attractive drug to treat our patients with, again, particularly the diabetic patient. We very often see people that are not well controlled despite underlying Metformin use, SGLT2 inhibitor use, DPP-4 use, insulin use and even GLP-1-based therapy. So in that sense, it would be an add-on therapy. If patients come to me and they're diabetic and they're not on anything, then, of course, this becomes an attractive therapy for me because I'm hitting all of those points. The other thing I would say is 10% of our patients with NASH are lean. And so the modest weight gain that's seen in a few of our patients treated with lanifibranor would actually not be an issue for those at all. So to summarize, I think, yes, there are situations where we would add on to GLP-1-based therapy. In my clinic now, many patients come to me on GLP-1-based therapy. They still have abnormal FibroScans. We know from the data that GLP-based -- GLP-1-based therapy while helping with weight loss over fat content reduction and mass resolution, heretofore, we don't have any data on fibrosis improvement. So this would be a great drug to particularly add to GLPs in that particular situation if they also have underlying diabetes. I think I hit on several of your questions with my comments back, but you said you might have additional questions.

Yes. And this is, I guess, for the Inventiva team. In NATiV3, you'd mentioned the percent that you have on GLP-1 and also on SGLT2. Is this going to be sufficient enough to characterize the impact on weight and safety in a statistical manner, will you be able to draw conclusions from that? Or is it still, I guess, exploratory and informative as opposed to something that could identify statistical differences between the different patient subsets.

Thank you, Annabel for the question. Maybe, Michael, you want to try to answer this one?

Yes. I think I -- if I understand the question correctly, and if not, please let me know. I think it's important to point out that not all patients have weight gain. So if we divided that up into categorically stable weight with a variance of up to 2.5%. That's half of the patient population, patients who are treated with lanifibranor. And when we talk about rate increase from baseline of 5% or more, that's 1/3 of the patients. So it is a proportion, but not the majority of patients who have weight gain. So the issue of weight gain, if it just -- it's an acceptance issue, I think, in the first place because of the -- not only the cardiometabolic health, but also the liver finding or independent of whether or not a patient has weight gain or not on lanifibranor in contrast to placebo. So it is a patient acceptance issue and -- but it affects only a minority of the patients who are treated with lanifibranor. And as such, I think the question of the necessity for the combination as is typical, I think, for the treatment of conditions that fall under metabolic syndrome, ultimately, the physician and the patient will find the treatment that is best for them, and it's usually a chronological evaluation of treatments that come to combination treatments. That's how type 2 diabetes is treated. That's probably how NASH will be treated as well. Some patients will benefit from a combination. Others will be fine with one drug. So I think whether or not lanifibranor needs to be combined with an SGLT2 inhibitor in clinical practice will be determined by the response of individual patients. I hope that addresses your question.

And Annabel, to your question about will we do -- what will we be doing with this patient under GLP-1 and SGLT2, yes, we plan to do some analysis to deep dive on this type of patients and see what are the effect of the combination. If I take GLP-1 with 17% today in the trial with more than 100 patients that we plan to recruit that plenty to a very interesting data on this very promising combination.

Okay. Great. And then I guess one last question. When we look at the many combination data from the hepatic steatosis perspective, the benefit there for the lani combo was not as strong as lani alone. Are there any ideas as to why this is the case? And will this be a problem going forward patients -- physicians have to weigh the hepatic steatosis versus the metabolic benefits, was it sufficiently different? Or did it -- was it just a significant difference there?

No. There's no significant difference, and we really have to take into account is a relatively small sample size which is more driven by the low number of patients and lack of synergy of combination of effecting -- of the other combination. So I would not read more into that.

Our next question comes from the line of Ed Arce from HC Wainwright.

Great. Congrats on the data here, especially on the weight gain and the broad cardiometabolic health markers that you went through. First question for me is actually for Dr. Harrison. Wanted to get a better handle on, if possible, whether you see from the data set here, any additive effect with the combination in terms of inflammation or fibrosis. In particular, I noted that the CET1 reduction looked pretty strong in combination. I think over 40% of the patients met that threshold of reduction. But it didn't seem like it was clear that there was any additive effects. And perhaps this is something that the team would continue to look into as they go through specific data, but I just wanted to ask if there was any additive impact there. And then separately, for the company, I wanted to ask if there's any updates for us on the enrollment progress with NATiV3.

And this is a very intuitive question. I mean, certainly, there's additive benefit on A1c and even the percentage of people who have at least a 1% decrease in A1c, we see additive benefit on insulin HOMA-IR, at 24 weeks on ALT and AST, probably not a lot of change there. Same thing for liver fat content. These are small numbers. And I think just to reiterate what Frederic said, if -- we don't have liver biopsy. We have small numbers of patients. And I think it's unfair to draw conclusions one way or another about what to expect histopathologically. I do look at the CET1 number though and look at the percentage of people who have greater than an 80-millisecond change as a very favorable one. And even though you're not seeing numerically greater percentages of those with the combo therapy. It doesn't mean that there's not -- you're not having an additive effect. It might be that perhaps you need to treat longer than 24 weeks or there just needs to be more people in the study to evaluate these noninvasive tests that could be translatable into a histopathologic improvement. I don't think we can fully answer the question directly.

And to your question about NATiV3 enrollment, so we are pleased how things are evolving. First of all, the patient that trigger the [ fibrosis ] continuing to progress is not in the hospital anymore. More importantly, on the operational side, we've had a lot of webinars with all our sites, meetings, and we received the first positive feedback on the way we handled it, positive feedback on how we have communicated and especially motivation on getting back to work and starting screening, we have received many confirmation or a confirmation that the patients that are waiting to be screened. Of course, the focus goes on the sites that are under central IRB in the U.S. and Canada. That's a bit more than 120. And so all of that gives us hope that we can meet our target for last patient first visit for the end of the first half of this year.

Great. And if I could squeeze one last question in on the LEGEND results. Is this something you think could be presented at EASL?

Yes. Will it be EASL or AASLD, I don't know, but certainly, these are data that should make it to a presentation to one of these congresses and also for publication.

Our next question comes from the line of Rami Katkhuda from LifeSci Capital.

Congrats on the update. I guess with the caveat that it's a small sample size, it doesn't seem like the weight gain with lani monotherapy tapers off by week 24. Do you expect the tapering of weight gain over time? And when do you think that could occur? And then maybe a question for Dr. Harrison. Is hypoglycemia a meaningful concern with the lani SGLT2 combo, is that a consideration when picking an optimal combination partner for lani overall?

Do you want to take the first question, Michael, or do you want to...

Yes. No, you're right. I mean, up to 24 weeks, the weight gain is not plateauing, but we know from a previous study, which was done in patients with scleroderma that after 6 months weight gain does plateau. So that's the data that we do have in NATiV3, of course, we are blinded, and so I would not make comments on blinded data, but we are -- I mean, there is enough data, I think, right now to show that there is not a continued increase, if you treat longer. But I would refer here specifically to the scleroderma study where we've shown that in unblinded data. So that's, I think, reassuring with regard to the course of the weight change. And I would like to say, again, we have to keep in mind that the rate change is not something that affects all patients. So it does not affect at least half of the patients who are on lanifibranor.

Yes. I think -- this is Dr. Harrison to address your question about hypoglycemia. Certainly, there's not an issue with lanifibranor in hypoglycemia. You're improving insulin sensitivity, you're not impacting beta cell function in a negative way. So there's really no reason to get hypoglycemia. SGLT2 inhibitors, I guess, theoretically, there can be some hypoglycemia. I can't -- I don't think -- obviously, we haven't studied that in a large data set to know. I guess, hypothetically, if you're improving insulin sensitivity, maybe in that setting, the combination could lead to some hypoglycemia. But again, we'd have to do longer studies and large numbers of patients to know for sure.

Our next question comes from the line of Jacob Mekhael from KBC Securities.

I have a few, if I may. First of all, congrats on the data. And on the weight increase seen in the Phase IIb trial, was there a difference between the doses? And do you expect that empagliflozin will be able to stabilize the weight gain on the higher dose of lani as well? So that's my first question. And the other one is more broad on how you look at the market opportunity for NASH. I've seen some numbers from Madrigal, where they estimate to target just over 300,000 patients. Do you expect the patient population to be different for lanifibranor? And do you expect that the market will grow in the next few years as more treatments become available?

I can take the last part of your question. So the 300,000 patients is simply drilling down on the fact that we think there's about 1.5 million U.S. patients diagnosed with F2/F3 disease. About 0.5 million of those are seen in GI and hepatology clinics. And so the goal has been to target 2/3 of those for potential treatment as patients were coming in for routine clinical follow-up with their GI and hepatology provider. I think the plan there was to establish a beachhead and then once that's done, drug is able to be more available over time that then broaden that beachhead to target additional providers, primary care endocrin, that sort of thing. I think, first of all, it's important to realize that with -- in my opinion, with the first approved drug in NASH, there will now be a massive disease awareness campaign, both at the patient level and at the provider level. I think this will bring more people in for evaluation of underlying steatohepatitis, and we know from data presented at NASH-TAG earlier this year, Mike Charlton presented only 2% of people are diagnosed in the U.S. So we have a long way to go to build disease awareness and drive those patients that are sick. What we have seen since 1990 till now is a doubling the number of cirrhotic patients due to NASH from 100-and-something thousand to almost 350,000 patients. And the sobering statistic is most of those patients present for the first time in the ER with decompensated disease. So to make a long story short, I think there will be improved disease awareness, this will have throughput into patients presenting to providers for evaluation of underlying MASLD and MASH. I think as we evolve our noninvasive testing strategy, as I mentioned earlier in the program that, that will then translate into more patients being referred for consideration of therapy. So absolutely, by the time we get to lani hitting accelerated approval filing the NDA and getting approved, this pool of patients will grow exponentially.

Yes. And I can take the first question, which was the difference between the doses on weight gain. In the LEGEND study, we have 1 dose, 800-milligram but in NATIVE, we had 2 doses, 800- and 1,200-milligram. And the difference on weight gain after half year of treatment is minimal. In -- for the 800-milligram, there was an average increase of 2.4-kilogram, that's mean value, and for the higher dose, 2.7 kilograms. So it is a minimal difference in that study of 0.3 kilograms after half year of treatment. Therefore, I don't expect it will make any difference. And you would see the same benefit of empagliflozin with a higher dose, even -- although we don't have the data, of course, yet. But given that we know that the difference between the 2 doses with regard to weight gain is minimal, I think it will not make much of a difference.

Our next question comes from the line of Lucy Codrington from Jefferies.

I only have one left, I think. So just on the -- again, on the weight side of things, just thinking about that the VAT/SAT ratio. I just wonder if you would have expected a more than 5% reduction for lanifibranor -- lani alone based on kind of prior discussions about this shift there were more metabolically healthy weight. So is that 5% in line with your expectations?

Yes. Maybe -- I think essentially, my answer to that would be the sample sizes are such that we cannot make conclusive -- been conclusive about this question. It's a very good point, of course. Variability in 1 or 2 patients maybe me explain what we've seen. I think it's important that the ratio with placebo goes up with -- towards more visceral adipose tissue, and it goes down with lanifibranor. So the trends are clearly -- the movements are clearly in the right direction. And if you would have -- if you had more patients, of course, then you can be more conclusive about this at the end what the difference would be between lanifibranor and combination treatment. On the specific ratio. So it's a good point, but I think we have to be careful to conclude on that given the small sample size of the study.

That's also, I think, placebo took 11. So the delta is quite large. It's actually 16. So it's another way to look at the same data.

Yes.

Our next question comes from the line of [indiscernible]

A question about the improvements in adiponectin. In the disease patient population, is there some threshold level of improvement in adiponectin you need to see the improvement in insulin sensitivity? Or should we think about those increases as being more linear?

Yes, that's a good question. There's not a defined threshold level. What we know is, and that's also been shown in other studies that with placebo, you don't see much of a movement in adiponectin and insulin sensitivity also does not improve much. And the way adiponectin effect insulin sensitivity has also been well studied. So basically through an effect on lipid metabolism and the reduction of lipid intermediates that interfered with insulin signaling. So what we can say is that compared to data available in the literature about the effect of lanifibranor or the effects of adiponectin in this disease, that patients have low levels but with variability. We see it in our study. And fault increase of, even a doubling of the value, it does have an impact on cardiometabolic health. And we see with lanifibranor, a higher increase than that. In NATIVE, we actually looked at the correlation between the fault increase and the effect on metabolic markers and patients who have the higher the adiponectin increase, the more you see improvement of metabolic markets. We've shown that for steatosis and it's been in one of our posters and an upcoming paper. So yes, there is a correlation between the degree of adiponectin increase and improvement of cardiometabolic markets, but not a real threshold. I think that has not been established for adiponectin as such.

Okay. Great. And then just in terms of how the visceral and the subcutaneous adipose tissue ratios are assessed. How accurate is that measurement.

It's done with MRI. So it's pretty accurate within the section that are made with the MRI machine. So that is a pretty accurate measurement of course, subcutaneous adipose tissue is distributed in throughout body -- so it is a section, if you wish. But I think the importance is accentuated by the fact that it's combined with the improvement of insulin sensitivity. And I think that makes the strength of the message because adipose tissue or subcutaneous adipose tissue is not by definition insulin sensitive, but it is combined with the fact that we do see an improvement of insulin sensitivity that this is a strong message, and that has also been published previously by Kenn Cusi's group with regard to PPAR-gamma agonists, pioglitazone, specifically.

There are no further questions at this time. So I'll hand the call back to Frederic for closing remarks.

Thank you, and thank you all for attending, a special thank to our guest speaker today, Professor Harrison and Professor Sven Francque, for then we're really sorry about the technology. What we will do that we will record them and put this presentation on our website. It's really quite an interesting piece of work that has been done together with the Sven group to show the improvement in the vascular aspect of -- that are induced by lani, which I think are very important in patients with MASH and especially in patients with compensated fibrosis, so we will put the slide and the record on our website. So thank you, everybody, for participating, and I wish all of you a great day. Thank you.

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