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

Good day, and thank you for standing by. Welcome to the top line results, efficacy, safety and mechanism of action of lanifibranor, IVA337 in patients with type 2 diabetes, T2D and non-alcoholic fatty liver disease, NAFLD conference call. [Operator Instructions] Please be advised the conference is being recorded. I would now like to hand the conference over to your speaker today, Frederic Cren. Please go ahead.

Thank you. This is Frederic. Welcome, everybody, and I'm really happy that you have the time to join this conference. I think we will share with you today important results on the intrahepatic triglyceride content as well as on the hepatic and muscle insulin sensitivity, and you see how [ manusification ] from these parameters. We're very pleased today to have with us Professor Ken Cusi, who has led the study. We'll go through the [indiscernible] also introduced and [indiscernible] in severity, of course, of NAFLD, but also that's of interest for us, of course, of patients with NASH. I think it's important to note that insulin resistant does not only affect patients with NASH, who are overly diabetics, but also that's really important that have prediabetic, overweight and inpatients. I think that the results we show today are really proper. And I think lani is the only oral drug that has demonstrated efficacy on insulin sensitivity in glycemic control. So with that, I'll leave the floor to Ken, and I'll move to Page 4, which was a bit of an introduction about insulin resistant in patients with NASH.

Thank you, Frederic. It's an honor to be today here and very excited with the results that we're going to be presenting. If you can put the first slide, I think this audience is very aware of the relevance of insulin resistance and how this modulates not only liver disease, but also will affect cardiometabolic health with cardiovascular disease being the #1 risk factor for mortality and morbidity in our patients with NASH. Now the question that comes up is why is it important to treat insulin resistance. And the importance of that is based on insulin resistance has been implicated in the pathogenesis of NAFLD at different levels and it's also involved in the development of metabolic syndrome, type 2 diabetes and cardiovascular disease. And I think the [indiscernible] is aware that the emphasis of metabolic syndrome is going to be highlighted with the change in the nomenclature of NAFLD for the word metabolic dysfunction in its title. I'm not seeing the slides on my end. Anyway, patients with worse insulin resistance, whether they're lean, overweight or obese, have more severe NASH, and this audience also is fully aware that they're more prone to disease progression and to cirrhosis. Now knowing what the hepatic and muscle insulin-resistant role is important because therapies that can turn this around have shown to impact steatohepatitis, we can call that weight loss by different means and pharmacotherapy that improves insulin sensitivity. Frederic, can you put the first slide?

Which number? 5?

Yes. Number four. Now along this line, liver and muscle insulin resistance are important, but we also know that this functional adipose tissue, particularly in visceral fat but also subcutaneous path are a major risk factor for worse steatohepatitis. And our group and many others have highlighted the role of lipotoxicity with adiponectin being a clear marker of how healthy your adipose tissue is and lower levels being typical of people with type 2 diabetes, obesity and steatohepatitis and increases in connecting by any therapy, but particularly insulin sensitizers within the PPAR gamma group have shown marked benefits and marked histological improvement. So Frederic, have you been able to put the slides up? So the key message here is that lanifibranor as a pan-PPAR agonist that has a moderate and well-balanced activity among the 3 isoforms, PPAR alpha, gamma and delta are going to target the broad spectrum of the metabolic abnormalities that we see in people with NASH. Lanifibranor is a small molecule that activates the 3 isoforms. It's given as -- this audience also knows as a single tablet and it comes in 2 dosings of 800 milligrams, which is the dosing used for this study and 1,200 milligrams, which you're also familiar from the NATIVE study. Now the interesting aspect is that when people talk about PPAR gamma, alpha and delta, you should think that this is just like the last name of a family, and there are significant differences within each family on the way that they impact their receptors and their biological effects. Each of these affects hundreds of genes and a unique signature of each agent can only be elucidated with controlled clinical trials. And I'm going to see if we can get Slide #5, Frederic or Pascaline. Anyway, the key thing -- the key message for our audience today is that these 3 isoforms in lanifibranor are presented in a single molecule, in a single tablet in a fairly balanced way. And again, for the audience, that's not so familiar with the effects of these different isoforms, think about PPAR alpha as drugs that have been approved for decades to modulate lipid metabolism like a [ fibrate ] that have a very strong effect on lipoprotein metabolism in the liver with a great impact on particularly increasing HDL cholesterol, which we'll be sharing with you later. Then we have a PPAR gamma effect that you are familiar with in pioglitazone. It has perhaps some PPAR alpha effect or in rosiglitazone. And finally, PPAR delta, which is believed we've learned from elafibranor maybe some fact in inflammation and a lot of animal studies showing that improves inflammation in the liver and may stimulate insulin sensitivity and muscle. And I hope that by the end of this presentation, you'll be fully aware that this broad spectrum of pan-PPAR agonist activity reflects very well in the metabolic effects that you will see at the end of this short talk. So without further delay, let's move on into a couple of concepts that I think that are really important for this audience to understand within the myriad of new drugs being developed why lanifibranor is very well positioned to play a key role as monotherapy, it's combination therapy. And that comes from understanding the natural history of NAFLD and how we go from steatosis to cirrhosis in a nutshell. I promise it will be very short. So one fundamental defect is that in obesity and in type 2 diabetes or even lean individuals that develop NASH or type 2 diabetes, you have very dysfunctional and sick adipose tissue, which releases of fatty acids from breaking down its triglycerides into other tissues. Two of the tissues that are most affected will be obviously the liver, which is the center of our efforts from a pharmacotherapy development but also muscle because if you have insulin resistance in muscle that disturbs glucose metabolism from most more insulin resistance, which, in the end, leads to the synthesis of triglycerides in the liver and the delivery of these fatty acids that can't get into the adipose tissue to the liver. So now the liver is faced with the dilemma of what to do with this massive amount of fatty acids, they just think about them like little packs of energy. And the first defect that you're familiar with is steatosis because it accumulates in the hepatocyte. Now, we now know that it's not the triglycerides, but toxic lipids that accumulate in the liver cells, this affects the cellular function and energy, promoting mitochondrial-based function. And this promoted by a number of pathways poorly understood in humans fibrosis, okay? Now why am I telling you this? Well, as we -- many -- our group and many others have seen is that in the past 10 years, the approach to NASH has -- or the focus of NASH drugs is progressively shifting to more upstream targets. So initially, there was a disproportionate emphasis on fibrosis, and that's a good target, obviously, because that's what's going to lead to cirrhosis. But a number of agents that have focused on antifibrotics, failed to deliver what we had very high hopes upon. And if you think about it, a lot of these agents had the problem is that we don't know the biology of fibrosis in humans. It's all arrived from mice studies. And again, we have learned painfully that results in mice many or most times are not reproduced in humans. So this led to a frank evolution in our thinking of therapeutics and looking at upstream targets and thinking of the importance of reduced the mass of fat with perhaps significant lifestyle intervention, but also changing the nature of adipose tissue and removing that very toxic insulin-resistant environment. And that's where lanifibranor will play a pivotal role moving forward. I'm not seeing the slides yet. Can we resolve that, you think? Okay. So I'm going to go to the study design and objectives. It's a fairly straightforward design. We felt that we wanted to see really what is the mechanism of action of lanifibranor. And basically, we recruited a group of people with type 2 diabetes, with a fasting glucose that had to be between 100 and 250 milligrams per deciliter, A1c between 6% to 9.5% and with hepatic steatosis, which basically what happened was that the -- we wanted to have a level of fat in the liver equal or greater than 10% that would guarantee that these individuals are typically having a degree of steatosis that is associated with NASH. So we treated the people for 24 weeks and then we gave them either placebo or lanifibranor in a double-blinded fashion. And we established that the primary endpoint was reversal of intrahepatic triglycerides. And then we took a number of secondary endpoints, which was the decrease in intrahepatic triglycerides from baseline equal or greater than 30% or the proportion of patients with NAFLD that had what we call a resolution of steatosis. This means that the amount of fat by the end of the study would be less than 5.5%. And we also looked at a number of parameters of hepatic, muscle and adipose tissue function and examined also aspects of lipid metabolism, like levels of adiponectin and some lipoproteins, and of course, examine its safety. So a total of 38 patients were randomized and treated. Again, we did a full analysis of this data sets of all people who received at least 1 dose of the drug, 18 received placebo, 20 received lanifibranor, of these 14 patients completed the study in the placebo and 14 in lanifibranor. This study was started in the COVID era. So we lost several patients during those difficult times. And again, the baseline characteristics of the patients we're pretty standard for such these kinds of studies, roughly middle-aged individuals age 58 to 61 with a predominant female distribution of 2 to 1, BMI of 34 and again, a fasting glucose between 120 to 130 and an A1C around 7%, indicating these people were overall well controlled. They were insulin-resistant, looking at fasting insulin, liver and muscle parameters and their intrahepatic triglycerides were ranged between 17% to 21%. And -- but liver enzymes are basically normal as these individuals were identified for having diabetes and not based by themselves selected by other features. Now let's dive now into the main results. Again, we're going to be expressing this as that [indiscernible] means a relative percent change from baseline and liver fat, which is the primary outcome. If you take the full analysis set, placebo decreased intrahepatic triglycerides by 12%. I need to remind that our ethical duty was to give standard recommendations about diet and lifestyle to all patients. In contrast, people who took lanifibranor had a 44% and highly significant difference. Again, the full analysis set is an analysis that takes individuals who dropped out as having no change. But if you look -- if you take those 28 completers, the reduction induced by lanifibranor was 50%, again, also highly significant compared to 16% in the placebo. Now moving on to a more granular description of the data. We were interested in looking at those patients who achieved a 30% or greater reduction in steatosis. And the percentage of patients achieving a liver fat reduction of that nature were almost 2/3 on lanifibranor, 65% compared to 22% on placebo. This is highly significant, a delta of more than 40%. And if you look at those who had what we call NAFLD resolution, so no steatosis, hitting that mark below the 5%. That happened in 25% of the patients that was also quite significant. Now it's important to put this into the context of other drugs. And again, this has an exercise just to get a feeling for the effect. Again, these are different patient populations, different study designs. But in studies, roughly between 24 to 52 weeks, the reduction of 50% is a quite considerable -- consider very impactful as this will translate into improvements in [ microinflammation ]. And again, this audience is very aware that from the NATIVE results that confirms lanifibranor as one of the few agents that has achieved a reduction in steatohepatitis and fibrosis. Now moving on, let's dive now into what this means for the patients with diabetes in terms of reversing insulin resistance and achieving targets of A1c that will prevent the diabetes complications. So if you look at the hemoglobin A1c change, the difference was highly significant with a reduction of 0.9% with lanifibranor compared to a mild reduction of 2% up -- 0.2%. So this was -- had a high significant -- statistical significance. And remember that these patients were well controlled. So in the diabetes world, we know that when the A1c already starts near target like in our study, 7%, typically, the reduction will be less. So as an endocrinologist, I'm very excited about this finding because I would expect that if the A1c will be higher, this impact will be even greater. Now let's begin getting into the results of -- on insulin resistance. So if you just take a raw measurement like insulin, the fasting insulin correlates very well with your metabolic well-being. If you reduce that by exercise or any weight loss, it goes down. Here, we had an impressive reduction of 6.7 micro units per ml. It was a reduction, as I recall, about 30% to 40% compared to a minimal change of minus 1 in placebo. So this pretty much predicted the results that we saw with our gold standard technique. I have to clarify that this study did measure insulin sensitivity by what is called the euglycemic insulin plant in the endocrine field. This is a gold standard technique that measures very, very carefully liver and muscle insulin sensitivity and is highly reproducible and it's the gold standard to measure insulin sensitivity in patients. So with that technique that is available in very few centers in the world, we were able to very, very carefully measure endogenous glucose production. Endogenous glucose production is largely 90% hepatic glucose production. A small amount comes from the kidney, but it's really the measure of how healthy your liver is. And typically, that will be associated with positive lipid and glucose related endpoints. And the reduction in hepatic glucose production was highly significant and in the range of about 20%, 25%. Hepatic insulin resistance index. This is an index derived from the 2 parameters I just mentioned. I mean, knowing the rate of hepatic glucose production going down is important. But more importantly, this happened with even lower insulin levels, indicating a large impact on hepatic insulin sensitivity. So a large effect of lanifibranor on the liver, which clearly reflected later the improvement in A1c over time. Finally, we looked at the muscle. The muscle is probably the hardest tissue to improve its insulin sensitivity. Exercise improves it a little bit, about maybe 10%. Here, we saw a very, very significant change in muscle glucose uptake. This means just to put it into logical context when we eat insulin comes from our pancreas and tells the liver stop making glucose. That's what we mentioned improved in the prior mentions of endogenous glucose product, but the muscle needs to update glucose. If not your glucose are going to remain high for a long time, and this we proved markedly with lanifibranor. So big effects on liver and muscle, which reflected in the changes in the A1c. The last piece of data, which we found very, very exciting is the effect on HDL cholesterol and adiponectin levels. I mean I know this audience knows very well that every 1 milligram increase in HDL will translate in reduction in cardiovascular disease and people with NASH have a very high rate of cardiovascular disease. And again, as you know, it's probably the #1 cost of death and morbidity in our patients. We saw a robust increase in HDL, and this speaks very highly of PPAR alpha engagement, and moreover, we had a robust increase in adiponectin and this robust increase in adiponectin, which increased by 7 micrograms per ml, basically greater than a doubling of adiponectin has not been reported with any other agent in the NASH field or in the diabetes field for the sake of putting this into perspective. So big effects on the liver, big effects on muscle, effects on lipoprotein and cardiovascular profile and improvements in the target tissue we want to modify which is adipose tissue. So to finish, I would like to share with you the treatment-emergent adverse events, and it had a -- really comforting aspect is we had no significant adverse events associated with drug administration. We had one person in the lanifibranor arm developed COVID and this person later was admitted with complications from COVID, but did well afterwards. So that was our only serious adverse event. We had -- the drug was well tolerated. There was minor weight gain within the lanifibranor or 2.5 kilograms over 6 months, similar to the reported effects over 6 months with the NATIVE trial the placebo lost 1 kilo. Again, events leading to discontinuation. Again, with the COVID pandemic, we had several who withdrew consent, two of them in each arm. We had the placebo, a couple of patients who were discontinued because the elevation of the liver enzymes and increase in lipase. And we had on lanifibranor, one patient that was very strong because increase in lipase, one with leukopenia and one with GI side effect. So overall, we did not have any serious adverse events. We look carefully for anemia, which was mild and not significantly different between the groups. We -- the distribution of the most frequent adverse events was fairly comparable among both groups. So overall, a safety profile that makes this approach to reverse in some resistance quite exciting. So to finish, let me just summarize in 3 or 4 points what we talked about. Lanifibranor met the primary efficacy endpoint by inducing a liver fat reduction that was highly significant between the groups with 65% of the patients with type 2 diabetes and fatty liver disease. It's a very insulin-resistant group that achieved greater than 30% reduction in liver triglycerides and 25% reached a level that they didn't have NAFLD by the end of the study. The dose that we use at the lower dose of 800 milligrams still, there were marked effects on insulin sensitivity, both at the liver and the muscle. And very exciting to see a robust increase in adiponectin and improving in HDL cholesterol that make it a promising agent to reduce cardiovascular events. So here, we have a drug with a good safety and stability profile that reverses the really fundamental defect among the many pathways we know from animal studies, it boils down in humans to reversing insulin resistance and reversing the development of cardiometabolic risk factors. And here, we have an agent that reverses with a pan-PPAR approach effects on the liver, muscle and changing the biology of adipose tissue and with the potential to treat diabetes, the potential to reverse cardiovascular disease to be shown in long-term studies, but that would be a very exciting addition for the management of our patients. So with that, I'm going to stop and give back the mic to Fred.

Thank you, Ken. That was very clear. I think it's now time for Q&A, and the operator will explain how you can ask your question.

[Operator Instructions] Now we're going to take our first question. And the question comes from the line of Lucy Codrington from Jefferies.

I've got a couple. But firstly, can I just check on the safety slide. I may have misheard, but I thought Professor Cusi said that the serious adverse event occurred in a lanifibranor treated patients with a COVID admission. But it looks like on the slide that's under the placebo arm. So I just wanted to check where I misheard that or other columns to where were we on way around on the slide. And then moving on to my questions. Just in terms of when we're looking at other studies or in fact, the Phase IIb data, is there anything that we can take from those data sets to indicate what degree of liver fat reduction you might have expected with the 1,200-milligram dose relative to the 800 milligram? And then next, just to say on -- to double check on the weight gain with that, that you said it was 2.5 kilos versus the 1 kilo weight loss in the placebo group. Was there anything about fluid, any fluid retention observed in the study?

So first one was on the safety, maybe, Ken, you can address that and also cover [indiscernible] versus the technique we use.

Can you hear me?

Yes. Yes. No, we can hear you.

Okay. So -- different questions. So number one about the comparison of [indiscernible] explained that the [indiscernible] and actually, MRP has used as [indiscernible]. We also did that [Technical Difficulty].

Maybe, Michael, can you cover the question about the 800 versus the 1,200?

Yes. We've also seen, of course, some reduction in hepatic fat and steatosis -- and there's a lot of noise from the line, I do wish you hear me, but it's -- there's a lot of noise, sorry. But -- so we have seen a reduction of hepatic fat in the NATIVE 2 study as well in the Phase II study. The methods were different, how we measured it and [indiscernible] so they are made of different physical properties of molecules and tissues, but essentially the major triglycerides in the liver. We have seen both histologically that the grading system, the [indiscernible] system as well as with ultrasound-based Fibroscan cap that there is a significant reduction in hepatic fat in the lanifibranor arms at 6 months of treatment and not in the placebo arms. And similarly to what Ken showed actually about 1/3 of the patients have go down in the steatosis assessment to something that corresponds to no steatosis histologically. So the effect is very similar. What we have seen throughout the entire spectrum of metabolic markers, including hepatic steatosis that both the 800-milligram and the 1200-milligram have the same effect and same degree of improvement of the cardiometabolic markers which includes hepatic steatosis. So there was no difference between the 2 doses. And that's also one of the reasons why for assessment of metabolic benefits, 800 milligrams is quite appropriate.

Can you hear me?

Yes, we can hear you. Then on the...

So again, MR spectroscopy is basically a gold standard. It's not used so much in clinical trials because you have to be in the university, have a very good -- one of the leading imaging centers in the United States at the University of Florida. And we also have the MR PDFF data, we do both in all our studies. Regarding this, as you know, liver fat measured by MR-based techniques is the gold standard and much better than doing that by elastography like other methods. And again, in magnetic resin elastography again, is the gold standard for measuring liver fibrosis. But again, I know the audience is used to biopsy studies. The purpose of this study was not to look at liver fibrosis changes. So we selected many patients did not have significant fibrosis. So again, you're not going to improve fibrosis if you don't have it. So in the end, we -- our focus is largely to give a rationale of why to use a drug that targets insulin resistance, and I think we have addressed that answer -- that issue about the mechanistic potential very successfully.

See, all right. [indiscernible]. Seems to be the column, seems to...

Yes. There was a question about edema. There we had only one patient in the lanifibranor arm with very mild edema and the person continued the entire study without problems and -- but it was not an issue. No other patients develop edema of any kind.

Yes. And Lucy, you're right. It seems that there is 2 column are inverted, so we will upload on our website, the correct version of the presentation. Thank you for spotting that.

And the next question comes from the line of Ed Arce from H.C. Wainwright & Co.

Can you hear me okay?

Yes.

Great. I appreciate the review of the data this morning. A couple of questions for me. Probably First one for Professor Cusi and then the second for management. Firstly, I wanted to get a sense if we could to sort of recap what competitive differentiation, particularly in NASH is provided by the results of this study. And clearly, targeting the insulin resistance is the focus. But I was wondering if could better sort of specify in your view, where that fits relative to other compounds that may have some effect on incident? And then the second question for management. I guess, I noticed the 25% of patients on the full data set, 38 patients that resolve NASH on the lani arm, but that was just barely static. Is that a function of the small sample size? Or what do you think led to that?

Great. Great question. So this is a very good question. So for people who are navigating and trying to understand which are the pathways that are going to be more successful. There have been many pathways that you're aware of, and some of them have tried to target inflammation fibrosis but there is one fundamental defect that drives most of these pathways, which is insulin resistance. So I -- it's hard to believe that unless you are [indiscernible] will shift the name that will represent in the nomenclature committee that start to metabolic dysfunction. Unless you address that metabolic dysfunction, I mean you are not going to have great results, I think, with any drug. Weight loss by any means exactly does that, reverses metabolic dysfunction and interventions from lifestyle [ modification ] surgery, GLP-1 are successful because of that. But they don't fundamentally change the biology or your adipose tissue. So the way to look at this is the fundamental defect of insulin resistance can be reversed with intense exercise, large amounts of weight loss. But what lanifibranor does is to change the biology of fat, and we know that there's target engagement by the massive increase in adiponectin. Converting that fat of this individual into a fat that functions again like that of a lean individual. The level of lanifibranor that the adiponectin achieved are very similar to people with outside liver disease and metabolically healthy. So the importance of this study is that it provides a robust rationale from this approach. And again, as I was saying before, 2 PPARS are not the same. You can have 2 PPAR gammas or 2 PPAR alphas, they have different biological activity until you test them in the field with a controlled trial, you don't know really what you get. Now we know where we get is lanifibranor, and this provides a very strong foundation for what we found in NATIVE and for other biopsy studies moving forward. Now the last thing to mention is that we chose the 800-milligram dose. And again, what was asked before, I forgot to answer what to expect from a 1,200-milligram dose. Well, we know from other PPARs that there's dose dependency and the efficacy. So we would have -- I mean, I don't want to speculate how much more, but with a 50% increase in the dose who had clearly have gotten a significant greater benefit. So this is the low bar of what you get. And again, maybe you can extrapolate from the native study for some of these effects. So I think the second question was about the 25%. Are you going to address that, Fred? How is your connection going? I think Frederic was having some issues. So the question about 25%, would you want to repeat that question exactly?

Yes. Just wondering what was driving the statistical result where the 25% in the lani arm turned out to be just barely static.

Well, remember that we chose people -- can you hear me now? Yes. Okay. Yes. So well, remember that if you have 20% liver fat, getting below 5% is pretty difficult. And this, remember, is the full analysis set, which ameliorates the effect of just the completers. We didn't put the data for the completers. But if you put only completers, that is around 1/3 of the patients. So we have published that in reality, the effects of pioglitazone or the effects of -- in this case, we haven't done the same analysis. But the effects of insulin sensitizers is independent of whether they cross that line or not. So in other words, the improvement in insulin sensitivity and the improve on histology is somewhat independent of that. So you can still have 8% liver fat and have a complete resolution and we published that. So we put that there as an endpoint that we had mentioned before. But we published after we wrote the protocol of that. It really -- what really matters is how much insulin-resistant can improve even independent of whether your liver fat decreases by 30% or greater. And we see a very consistent improvement in insulin-sensitivity across the board.

Great. Perhaps, I don't know if management or Fred is still available, but I would like 1 follow-up, if I could.

Sure.

So given the explanation you gave so elegantly around the competitive differentiation and the insulin resistance effects. I'm just wondering because metabolic dysfunction is largely driven by these pathogenic lipids. Is there -- are there plans to further study the specific effects of lani in these known pathogenic lipids?

Well, I mean, we'll have to ask somebody from Inventiva, but I would be delighted to do this because as you might have seen in the slide, there are a lot of key pathways. The challenge, I think, is that animal models don't reproduce the human biology. We would have cured diabetes and fatty liver long ago if that was the case. The clinical studies are very complicated and that you would have to probably get paired liver biopsies and you don't get enough tissue. But I'll let the leadership of Inventiva [indiscernible].

Yes. Maybe let me -- sorry. Fredric, you want to say something? This is Michael.

No, no, go ahead. Michael.

To add to what I can just explain the advantage of the strength of lanifibranor in the treatment of patients with NASH is that it really addresses all aspects of the broad disease biology of NASH. Upstream the metabolic abnormalities insulin resistance, which really NASH has in common with 2 diabetes all the way down to fibrosis, and this has been also shown in the data from native. And the study that we present here, the data that can focus really on a deeper understanding of the mechanisms of the metabolic improvements that lanifibranor induces. In the native study, we've shown that you have basically these effects as well with different measurements, some different technologies used. You can see also an effect on insulin resistance, improvement of lipid profile, reduction of inflammation as well as the effects on liver fibrosis. So that's, I think, the unique strength that lanifibranor has thus has a pan-PPAR agonist improve really all aspects of the disease biology from upstream mechanism to downstream mechanisms. And the importance of insulin-resistance has a very key pathogenic events in the course of the disease literally is that it also plays a role in those patients who are not who have NASH, but don't have over the diabetes or don't have over diabetes yet. So we know that we also have insulin resistance and also have pre-diabetes or don't even have prediabetes yet. Over time, they may develop diabetes. So the relevance of these findings are quite obvious in the patient population, which is roughly 50% and more as time goes on that have off conditions clinically, but also those patients with NASH who do not have yet over type 2 diabetes.

And the next question comes from the line of Dylan Dupuis from Roth MKM.

Congratulations on the data, very exciting. Just a couple of questions for me. One, if you can comment on the distribution of background diabetes medications the patients were on -- in the study. And if you've seen any difference in effect based on what the background meds were? And then number two, I don't know if this is something you looked at, but if you had taken a look at the radio effect, if this was something that occurred rapidly picking of insulin resistance, in particular, [indiscernible] rapidly in the beginning of the study or this is more of a linear improvement that occurred throughout the study? And then my third question was just answered, so I'll just leave with those 2.

I can answer that or Frederic or? I'll just start with a couple of comments. So the improvement of PPAR takes weeks. So in general, it will take from experience with other PPARs and our observation in the study is that it takes 2 or 3 months and probably plateaus at some point around that. By 6 months, you should see a full effect. And again, if you stop it, the effects persist for probably 8 to 12 weeks as well. So we saw that that's a typical pattern, and it is because it's not differently than taking insulin or [indiscernible] from our diabetes perspective, you are changing really the biology of fat inducing protein, changing the function of the cells in a fairly positive and radical way. Now the background medications, they had to be on the backbone of [indiscernible]. They were allowed to take DPP and we added in the running if they were uncontrolled, we added. DPP4 is, let's say, I don't want to sitagliptin, saxagliptin, linagliptin. And -- but they had to have stable glucose in the run-in to get into the first arm, and they were equally distributed in terms of medications. Later, we allowed patients who were on a stable dose of GLP-1, but I think we had 1 or 2 patients. I don't recall exactly, but it will be in the manuscript. But -- so the background medication was fairly neutral in terms of expecting to have any impact on the results.

And the next question comes from Annabel Samimy from Stifel.

Thanks for taking my question and for great detail here. So again, I'm going to ask a bigger picture question. So right now, the program is geared towards NASH patients, which obviously are later in the stage of disease and some may have type 2 diabetes some may not have type 2 diabetes. But given this work so upstream in the process to cyclical metabolic pathway and really the whole disease path that leads up to NASH. How do you foresee capturing that benefit? Obviously, you're having an impact from these natural patients these type 2 diabetic patients and it could potentially result in slowing progression or even not allowing them to progress to NASH. So I guess I'm trying to think bigger picture where this could be positioned across the broad spectrum that looks like a lot of people are targeting just the end stages where you've got fibrosis already. So that's sort of what I'm trying to understand from a bigger picture perspective?

I'll make a brief comment, medical point, and I'll let Michael or Fred comment on the strategy Inventiva might have in mind. So I'm speaking as an endocrinologist, although I'm kind of a gastroenterologist. [Technical Difficulty]

I think Ken disconnected. So while he tries to reconnect, I'll take over. I think it's an excellent [indiscernible]. We have [indiscernible] I cannot believe that. The first efforts to treat NASH have been focused on antifibrotic approaches, which are valid by themselves, of course, for later stages of the disease. We know that once you have fibrosis, once you have advanced fibrosis mortality is associated with the degree and the progression of fibrosis. But fibrosis does not happen in a void. It is caused by tissue injury, by inflammation. And so if you take away the tissue injury and the inflammation, which is happening when you improve insulin resistance. Obviously, the forces, the messages, the cytokine, et cetera, the environment that drives fibrosis and fibrosis progression that disappears. And I think in this context, you can make a comparison with, for example, hepatitis C, which is, of course, a viral disease, but it is also leading to inflammation tissue injury, fibrosis cirrhosis and so on. So the downstream effects on the level are quite similar. If you have an antiviral that removes the virus, fibrosis is not a problem anymore. It will stay the same or it will regress, but it doesn't progress. And I think this is where the advantage of having an approach that treats NASH upstream comes in. And again, here, I'd like to stress the point that lanifibranor has this broad effect. It is a [indiscernible] agonist does have the right antifibrotic effects. We know that from PPAR gamma effects on studied cells and so on. It does have an anti-inflammatory effect, and it has a beneficial effect on the metabolic abnormalities. So we actually, with lanifibranor, address both the what I call the downstream manifestations the fibrosis progression and complications thereof as well as the disease mechanisms that drive fibrosis in the first place. And I think that's where the strength comes from that with lanifibranor will address the progression of the disease in its entirety.

Okay. And I guess, how do you approach this from a regulatory perspective and from a clinical development perspective to be able to tap for that broad effect that they could potentially get earlier on before they move on to NASH?

Yes, definitely. I mean this is an excellent question because the data or the basis for the regulatory interactions and of course for the regulatory interactions here we focus in the first place on the FDA. And the FDA -- actually, the FDA endpoints described in the draft guidance for the development of treatments for NASH, except that both resolution of NASH and no worsening of fibrosis or improvement of fibrosis with no effect on NASH itself or acceptable endpoints for accelerated approval. So they recognize that addressing the steatohepatitis component, which reflects the metabolic and inflammatory abnormalities is adequate for accelerated approval, assuming or knowing that ultimately, that will also have an effect on fibrosis and lead to the absence of progression of fibrosis. So the regulatory draft guidance actually already addresses that. Now because we have seen with lanifibranor that we have this broad effect and also based on the data from the Phase II study, our endpoint is actually our primary efficacy endpoint for accelerated approval is based on reaching both endpoints. So both the effect on NASH resolution as well as an antifibrotic effect, a reduction of the fibrosis at stage logically. And that remains the primary efficacy endpoint for accelerated approval, for full approval, of course, the outcome improvement is required. And I think it's quite logical to -- or reasonable to believe that if you have an effect on all the disease mechanisms that cost progression of this condition that will reflect in an outcome improvement.

Okay. And I guess from -- okay. If I could just ask 1 more question. I guess in terms of the NAFLD resolution, 25% versus 0. Is this the standard measure used for I guess, for NAFLD patients specifically? And to what extent does it suggest or indicate the potential, obviously, to be continuing to the extent to it, it's continuing support of the fibrosis impact that we saw in NASH in the native study? I mean, I guess, logically, it seems like there would be an adequate progression. So that gives us more -- that should give us more confidence in the potential NASH measures of fibrosis. I'm just trying to think of how we can translate 1 into another.

Yes. If Ken is connected [indiscernible]. It's also a very good point. I think the -- well, first of all the NAFLD resolution or the resolution of steatosis is a category [indiscernible] it does not take into consideration that the majority of patients actually have a clear reduction of patient hepatic fat. So the effect size is there in all almost all patients. If you look at adiponectin is related to the improvement of litho metabolism and improvement of insulin sensitivity. You see that 90% of patients have a quite significant sort of response with adiponectin, and you don't see that in the placebo arms. So it means, in fact, that this improvement of these upstream metabolic pathways thus have a significance in the vast majority of patients who got treated with lanifibranor. And 1 additional point, and Ken can correct me, but we measure actually triglycerides with the methods applied to quantify steatosis. It doesn't tell us necessarily what the amount of toxic lipid intermediaries is. So that's not captured the imaging technologies. Correct me if I'm wrong. So what is really important is looking at [indiscernible] insulin resistance in muscle in liver as was shown here as well as the lipid profile, specifically [ implant ]. But Ken, please add to this.

Yes. So I think that sometimes we read too much into liver fat. But again, I mean, it is reassuring that in the context of this improvement of insulin resistant with a lower dose. If you just looked at the completers, 80% reach this target at 30% or greater and about 1/3 reached this target of not having NAFLD afterwards. Now the benefit that we have here is that the native study showed us what's going to already happen in this setting. And again, it just confirms that the impact on metabolism is very, very big. Now this cutoff of 30% is still controversial because as the comparison is with NASH resolution, NASH resolution has steatosis in that equation, right, steatosis inflammation, if I guess. So I think it's mechanism of action dependent I would take this as just look at it a robust effect. If you want to conceptualize things, the liver is your mirror of your metabolic health. If you are lean and have steatosis, you have insulin resistance. Insulin resistance not only dependent of obesity or diabetes. It happens in a lot of people without a parent risk factors or minimal. So from the native study, we know that the effect on insulin sensitivity will happen in any person who has this functional fat that they're also overweight subjects. So this is a drug that will have broad implications within type 2 diabetes and even with people with prediabetes preventing the progression to diabetes, you know that fatty liver doubles or triples the risk of diabetes and also for people with normal glucose tolerance that still we have a lot of people at NASH and without diabetes. So bottom line, I think this just now provides a very robust basis for the Inventiva program. And it affects really the universal defect. You don't have NASH without insulin resistance, and now you have a way to overcome that. And again, let's think about this. The weight gain that happens, happens in the content of a clinical trial where we don't encourage extremely actively the people to [indiscernible], we give them the information they need some follow, others don't. But as an endocrinologist or primary care doctor, they're going to do intensive lifestyle modification, they're going to send them to a nutritionist, and in my experience, many times, we can prevent the weight gain with insulin or pioglitazone or other agents by lifestyle changes. So Again, I think it's a very exciting tool that we will have in the future.

And the next question comes from the line of Seamus Fernandez from Guggenheim Securities.

So just really 2 questions. In terms of background medications for potential combination and where we've seen other benefits on NAFLD as well as potential prospective benefits in NASH. Can you just talk about the opportunity to combine lanifibranor with GLP-1 agents or other incretin therapies as well as the opportunity to combine it? Obviously, we have the Phase II study with the SGLT2 inhibitors. Just wanted to get a sense of those 2 opportunities to combine lani with those products and how you think that will -- would or will potentially impact patients with NASH?

Well, you want to me out -- I'll give you some -- I'll give you the endocrine perspective and probably Michael will tell you what Inventiva has in mind. So in a nutshell, I mean, most -- 80% of my people with diabetes are on combination therapies. And when we use insulin when we use prednisone, when -- those are the 2 agents that achieve great results, but they promote weight gain. And the reason they promote weight gain, just to explain conceptually is as you lower glucose as you saw with its compound you stop pouring glucose in the year-end. That's 1 mechanism. Once your glucose gets below 180. So it's a natural mechanism. The other with piaglitisone specifically, I mean, and probably lanifibranor is that you're getting your fat to function again. And if you don't change behavior, the excess nutrients instead of going to the liver and harmony of liver and causing cirrhosis, they're going to be put in the, say, in the trunk of your car. So in other words, you get the junk -- the extra energy instead of in the engine of your car, you put them in the truck. I would rather not have it at all. But getting back to your question, SGLT2 inhibitors promote a 2% or 3%, 4% weight loss, and this has been already tested with pioglitazone, showing a net reduction in a study 1.5 years long showing net weight loss when you combine SGLT2 with TZD. When you combine a GLP-1 like semaglutide that has effects in NASH with bioglitizone, you should look at a study called SUSTAIN2, you still had in that study, 6, 7 kilos of weight loss in a combination. So I think that, that is going to probably be the future. But, Michael?

Yes. Thanks, Ken. Indeed, so I think combined -- like type 2 diabetes, NASH is metabolic immune liver disease and combination treatments will be I think the rule rather than the exception for patients with NASH, similar as we actually treat type 2 diabetes I think, again, what I said before, lanifibranor has a strong position there because it really addresses all aspects of the disease biology. But still, I think patients who -- or at least a proportion of patients will benefit from a combination with an additional compound that further improves the metabolic profile and also accommodates the weight change that you see in the proportion of patients with lanifibranor, which is metabolically healthy, but it may be something that patients is important for patients. So we are studying lanifibranor in combination with SGLT2 inhibitors, as you know, in a Phase II study to address this additional benefits of the combination treatment. And with regard to GLP-1 receptor readiness, of course, there has been what we can call, I think, totally a change in the way. These compounds have found a way in medical practice, both for type 2 diabetes as well as for obesity. So they become an important part of the treatment of these patients. And we will -- we accommodate that, of course, in our study. Patients in the current Phase III study in native 3 patients who are on a stable dose with the GLP-1 receptor agonist can enter the study. And so we'll have data on the combination of lanifibranor with GLP-1 receptor agonist as well form the NATIVE study that's indeed a very important aspect, I think that will only increase in [indiscernible] GLP-1 receptor agonist has become a very important part of treatment everywhere essentially. So we are addressing that and accommodating the study to have data on the combination of lanifibranor with semaglutide or another GLP approved GLP-1 receptor agonist.

Great. And just as a clarification to that, and you sort of anticipated my next question. But as a clarification, just are -- is that portion of the study stratified? Are you stratifying by certain types of background medications, including SGLT2s and GLP-1s? Or is that just kind of a standard sort of follow-on analysis as it relates to background medication?

Yes, it's not stratified the priority because certification, of course, complicates the study. We have already certifications. So -- but there will be, of course, a subgroup analysis for patients who are on these medications.

Okay. Great. Appreciate it. Congrats on the [indiscernible].

[Operator Instructions] And the question comes from line of Jeroen Van den Bossche from KBC Securities.

Hello, can you hear me?

Yes.

Great. Congrats on the study. Maybe a few, let's say, broader questions after everybody had a pretty unique one. It's pretty well established the percentage of patients in type 2 diabetes that have NAFLD and then progressive NASH. What about the opposite? Do you have the data and maybe I've missed it on the percentage of patients that have NAFLD and of those that have type 2 diabetes. Is that also 50% or end of that increase with NASH? And will you be able to study that also in the NATIVE3 trial, where I believe having type 2 diabetes as a model exclusion criteria? Will you then do subpatients -- well, sub-population analysis looking at similar data sets here? That's 1 question. Second, I believe I read somewhere that for this patient population. There's also an effect on liver fat on liver perfusion that you we see that in this study, too? And maybe 1 of the top data analysis and I'm definitely not an endocrinologist or physiologists, I might have missed the connection there. And finally, how does this look on the long term. So what I mean by that is, imagine now you stopped the study after 4 weeks post trial follow-up. But how do you think patients do you have any idea or any visibility on how this will evolve for patients on the longer term -- and obviously, this will have a lot of things to do with how they change their lifestyle that I understand. But will they regress will the liver -- the methodical unhealthy fat return after stopping treatment with lanifibranor in short term? Or there's a longer-term effect that you can expect provided I'm guessing positive lifestyle increase improvement overall. So those are your few questions.

Yes. I think I'll start with the question to beginning about the relationship between NASH, NAFLD and type 2 diabetes in both directions. It's well known that both conditions reinforce 1 another more advance your type 2 diabetes the more -- there will be progression of NASH and the fast, more severe NASH will be and the other way around. So that's -- those are several papers on that, which is not surprising given the common underlying this biology. And we know that as patients progress with patients with NASH progress towards cirrhosis. Of course, it's also a matter of time. But once you have cirrhosis, you will find publications, but 90% of patients actually have that in diabetes. So addressing both conditions, if you wish, which we do with lanifibranor should, and that's what we also expect delay the progression of both conditions considerably, ultimately leading to a measurable outcome benefit. So that's on the first question where we see that going long term. Yes. I mean long term will be defined as outcome benefits that you ultimately measure in mortality and in the progression of liver disease to decompensated cirrhosis, which we will address in a separate study. But I think we have all the ingredients to expect that effect based on the data that we have shown here and the data from NATIVE from the Phase II study. I think part of your question was also on perfusion. We're not measuring perfusion directly in our studies. What we do know, we do know that lanifibranor again, as a pan-PPAR agonist does have an effect -- vascular effect reduces [indiscernible] as an effect of the capillarization of the material cells in the liver, which is relevant for development of core repression and perfusion of the liver. So that is an additional aspect that additional beneficial aspect that lanifibranor as well.

Again, 1 comment as an -- 2 comments. Number one, in general, same as for lipid management, blood pressure. If you stop treatment obesity comes back with the GLP-1s and your metabolic dysfunction comes back over time. Now the beauty of a tablet is that it's easier to be taken long term more than an injectable. You know that with GLP-1 when you stop the injectable, there's significant regain -- weight regain, that's not the fault of the GLP-1, but just because now satiety centers are on the list again. From a perspective of this drug, I think that this is going to be a drug used broadly in primary care and by endocrinologists. And we have a hint of long-term benefits of using an insulin sensitizer look at a paper in diabetes, obesity and metabolism in May of 2022, there's a trial called the EDICT trial, E-D-I-C-T, where they combine metformin with the GLP-1 and with pioglitazone compared to standard therapy. And over time, glycemic control remained normal in those treated with an insulin sensitizer and also steatosis and fibrosis measured by liver stiffness measurement and liver fat by MRP FF remain normal. So long-term use is going to be associated with long-term reversal of the disease. And so with the results we have today, prolonged use, we'll very likely have this long-term benefit. So I think it's really a game changer.

Maybe 1 last question. I'm being a bit provocative. Will this or the LEGEND trial have any positive effects with regards to the senior farm deal that you could comment on?

No. I mean, this is Fredric, I hope you hear me. No. I mean these are good news for us, and these are good news for our partner. We actually to reinforce this, the rationale to move into NASH and to continue the development. So I don't expect these deals to have any real impact, if only positive.

Right. No, no, but I was more wondering about milestone payments. Are there any?

No, no, no. The milestone payment -- sorry, I did not understand that. No, the milestone payment linked to the -- I would say, to the NASH program. So there are regulatory commercial regulatory development and commercial milestones, but linked to the development of lani in NASH in Greater China.

All right. Congrats once again and positive news from the market. So that's good.

I think that's it. I don't think we have any more questions, but we have some question on the platform, which I think have been more or less covered. There is only 1 which we're asking about the grade of the GI talk, especially if we had any bloody diarrhea, I don't think if this is the case. I don't think we had any bloody diarrhea. Can confirm exactly.

No.

Exactly. And all the rest were linked about body weight gain, there was a body weight gain, if we think it will continue after 6 months. What we have seen in the 1-year study with lani in a different population is that the weight gain plateaued after 6 months, and we hope that we will see that in our Phase III study. I think these are -- I guess, a question that were not covered in the conference call. So I think with that, we conclude the phone call. I would just really would like to thank Ken and all his team for all the hard work.

Thank you.

Great to see lani, these results are -- it was great. And of course, a great collaboration, which I think and I hope we will we produce in the future. And for all the listeners, thank you to share 1 hour and half of your time with us, and we hope to see you soon, hopefully, at [indiscernible] in -- it's already next week at [indiscernible]. Thank you, and have a great afternoon.

That does conclude our conference for today. Thank you for participating. You may now all disconnect. Have a nice day.