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

Good day, and thank you for standing by. Welcome to the Inventiva 2022 Full Year Results Call and Webcast. [Operator Instructions]. Please note that today's conference is being recorded. I would now like to hand over to your speaker, Mr. Frederic Cren. Please go ahead, sir.

Thank you, operator, and welcome to everybody to this full year 2022 financial results. As usual, I will be making with my colleague forward-looking statements. So please have a look at the regulatory documentation that is available on our website. In terms of speakers today, I'm very happy, as usual, to have Pierre with us, our CSO and Co-founder; Michael, our CMO, will go through an update of our 3 important clinical trials with lanifibranor, of course, the Phase III, but also 2 Phase II that are ongoing. And then Jean will conclude the presentation with an update on the financials. Of course, at the end of the session, we will have a Q&A session. So let me give you, first of all, some highlights for the full year. So let's start with our lead program lani in NASH and start with NATiV3, where we've been, I would say, very happy to work and extend develop the Phase III in 23 countries. And now we have more than 350 clinical sites that are active and more than 300 that have screened at least the patients. We have, throughout the year, and we continue to do so, implemented a series of measures to boost enrollment. And I would say that this continues throughout 2023. We have done many things, and we am very proud of those and grateful to our team. We have reviewed and implemented the new process to speed up how biopsy are analyzed. We have train sites. We have put in place incentives. We have included site networks, which are specialized with a strong NASH expertise and we also have closed sites that were not performing to our expectations. We have developed patient material, including opening recently the patient website. We have provided support to prescreening activities to sites, including providing screening algorithm to better identify patients. We are organized and we are currently organizing investigator meetings and also made several protocol improvements. All of that, I would say, make us confident that we will achieve our target to have the last patient first visit as targeted for the second half of 2023. We have also, and you know and Michael will go through that, developed a new design for NATiV3, which is much more patient-centric. We have started to implement this new protocol. It has been submitted, and we're very pleased to see that it has been approved in key countries, including the U.S. This morning, Akero announced their design for the Phase III, and we're very pleased to see that Akero is working on our footsteps with a design, which is very close to ours. And especially, they have selected the same primary endpoint as our primary endpoint in NATiV3. On the other trial, I think it's important to point out that LEGEND we have activated the first clinical site in U.S. and in Europe. And of course, we are randomizing in all of the countries where LEGEND is open. And then finally, we are looking forward to the results of the investigation study conducted by Professor Cusi from the US of Florida. The last patient was enrolled in September '22. We recently exchanged with Professor Cusi who is going through the database, finalizing the last cleanups and getting ready for the database slots. So we're looking to be able to publish those results by middle of Q2 '23. '22 has also been very active in terms of partnership, very proud of having secured a strong partner with Sino Biopharm after an extensive due diligence from their part, which proves that our drug is well positioned in China, which, as you know, is a very promising market for NASH given the prevalence of the disease in China. It has allowed us to secure close to EUR 30 million of upfront payment and were eligible to additional milestone that can reach EUR 290 million on top of royalties. You know that depending on various discussion and interactions, Sino Biopharm will have with the regulatory authorities that will be -- that can join the NATiV3 trial. And then finally, I would point out that we're very pleased by the strategy of finding partners in Asia. This allows to speed up the development and the entry to market, and we continue exploring all the potential commercialization of lanifibranor in Asia. And then finally, in terms of IP, we are securing in the U.S. a patent that strengthened our IP estate, especially in patients with -- especially in cirrhotic patients. Looking at the other program in terms of ABBV-157, unfortunately, you know that we received -- we were notified by AbbVie that following an expected tox result in long-term tox studies, they have decided to hold this program. We received the notification in October. On odiparcil, we had a very constructive discussion with the FDA over the summer. They confirm that we can move with this drug in children, given the safety profile of the drug and also has validated that a single Phase II/III trial in children would be sufficient to secure a positive accelerated market approval. Financially, we've been very active as well. We secured a EUR 50 million loan from EIB, one of the largest for biotech in Europe. Out of the EUR 50 million, EUR 25 million are to be used and are not included in our cash runway. On top of the EUR 30 million -- or close to EUR 30 million, we received from Sino, we also raised close to EUR 10 million from our ATM program and also secured additional facilities backed by the French government of close to -- actually a bit more than EUR 5 million. And then of note, we were selected as very limited number of players to be part of the Euronext Tech Leaders segment. And also, we are very pleased to welcome Dr. Lucy Lu as a new Board member. So let's talk a little bit about lanifibranor. And before I give the floor to Michael, let me just remind you some key features of lanifibranor. Very importantly, the profile of the drug is really unique. We are, to our knowledge, the only pan-PPAR currently in development in NASH, and this profile is really important because of strong results we were able to show during the Phase IIb that granted breakthrough therapy role is according to us due to really the ability to activate the 3 isoforms. We also remind you that we are not a TZD that we have not seen any of the typical liabilities that characterize TZD, especially during the preclinical program. The safety continues to be, in our mind, very favorable. Recently, had the DSMB in our NATiV3 and the conclusion rule for the previous DSMB we have had throughout the course of the history of lanifibranor that we can continue the trial with no changes. I mentioned the very strong results of the Phase IIb. I think it's important to try to position lanifibranor compared to the potential competitors. This is, of course, very difficult because the trials are, of course, different. And also, we have reported our data, giving the ITT population because this seems to have the relevant population because this is the one that is considered by regulatory authorities, while most of our competitors only reported data for protocol. But I think it gives an idea that lanifibranor when we look on NASH resolution and no worsening of fibrosis, a very compelling data, certainly, with a profile very competitive and probably superior to the other oral drug in development and also competitive profile versus injectables. This is even more true when we look at fibrosis improvement, which for us remains, given the disease and given what we want to achieve, which is that patients with NASH avoid to become cirrhotic. We see that on fibrosis, we have a very compelling profile, very competitive even with injectables. And lastly, I also would like to show very briefly as you know, the primary endpoint we have selected and that also Akero has selected for the Phase III. You see that this primary endpoint was met by both our low dose and high dose, 800-milligram, and 1,200, that was 3 to 4x more responders. Lastly, I also would like to point out that this is, I think, a compelling endpoint because it enables to really reduce the placebo. We have 7%. You see that Akero was at 5%. So you really see that with this approach, we are able to reduce the noise of the placebo effect. Finally, let's talk of the interaction we have had with the FDA, a positive interaction that have led to the new design Michael will present. And I think this is a very good step for all the field with this approach to have a trial based on surrogate histology endpoint in patients with non-cirrhotic NASH and enable the possibility to secure full approval with an outcome trial in patients with compensated cirrhotic NASH. I think that makes the development more feasible also from a timing point of view, shorter development to secure full approval. And also in our case, we would expand the population that we could address by also including patients with compensated cirrhosis. So that's all for my brief introduction, and I will now turn to Michael who will give you an update on NATiV3 and also the other 2 Phase II that are ongoing.

Thank you, Frederic, and good morning, good afternoon to everybody. I'm on Slide 15 now, which summarizes the development program for lanifibranor. On the left in green, you have the completed study that was summarized by Frederic just a minute ago to the Phase II study. And I would just highlight also that this was a 6-month treatment with a very robust efficacy on histology, both NASH activity and fibrosis, which is a testimony to the efficacy of the compound to have that degree of effect on fibrosis after a short treatment period for fibrosis evaluation. Based on these data, the efficacy and the safety of the compound, the FDA has granted Breakthrough Therapy designation for lanifibranor in NASH. And on the right, in orange, the Phase III study, which is currently ongoing. We are in the midst of the Phase III study. And as you know, and I'll also speak about 2 earlier Phase II studies that Frederic also mentioned. So on Slide 16, and as you heard, we have updated the design of the study to make it more attractive to patients, investigators, removed the 7-year placebo-controlled treatment period and have had very good interactions with the FDA on this change. And as you know, the FDA has also made public communications that correspond to this due to the overall development approach that we currently have in place. So what are the main changes in NATiV3, the readout for the surrogate efficacy endpoint, which is histology after 72 weeks of treatment has remained unchanged. We have 2 active arms and the placebo arm. And there will be 2 biopsies, one at baseline, maybe historical, but one biopsy at baseline and one at the end of treatment for a total of about 950 patients. After that, patients will remain in the study, but they will be rerandomized to an active treatment arm. So they will not be receiving placebo beyond that time, which is seen by everybody as a very positive approach. And the active treatment extension will be at least 48 weeks after that readout for the secondary -- or after the second biopsy. So that will provide also data on longer-term treatment with lanifibranor. In addition, and this is also a new aspect, we will enable patients who screen failed because of histology, but who have NASH and fulfill all the other inclusion criteria to enroll in an exploratory cohort of about 200 patients, again using 2 doses and placebo controlled. And this exploratory cohort, for example, enroll patients who are staged for the fibrosis by [ F3 by 1 pathologist, 4 by the second one and the tiebreaker data ] for these patients who would have very early cirrhosis and would be eligible to enter into the exploratory cohort. Just 1 example. So the main changes are really the shorter duration of exposure to placebo and 2 biopsies instead of 3. And the expert record also will not have a second biopsy. So we can go to the next slide, 17. The readout of the histology at 72 weeks is the basis for a submission for accelerated approval in the United States with the FDA and the corresponding conditional approval by the European Medicines Agency, the EMA. And this is with regard to the FDA corresponding to several communications that they have made in their continued support for accelerated approval in the field of NASH. The principal investigators are Dr. Francque from Antwerp, and Dr. Sanyal from Richmond, Virginia, 2 very well-known leading experts in the field of NASH. And the main inclusion criteria, of course, have remained the same. So without patients with a degree of activity based on the SAF scoring, which is a scoring system for the degree of tissue injury, ballooning and inflammation and fibrosis, stages F2, F3. So patients with advanced fibrosis but not proceeded to the degree of -- to the stage of cirrhosis. We do allow patients who have a stable dose of GLP1-receptor agonists. They have to be at least 3 months on a stable dose. And I think that will also be very important for enrollment -- and to get data on this -- on the treatment of those 2 compounds. So that's, I think, an important aspect, especially since GLP1-receptor agonists have become -- have an increasing uptake in patients with metabolic disorders. We have a randomization according to type 2 diabetes and fibrosis stage. The study is powered based on the Phase II data, which were very positive. So we have 90% power for the primary efficacy end point. And then of note, the biopsy reading is very robust. We use 3 expert pathologists and it's based on -- the fact that every biopsy is read by 2 of them. And in the case of nonagreement on certain aspects that affect eligibility, the third pathologist is a tie breaker. So the primary efficacy endpoint is, again, based on the Phase II data, both NASH resolution and fibrosis improvement, which is, of course, also related to clinical benefits, which is significant compared to having only 1 and also corresponds to the mechanism of action of the compound, lanifibranor, treating all aspects of the disease biology. So we do have an effect on all these aspects of NASH. And then there are several secondary endpoints. Here, the key secondary endpoints are listed, which are NASH resolution and no worsening of fibrosis and the other way around fibrosis improvement and no worsening of NASH, but we also have the large amount of secondary endpoints that relate to the beneficial effect of NASH on the metabolic immune markers of NASH, and of course, also safety and tolerability to have a good benefit risk ratio which is the basis for approval. Going to Slide 18. The current NATiV3 updates will provide the data for accelerated approval. In order to get full approval thereafter, we have to have data on outcome benefits. And our plan, and this is an agreement with communications of the FDA will be coming from a study -- an outcome study in patients with NASH, who have compensated cirrhosis. So at [ 4 but early ] without any decompensation at study entry. There are a lot of data that inform us about the natural course of patients with early cirrhosis. In other words, when decompensation events will occur. So that enables us to predict the sample size of such a study quite well. We plan to have about 900 patients, select 1 dose of lanifibranor and of course, placebo control. The outcome will be event-driven. And this study then will provide the data for approval based on outcome benefits, which is defined as essentially an improvement on decompensation events in the -- hepatic decompensation events. The first ones that appear in patients with cirrhosis are hepatic encephalopathy; progression of portal hypertension with either bleeding from varices or the need to prophylactically treat these varices, which is common practice today; and the new onset of ascites that is symptomatic, in other words, that requires treatment. Also all-cause mortality, worsening of liver function measured by the MELD score of 15 or more, which is quite a degree of worsening of liver function and the need for liver transplantation in that period. So the trial is expected to last up to 3 years and is, as I mentioned, an outcome benefit study for full approval. So going to Slide 19. In NATiV3, the study is conducted quite -- on a quite worldwide scale. As you can see, we have several studies on both sides of the Atlantic, the Americas, Europe, also some sites in South Africa and Australia. And as Frederic mentioned, through our partnership with [ CTTQ ], we also -- we have sites in China before the end of [ revolvers ]. That is currently ongoing. So quite a global approach. Next slide, #20, with regard to the time lines. In the second half of 2023, the last patient first visit target of the circa 900 patients is planned, so completion of enrollment essentially at the end of this year. And then in the first half of 2025, we'll have the -- for the current design of the study last patient last visit, and that will bring us to topline data in the second half of 2025 and an NDA submission for accelerated approval with the FDA at the beginning of 2026. Going to Slide 21, I'll say a few words about the 2 Phase II studies. The first one is a patient -- a study in patients with NAFLD, non-histologically defined and who also have type 2 diabetes. It is a study that has completed enrollment last year. It is -- as Frederic also mentioned, the study that is sponsored by the University of Florida and conducted by Dr. Cusi. And it is a truly mechanistic study that will provide much more granularity and data on the effects of lanifibranor as a pan-PPAR agonist to really address all the metabolic events that occur in the cascade of NASH development and also in type 2 diabetes, 2 conditions, which have very similar common underlying disease biology, which is really in its upstream mechanism revolving around insulin resistance in multiple tissues and the corresponding deregulation of lipid metabolism and accumulation of toxic lipid intermediaries that lead to the inflammation and tissue injury and fibrosis in the liver, but also to an atherogenic lipid profile that causes atherosclerosis, et cetera. So many of these disease biology aspects will be evaluated in this study. And I think, therefore, it will be giving us a wealth of information about the benefits of lanifibranor in addition to the hepatic benefits, which we have discussed and published earlier. The NAFLD or NASH and NAFLD and type 2 diabetes occur very much in parallel, as you know, and the more advanced the disease becomes and that's true for both the 2 diabetes and NASH, the more frequency overlap becomes, which has to do by the fact that both diseases reinforce one another. So it is a very significant medical issue. And I think, therefore, studying lanifibranor in patients with these overlapping conditions helps us understanding the disease and its medical value quite a bit. So it has to do with insulin resistance and lipid metabolism, as I mentioned. So Dr. Cusi has enrolled 30 patients who had type 2 diabetes with a fasting glucose level below 250 milligrams per deciliter and HbA1C below 9.5. So they were controlled. And with the amount of hepatitis steatosis defined by MR spectroscopy of 10% or more and stable weight. The randomization was 1 to 1 active 800-milligram versus placebo and the treatment of half a year. And if you go to the next slide, just mentioned that, in summary, the site uses a spectrum of state-of-the-art imaging technology to evaluate truly the fat amount in the liver, fat distribution and also inflammation and fibrosis in the liver through various software methods that we have today available based on MRI as well as ultrasound Fibroscan and then also very sophisticated ways to measure insulin resistance using the hyperinsulinemic clamp and the use of stabilizer drugs to measure glucose uptake by muscle, et cetera. So to get really a very detailed picture of the effect of lanifibranor on insulin resistance. And the primary efficacy endpoint in that space to have just to define the sample size calculation is based on the reduction of intrahepatic triglycerides measured by MR spectroscopy at week 24. But there are this really wealth of secondary endpoints that will give us that I think the profile from lanifibranor on its -- with regard to its broad metabolic beneficial effects in NASH, as I mentioned. So this study is fully enrolled since September, it's when the last patient was enrolled. And in Q2 2023, in other words, the next weeks, we'll have the results, the topline results of these analysis. And then a few words about the combination of lanifibranor and empagliflozin in another Phase II study, which is run by Inventiva, this is the [ sub-population ] study so also in patients with NASH and type 2 diabetes. The rationale for combination treatment in a disease like NASH, of course, has been discussed in many fora and there's a strong rationale given the biology of the disease stretching from metabolism all the way to fibrosis and cancer. So with regard to lanifibranor based on its mechanism of action, there was a very good rationale to combine it with compounds such as GLP1-receptor agonist and SGLT2-receptor agonist -- SGLT2 inhibitors, sorry. Lanifibranor in itself, of course, addresses all aspects of the disease. And so in many patients, it will probably be adequate as a treatment but some patients may have an additional benefit from the combination treatment. And the other aspect is that with lanifibranor, certain percentage, roughly about 1/3, if you define it as 5% or more of patients will have an increase in weight. We know that weight increase with lanifibranor is metabolically healthy. That has been clear from all the data that we have from NATiV, and that we have published. Yes, it is -- it may be an issue for some patients. And therefore, I think it is important to show that with a combination such as with an SGLT2 inhibitor, that weight can be balanced out. If you go to the next slide, #26. So we know from at least 4 randomized trials that have been published that when you combine pioglitazone with an SGLT2 inhibitor that you do see an improvement of metabolic markers, a further improvement, such as lowering of HbA1c and that the weight gain that you'll see with pioglitazone, which is a [ PPAR ] agonist is as I mentioned before, disappearing. So there's no weight increase, which may be an important aspect for some patients. And these data are quite robust. They are robust. They are based on 4 large studies, as I mentioned, with about 1,400 patients in different parts of the world. So this is a good foundation for our approach, and there has been no safety concerns for the combination of PPAR agonist with an SGLT2 inhibitor. And Slide 27 gives some more information about the LEGEND trial. I summarized the rationale. We will have information from that study, which is currently ongoing as well, about the distribution of fat because we use imaging as well. So multiscan, and we will have information about the additional metabolic benefits and the effect that the combination has on the weight change. So the study is based on the effect of lanifibranor on HbA1c that is used for the sample size calculation. And we have those data from NATiV. HbA1c, of course, is also as it underlies insulin resistance, an important marker for NASH as well as for type 2 diabetes that provides rationale to use this marker as an endpoint, as a primary efficacy endpoint, but the true information -- the true importance of the study is really that it will give us an amount of information about the benefits of the combination on the metabolic immune markers of NASH as well as the hepatic health markers assessed noninvasively. And on Slide 28, some more details. We ran the study in 4 countries. The primary -- the principal investigators are Dr. Holleboom from the academic medical center in Amsterdam; and Dr. Lai from Harvard, Beth Israel in Boston. And it's an ongoing study. So topline results are planned to be available this year. As you could see, it's a half year treatment as well. We have 1 dose of lanifibranor and 1 dose of empagliflozin, that's the SGLT2 inhibitor that we choose in 1 arm and 1 -- another arm is lanifibranor 800 milligram, and it's a placebo-controlled study. I covered the endpoints already. So I can go to Slide 29, which will then be covered by Jean.

Good morning, good afternoon, everyone. So we will get to the key information on our financial landscape. Happy to answer, of course, your questions later on if you have further questions. So first of all, in terms of shareholder base, no significant change. It was stable and therefore, [indiscernible] our key partners. We have recently extended our coverage, our coverage which we have communicated recently. I wouldn't like to elaborate too much about our market cap, which appears disconnected from what is the potential of the lanifibranor asset but at least at the moment, the consensus is still positive and a significant spread versus the current market cap. In terms of financial statements, 3 takeaways to mind. First of all, in terms of revenues, I guess it's the first time we reached this level of EUR 12.2 million in sales. And the good thing is it's the same cash wise because we recorded also the month upfront from the Sino Biopharm partnership in China where we are talking about. The second point important is the continuous efforts and we are seeing some of the actions to boost the enrollment and continue to match our operational target on [ '23 ]. This explains the significant increase in R&D expense. And we should, in '23, continue this trend to reach a plateau cruise speed in '23 expected to match again our objective by the end of the year. And then third point, in a very difficult market. This year, the financial fee, we have secured a short term, close to EUR 80 million, principally with the European Investment Bank deal 2 tranche of EUR 25 million. One has been raised in the fourth quarter. And we have also used our at-the-market program with EUR 9 million plus also in June, remaining $58 million on the shelf -- and we have optimized also kind of take back loan niche with EUR 5 million plus also cash in this year. So all in all, we finished the year with close to EUR 88 million without considering, let's say, the cash tranche of EUR 25 million and second tranche of the EIB which allow us to operate in the end of '23.

Great. Thank you, Jean. So on the catalysts in the near term, so as you understood for us is closing and obtaining the data from Professor Cusi on the Phase II, we're looking relatively confident on this trial, and we think it's going to be an important data for positioning any patients with type 2 diabetes. And of course, I mentioned all the efforts that we're doing and we target and we continue to target an end of enrollment for NATiV3 for the second half of this year. That would be also, I think, a very important achievement and positive news. And then the last one is, of course, the work we are doing on LEGEND with the data expected in the second half. So this is for a quick update of the 2022 financials and achievements. And I've give now the floor to the operator that will provide instruction to answer your questions.

[Operator Instructions] We are now going to proceed with our first question. And the questions come from Seamus Fernandez from Guggenheim Securities.

So a couple of quick questions. The first one is really hoping to know if there will be a disclosure of baseline characteristics of the patients now that the next -- or the first Phase III trial that's going to read out in 2025 is likely -- if those are likely to be presented and shared with investors. I think that's definitely an important dynamic as we think about the differentiation of this clinical trial versus some of the other competitor opportunities. And then the second question is just what your hoped for results or the opportunity is to really share with investors the opportunity that you see from the Phase II clinical studies? I think, Michael, you provided a lot of detail in your prepared remarks. Just hoping to better understand what or how those results are likely to be presented, whether it's in a press release with a sort of formal primary endpoint assessment or if it's more kind of exploratory analysis that will be provided and perhaps presented at a medical meeting specifically.

Thank you, Seamus. So maybe I'll take the first question and then for the communication strategy of the Phase II with Professor Cusi or Michael summarize the discussion we have had with scale. Concerning your first question about disclosing the baseline characteristic, it's actually a good suggestion. Honestly, we have not thought about that. And we're not able to answer. But yes, it's feasible that could be interesting to do. Of course, we have looked at the patients that have been enrolled. And Michael, maybe can correct me. But from what we have seen is that, of course, we are not changing patient population from the previous Phase IIb. And so we're really looking for patients of course, F2, F3 with moderate to severe level of inflammation and ballooning always selected with the same approach with an activity score of at least 2 or 3. What we have seen is maybe a bit more patient with type 2 diabetes. I think we had approximately 40% in the Phase II, now we're more at 60%. So I don't know what it is due to. I don't think it means anything. We have seen that the drug is as efficacious in both populations or now patients with NASH or patient with NASH and type 2 diabetes. But otherwise, a good suggestion may be to discover the baseline characteristic once we are fully enrolled. Maybe Michael or Pierre, you want to talk about communication strategy for the Phase II?

Yes, sure. For the study that is sponsored by University of Florida, we will have once the data are available and press release on the topline results. And then, of course, the data -- the details of the data, the primary efficacy endpoint and all the secondary efficacy endpoint will be presented, made public at scientific conferences in the first place by Dr. Cusi's team.

Great. And maybe just as one follow-up. Should we anticipate those results likely in terms of the medical meetings that you would be targeting. Is that more of an EASD conference just because this is a diabetic patient population or a little bit more along the lines of AASLD remaining focused on the liver-focused patient population? I know there's a blend of marketing to endocrinologists and to liver specialists.

Absolutely. And so we aim for both actually, and we are doing that now even. We have done a great of analysis of the metabolic immune markers of the NATiV3 study and presented those to both liver conferences, so AASLD and EASD, but also to the ADA. We also have a presentation this year at ADA. And with the conclusion, of course, we will discuss that together and the goal is to certainly also cover the endocrinology conferences, but that does not -- we also stay active with the liver conferences. I think there's enough material to cover both conferences.

And the questions come from the line of Annabel Samimy from Stifel.

I guess I want to look a little bit bigger picture. When we think about the Phase II trials that you're conducting, is the intention to potentially make lanifibranor available to all patients or are you trying to gear it towards a type 2 diabetic patient, which it seems to have some tremendous benefit for? And then also on the LEGEND trial. So you're looking at it in a combination with pioglitazone, but it seems that a number of these patients or a number of the physicians believe that these patients will already be on some kind of background GLP-1. So I'm just wondering, again, bigger picture, how do you envision some of these combinations to play out in real world? And are you intending to try to find another combination treatment to optimize lani? Or is it to -- that's maybe oral and more suitable for the population that you're targeting? Or is it just to potentially manage some of the weight gain issues or whatever optimizes the profile in general. So I guess I'm trying to understand how it works out with the GLP-1 as well as the combination trials that you're looking at right now.

Okay. So maybe on the Phase III. So currently, of course, we have patient F2, F3, and we stratify for patients with NASH and diabetes. Clearly, our intention and I believe that lani addresses both population, so -- and that has been shown in the Phase IIb. It's effective in patients with NASH and it's also effective in patients with NASH and type 2 diabetes. Where -- and while we work not on the antidiabetic properties of lani is because we look at competition. And when we look at competitors, we believe we are the only one that has this direct insulin sensitizer property. And so if you position yourself from the patient perspective and you have NASH and type 2 diabetes, if you are treated with lani, not only you would improve NASH, reduce your fibrosis. But on top of that, lani would help further control your HbA1C. So it's really a perfect drug for this patient. And we also have published that when we look at patients with prediabetes treated with lani during the Phase IIb, those patients during the course of the trial have seen their diabetes stop progression. So really, it's a patient population that we like. And then ultimately, when we talk to endocrinologists, we realize that they have a huge amount of patients that are sitting in their offices that have NASH. And so developing and producing the type of the data we will generate for this product, I think will help position the drug among endocrinologists. Now maybe for the GLP-1, I'll let Michael or Pierre answer. Just one comment, just to point out that in the current NATiV3, the Phase III, we are allowing patients under GLP-1 under a stable dose of GLP-1 for 3 months. So we are including patients with GLP-1 in the trial, and that will help us, of course, generate data about combining lani and GLP-1. Maybe Michael or Pierre, do you want to add something about LEGEND and combination with GLP-1?

Yes. So I think the -- in these diseases is also cardiovascular disease and diabetes treatment, treatment paradigms change as new treatments become available, and semaglutide specifically so GLP1-receptor agonists certainly have or changing that paradigm now that [indiscernible] receptor agonists are becoming or have become first-line treatment in type 2 diabetes. So I think that's something that we adapt to. I don't think -- I think that's actually an opportunity. I mean we will -- we do allow patients to have a stable dose to be enrolled in NATiV3. We may also, since Frederic referred to that consider to get -- use that opportunity to update LEGEND, if you wish. And that's something that we are discussing. But I think lanifibranor remains a very distinct drug from the other compounds in that as a pan-PPAR agonist, it does have this effect on metabolism as well as on inflammation as well as on fibrosis. And so for a disease like NASH and type 2 diabetes that go hand-in-hand, our approval will be for NASH but many patients will have type 2 diabetes. And even those who don't have type 2 diabetes, many of those have prediabetes, which the diabetology community also recommends to treat. So this is an advantage, I think, that we have in the NASH field. And the -- in the fact that the treatment field for type 2 diabetes is changing is something that we use to our advantage to position lanifibranor in combination with these newer treatments as well. So I think that's how our studies are currently designed. And I think that lanifibranor will have an attractive position in this field.

We are now going to proceed with our next question. The questions come from the line of Ed Arce from H.C. Wainwright.

Congrats on the continued progress. A few for me. Firstly, I just wanted to ask if you can disclose how many patients are currently enrolled in NATiV3? And then turning to the outcomes trial. I think you mentioned 900 patients is the total target. I think there's 800 on the slide. Just wanted to confirm the total number there. And then lastly, also with outcomes, which dose of lani are you planning to use for that trial? And then I have a couple of follow-ups.

Okay. So the first 2, I think on the outcome trial currently, I hope we do disclose the number of patients that we have randomized and enrolled, no, we have not. It's not standard practice. Of course, we monitor the situation daily. And we're very pleased with the enrollment, with the screen failure I mentioned. We have, let's say, [indiscernible] or anyway to concentrate in improving the screen failure, which was higher than what we expected. That is something that is general in the industry, but we've been really working hard, and we see different figures going down for the past -- regularly for the past several months. So that's very positive. As I mentioned, we have quite a large number of sites that are screening and actively screening. So we -- that gives us confidence that we can meet our target of an enrollment for the second half of this year. And on the third question, on the dose, maybe Michael, you want to give a highlight of the discussion with FDA?

Yes. If I understand the question correctly, correct me if I'm wrong, it was about total number of patients that we enroll in the outcome study. So our estimate is 800, about 800, with 2 arms, 1 dose of lanifibranor and placebo. And the 950, 960 is for the NATiV3, the study that we are currently running that is providing the data for accelerated approval. So did I answer your question?

Actually, Michael, the question -- the other part of the question was which dose would you be using -- intend to be used for the outcome study? Which dose of lani?

We have not decided yet, but we will choose 1 dose. I think when we finalize the design, we'll take all information into consideration, which includes the clinical pharmacology data, but also the data that we get from NATiV3 depending on where we are.

Okay. Great. And as a follow-up, I just wanted to ask Frederic. I think you mentioned at the beginning of your remarks, some work that's been done more recently on speeding up biopsies. I wondered if you could expand upon those activities and what you've done and how that's helped the study? And then lastly, I just wanted to ask about the financials. I think you said cash right now is runway to the end of the year, if you could confirm that? And also, what's the remaining amount on the ATM?

Okay. So on the biopsy process, so it's been many activities going on and improving that process that helps in improving the screening process. So by speeding up, I meant that the process between making a biopsy in a site and the time it takes for the reviewers to give their appraisal, it's a long process. So I think we have now sped up and optimized that process. And then secondly, the big change we made is that you know that we follow, say, the FDA guidelines to have biopsy reviewed by 3 pathologists with a tiebreaker. We started the trial with 2 pathologists involved and if 1 of these 2 pathologists disagreed or did not evaluate in the same way as the other 1, the biopsy of the patient would be excluded. And now we have introduced the tiebreaker also for the baseline. And so now, when there is a disagreement between the 2 pathologists, there is a tie breaker, a third pathologist that acts as a tiebreaker. So that also has been introduced. And all along the way, also, we have introduced training, alignment training between these 3 pathologists so that they really work as a team. That's also something that has taken us some time, and we see now a good alignment between these 3 pathologists. Then on cash, and all of that, I'll let Jean answer about the ATM and the cash.

So EUR 88 million, as we've seen end of '23 and very important without considering the second tranche of the EIB which represent, they say, cash of EUR 25 million. And we are still USD 58-plus million on the shelf for the at-the-market program.

We are now going to proceed with our next question. The questions come from the line of Frédéric Gomez from Pharmium Securities.

One of the -- on the LEGEND study -- yes, can you hear me?

Yes.

Okay. Perfect. Yes, so the first question is on the LEGEND study, the primary will be the HbA1c. Can you maybe clarify a little bit the statistical analysis plan, how you will perform the analysis between the combo arm and the lani arm. Just yes, I'm just wondering how you will say that the study is positive because we should expect an effect on the primary with the lanifibranor versus the placebo. And just to follow up a little bit on this analysis of biopsies and the change in the number of pathologists that will have a look at the biopsies. You started at 2, now it says 3 pathologists. Does it -- I'm curious to know about the potential impact on the outcome and also the baseline data because this shift may have an impact overall on the [indiscernible] if more patients have been looked by 3 pathologists versus 2. Can you maybe elaborate a little bit more on the potential impact of this change?

Sure. So for the LEGEND, we can start with that and maybe even for the tiebreaker, maybe, Michael, you can address that.

Sure. Yes. I think to start with LEGEND. We actually have based the sample size calculation and the power on the data that we have from NATiV2 on the effect on HbA1c. I don't have it in my head now, but those numbers we have. And also on the additional benefit that you expect when you combine pioglitazone with one of the SGLT2 inhibitors. And as I mentioned, there are 4 large randomized trials, it's actually a consistent picture that you have an additional benefit on the decrease of HbA1c after half year of treatment or longer. But most of these studies was half a year. And then that provides the basis to define an effect size that we should see and the power calculation to have a p-value that is adequate, that's what it's based on. Now it is a proof-of-concept study. So I'd like to point out that this is really because we -- this is the way we do it, but the main importance of the study is really to show that there is an additional benefit of the combination on metabolic markers for those patients who we need it and also on weight for those patients who may find this important. I can only repeat that the weight gain with PPAR agonist is distinct from weight gain that results from poor lifestyle, but that may still be an issue for patients who are obese. Not all patients with NASH or NASH and type 2 diabetes are obese. So it will actually not be an issue for all patients, for some it may be. And this is what it's based on. So we really see the value of the study in providing that set of data on the additional benefits that the combination may have in certain patients for whom this may be important. And it's in line also with how metabolic treatments -- sorry, metabolic diseases are treated, such as type 2 diabetes. Physicians will start with a treatment and then see how the patient evolves and may add another treatment if necessary in certain patients. So with regard to the biopsy, it was always our intention to start with 3 biopsy -- 3 expert pathologists, and we have started with 2 and have, as soon as the third one was on board contractually made the tiebreaker process, put it in place. That does not really affect the patients that we enroll as eligible. In fact, we have looked at patients who screen failed based on the initial 2 biopsies and see which patients would be eligible if or when the third one comes in as a tiebreaker and some of these patients would then be eligible again -- or would become eligible. But the key point is that the tiebreaker system gives a degree of stability, I think, in the histology scoring. That's an important aspect, of course. But for the evaluation of efficacy at the end of the 32-week treatment period, all histology will be reread. So the histology at inclusion and the histology at the end of treatment will be evaluated again by the 3 pathologists according to this pattern. So for the entire study, if you look at the evaluation of efficacy, the reading will be consistent.

We have no further questions at this time. I hand back the conference to Mr. Cren for closing remarks.

Well, thank you very much for attending. We have in front of us a very exciting 2023. NASH is a very exciting place. It was not the case last year, and we see now a much more renewed interest. There's going to be quite a lot of events this year, especially with the FDA, the [indiscernible] and the larger goal of admission. And concerning lanifibranor, we remain confident we have in our hands a drug that can make it to the finish line. And this year, operationally, we know we have to deliver on NATiV3. And as I mentioned, I think that we are on the right track. And then we'll also be looking forward with optimism, let's say, a cautious optimism to the data that will be generated by Professor Cusi in the type 2 diabetes study and also, of course, in the LEGEND study and that will keep us busy. And as usual, thank you very much for attending, and I look forward to seeing you, all of you, in future meetings.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect your lines. Thank you.