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spk06: 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 three important clinical trials with with an ephemeral of course the phase three but also two phase two that are ongoing and then john will conclude the presentation with an update on the financials of course at the end of the session you 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, NANI, in NASH, and start with Native 3, where we've been, I would say, very happy to work and extend, to develop the Phase 3 in 23 countries. And now we have more than 350 clinical sites that are active and more than 300 that have screened at least a patient. 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've done many things and we're very Proud of those and grateful to our team. We have reviewed and implemented a new process to speed up how biopsies are analyzed. We have trained 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. have developed patient material including opening recently the patient website we have provided support to prescreening activities to sites including providing a screening algorithm to better identify the patients we are we have organized and we're 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 Native 3, 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, Akira announced their design of the for the phase three and we're very pleased to see that uh akira is working on our footsteps with a with a design which is very close to ours and especially they have selected the same primary endpoint as our primary endpoint in 83. 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're looking forward to the results of the investigation study conducted by Professor Cusi from the University of Florida. The last patient was enrolled in September 22. We recently exchanged with Professor Cusi. He's going through the database, analyzing the last cleanups and getting ready for the database log, so we're looking to be able to publish those results by middle of Q2 23. The 22 has also been very active in terms of partnership, very proud of having secured a strong partner with Sinobiopharm after an extensive due diligence from their part, which proved 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 13 million euros of upfront payment and we're eligible to additional milestones that can reach 290 million on top of royalties. You know that depending on various discussion and interactions, you know, BioPharm will have with the regulatory authorities, they can join the Native 3 tribe. And then finally, I would point out that, you know, we're very pleased by this 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 land in Fibonacci nation. And then finally, in terms of IP, we have secured in the US a patent that strengthen our IP estate, especially in patients especially in cirrhotic patients. Looking at the other program, in terms of ABV157, unfortunately, you know that we received, we were notified by AbbVie that the following unexpected results, you know, long-term studies have decided to hold this program. We received the notification in October. On a departure, we have a very constructive discussion with the FDA over the summer. They confirmed that we can move with this drug in children, given the safety profile of the drug. And also, I validated that a single phase 2, 3 trial in children would be sufficient to secure this positive accelerated market approval. Financially, we've been very active as well. We've secured a 50 million euro loan from the IB, one of the largest for biotech in Europe. Out of those 50, still 25 are to be used and are not included in our cash runway. On top of the 13 million, or close to 13 million that we received from CINO, we also raised close to 10 million from our ATM program, and also secure additional facilities backed by the french government of close to actually a bit more than 5 million euro and then of note we were selected as a very limited number of players to be part of the uranex tech leader segment and also we're very pleased to welcome dr lucille as a newborn member So let's talk a little bit about lanifibrinol. Before I give the floor to Michael, let me just remind you some key features of lanifibrinol. 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 the strong results we were able to show during the Phase IIb that granted breakthrough therapy rule is according to us due to the ability to activate the three isoforms. We also remind you that we are not a TZD and 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. We recently had the DSMB in our native three, and the conclusion was that for the previous DSMB, we have had throughout the course of the history of Lanny Fieber-Nor, that we can continue the trial with no changes. I mentioned the very strong result of the phase IIb. I think it's important to try to position lanifibrinol compared to the potential competitors. This is, of course, very difficult because trial are of course different and also we have reported our data giving the ITT population because this seems to us the relevant population because this is the one that is considered by regulatory authorities while most of our competitors only reported data for per protocol but I think it gives an idea that Lanny Fieber norm when we look on that resolution and no worthing of fibrosis and very compelling data certainly you know 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 patient with NASH avoid to become cirrhotic. We see that on fibrosis, we have very compelling profile, very competitive, even with injectables. And lastly, I also would like to show very briefly, you know, the primary endpoint we have selected, and that also ACERO has selected for the phase three. You see that this primary endpoint was met by both our low dose and high dose, 800 milligrams and 1,200, and that was three to four times 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 here was 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. 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-serotic NASH, and then have the possibility to secure full approval with an outcome trial in patients with compensated serotic 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, it would expand the population that we could address by also including patient with compensated cirrhosis. So that's for my brief introduction, and I will now turn to Michael, who will give you an update on Native 3 and also the other two Phase 2 that are ongoing.
spk05: Thank you, Frederick, and good morning, good afternoon to everybody. I'm on slide 50 now, which summarizes the development program for London Fibrinol. On the left in green, you have the completed study that was summarized by Frederick just a minute ago, so the phase two study. And I would just highlight also that this was a six-month treatment with a very robust efficacy on histology, both NASH activity and fibrosis, 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 lanofibrinol in ash. And on the right, in orange, the phase three study, which is currently ongoing. We are in the midst of the phase three study, as you know, and I also speak about two earlier phase two studies that Frederik also mentions on slide 16. As you heard, we have updated the design of the study to make it more attractive to patients, investigators, removed the seven-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 the overall development approach that we currently have in place. So what are the main changes in native 3? The readout for the surrogate efficacy endpoint, which is histology after 72 weeks of treatment, has remained unchanged. We have two active arms and a placebo arm, and there will be two 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 re-randomized 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 bleed out for the secondary or after the second biopsy. So that will provide also data on longer-term treatment with lanofibrin R. In addition, and this is also a new aspect we will enable patients who screen fail 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 the two doses and placebo-controlled. And this exploratory cohort will, for example, enroll patients who have or staged for the fibrosis by F3 by one pathologist, F4 by the second one, and the tiebreaker says F4. These patients would have very early cirrhosis and would be eligible to enter into the exploratory cohort. That's just one example. So the main changes are really the shorter duration of exposure to placebo and two biopsies instead of three. And the exploratory cohort also will not have a second biopsy. So we then go to the next slide, number 17. The readout of the histology at 72 weeks is the basis for 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 and their continued support for accelerated approval in the field of NASH. The principal investigators are Dr. Frank from Antwerp and Dr. Sanyal from Richmond, Virginia. two very well-known leading experts in the field of NASH. And the main inclusion criteria, of course, have remained the same. So adult 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 stage of cirrhosis. We do allow patients who have a stable dose of GLP-1 receptor agonist to have to be at least three months on a stable dose. And I think that will also be very important for enrollment and to get data on this condition. on the treatments of those two compounds. So that's, I think, an important aspect, especially since GLP-1 receptor agonists have an increasing uptake in patients with metabolic disorders. We have randomization according to type two diabetes and fibrosis stage. The study is powered based on the phase two data, which were very positive. So we have 90% power for the primary efficacy endpoint. And then of note, the biopsy reading is very robust. We use three expert pathologists, and it's based on the fact that every biopsy is read by two of them. And in case of non-agreement on certain aspects that affect eligibility, the third pathologist is a tiebreaker. So the primary efficacy endpoint is, again, based on the phase two data. both NASH resolution and fibrosis improvement, which is, of course, also, you know, relates to clinical benefits, which is significant compared to having only one, and also corresponds to the mechanism of action of the compound, elanofibrinol, 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 NAS resolution, no worsening of fibrosis, and the other way around. Fibrosis improvement and no worsening of NAS, but we also have a large amount of secondary endpoints that relate to the beneficial effect of NAS on the metabolic immune markers of NAS. 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 native tree update 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 again in agreement with communications of the FDA, will be coming from an outcome study in patients with NASH who have compensated cirrhosis. So at four, 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 one dose of lonofibrinol, and of course, placebo control. The outcome will be event-driven, and this study then will provide the data for full approval based on outcome benefits, which is defined as essentially an improvement on the 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, a 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 three years. And it is, as I mentioned, an outcome benefit study for full approval. So I'm going to slide 19. In Native 3, the study is conducted 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 Frederik mentioned, through our partnership with HTQ, we also may have sites in China before the end of enrollment. That is currently ongoing. So quite a global approach. Next slide, number 20, with regard to the timelines. 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 visits. And that will bring us to top line 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 two Phase 2 studies. The first one is 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 Frederick also mentioned, a study that is sponsored by the University of Florida and conducted by Dr. Cousy. And it is a truly mechanistic study that will provide much more granularity and data on the effects of lanofibrinol as a ton P-paragonist to really address all the metabolic events that occur in the cascade of NASH development and also in type 2 diabetes, two conditions which have very similar and common underlying disease biology, which is really in its upstream mechanism evolving around insulin resistance in multiple tissues and the corresponding dysregulation 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 heterogenic lipid profile that causes atherosclerosis, etc. 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 lamofibrinol in addition to the hepatic benefits which we have described 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 type 2 diabetes and NASH. the more frequent the 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 lanofibrinoid 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. Cousy has enrolled 30 patients who had type 2 diabetes with a fasting glucose level below 250 milligrams per deciliter and an HbA1c below 9.5. So they were controlled with an amount of hepatic steatosis defined by MR spectroscopy of 10% or more and stable weight. The randomization was one-to-one active 800mg versus placebo, and they had a treatment of half a year. If you go to the next slide, just mention 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 stable isotopes to measure glucose uptake by muscle, etc. So to get really a very detailed picture of the effects of lanofibrin R on insulin resistance. And the primary efficacy endpoint that's based to have just to define the sample size calculation is based on the reduction of intrahepatic triglycerides measured by Mass MR spectroscopy at week 24. But there are this really wealth of secondary endpoints that will give us that, I think, profile of lanofibrin 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 top-line results of this analysis. And then a few words about the combination of lanofibrinol and impagliflozin in another phase two study, which is run by Inventiva, the so-called legend study, also in patients with NASH and type 2 diabetes. The rationale for combination treatments 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 lanofibrinol, based on its mechanism of action, there is a very good rationale to combine it with compounds such as GLP-1 receptor agonist and SGL-2 receptor agonist, SGL-2 inhibitor, sorry. 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 from the. Combination treatment, and the other aspect is that with a certain percentage, roughly about 1, 3rd, if you define it as 5% or more of patients will have an increase in weight. We know that way to increase. Metabolically healthy. That has been. you know, clear from all the data that we have from native and that we have published. Yet 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 SGL2 inhibitor, that way it can be balanced out. If you go to the next slide, number 26. So we know from... at least four 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 HP1C, and that the weight gain that you see with pioglitazone, which is the parahama 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 based on four large studies, as I mentioned, 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 FCH2 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 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, this study is based on the effect of lanofibrinol on HbA1c, and that is used for the sample size calculation, and we have those data from NADiV. HbA1c, of course, is also, as it underlies insulin resistance, an important marker for NASH as well as for type 2 diabetes that provides a good rationale to use this marker as an endpoint as a primary efficacy endpoint, but the true importance of this 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. On slide 28, some more details. We run this study in four 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 no planned results are planned to be available this year. As you can see, it's a half-year treatment as well. We have one dose of lanofibrinol and one dose of empagliflozin. That's the SGL2 inhibitor that we choose in one arm. Another arm is lanofibrinol, 800 mg, 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.
spk03: 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 shell debate, no significant change. It's rather stable, and therefore still with our key partner. We have recently extended our coverage, our analysis coverage, because Stifel came recently. I wouldn't like to elaborate too much about our market cap, which appears disconnected from what is the potential of the Lani Fibrano 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, three takeaways to mind. First of all, in terms of revenues, I guess it's the first time we've reached this level of 12 million point two in sales. The good thing is it's the same cash-wise because we recorded also this amount from the CCTQ-Synodio Pharma partnership in China, where we were talking about. The second point, important, is the continuous effort, and we have seen some of the actions to boost the enrollment continue to match our operational target on 93. 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 on the financial field, we have secured a short term close to €18 million, principally with the European Investment Bank deal, two tranches of €25 million. One has been raised in the fourth quarter and we have also used our at the market program with €9 million plus Also in June, remaining $58 million on the shelf. And we have optimized also a kind of state-backed loan niche with the 5 million plus also cashed in this year. So all in all, we finished the year with close to 88 million euros. without considering, let's say, the cartridge of the 25-minute second tranche of the EIB, which allow us to operate until the end of 23. Great.
spk06: Thank you, Jean. So on the catalyst of the near term, so as you understood for us, it's closing and obtaining the data from Professor Kuzi on the phase two. We're looking, you know, with... relatively confident on this trial and we We think it's going to be an important data for positioning Lani in 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 native three for the second half of this year. That will be also, I think, a very important achievement and positive news. And then the last one is, of course, the work We are doing a legend with the data expected in the second half. So this is for a quick update of the 2022 financials and achievements. I give now the floor to the operator that will provide instruction to ask your questions.
spk01: Thank you, sir. As a reminder, to ask a question on the phone line, you will need to press star 1 and 1 on your telephone and wait for your name to be announced. To withdraw your question, you can please press star 1 and 1 again. Once again, to ask a question from the phone line, please press star 1 and 1 and wait for your name to be announced. If you wish to ask a question via the webcast, please type them in the question box and click Submit. We are now going to proceed with our first question. And the questions come from Fernandez from Guggenheim Securities. Please ask your question.
spk09: Great. Thanks so much for the question. 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 three 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 two clinical studies. I think, Michael, you provided a lot of detail in your prepared remarks. Just hoping to better understand, you know, what or how those results are likely to be presented, you know, whether it's in a press release with a, you know, sort of formal primary endpoint assessment. you know, or if it's more kind of exploratory analyses that will be provided and perhaps presented at a medical meeting specifically. Thanks.
spk06: Thank you, Seamus. So maybe I'll take the first question and then for the communication strategy of the phase two with Professor Cousy, maybe I'll let Pierre or Michael summarize the discussion we've had with Ken. Concerning your first question about disclosing the baseline characteristic, it's actually a good suggestion. Honestly, we have not thought about that. We're not able to answer, but yes, this is 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're not changing patient population from the previous phase to B, and so we're really looking for patients, of course, F2, F3 with a moderate to severe level of inflammation and ballooning. always selected with the same approach with an activity score of at least two or three. What we have seen is maybe a bit more of patients with type 2 diabetes. I think we had approximately 40% in the phase two. Now we're more at 60%. 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, so patients with NASH or patients with type 2 diabetes. But otherwise, yeah, good suggestion maybe to disclose the baseline characteristics once we are fully enrolled. Maybe Michael or Pierre, you want to talk about communication strategy for the phase two?
spk05: Yeah, sure. For the study that is sponsored by University of Florida, we will have, once the data are available, a press release on the top-line 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. Cozy's team.
spk09: 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.
spk05: Well, absolutely. And so we aim for both, actually. And we are doing that now. We have done a great deal of analysis of the metabolic immune markers of the native study and sent those to both liver conferences, so ASLD, EASL, but also to the ADA. We also have a presentation this year at ADA. And with Ken Kuz, of course, we will discuss that together. And the goal is to certainly also cover the endocrinology conferences, but we also stay active with the liver conferences. I think there's enough material to cover both conferences.
spk09: Okay. Thank you.
spk01: We are now going to proceed with our next question. And the questions come from the line of Annabel Samimi from Stifel. Please ask a question.
spk02: Hi. Thanks for taking my question and the tremendous amount of details that you provided. for the phase two. I guess I want to look a little bit bigger picture. When you think about the phase two trials that you're conducting, is the intention to potentially make lanofrenor available to all patients? Are you trying to gear it towards a type two 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 combination with, 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 with one. So I'm just wondering, again, bigger picture, how do you envision some of these combinations to play out, you know, in real world? And are you intending to try to find another combination treatment to optimize Lenny? Or is it to, you know, 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, you know, optimize its 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. Thanks.
spk06: Okay. So maybe on the phase three, so currently, of course, we have patient F2, F3, and we stratify for patient with NASH and type 2 diabetes. Clearly our intention and belief is that Lani oppresses both populations, and that has been shown in the face-to-be. It's effective in patients with NASH, and it's also effective in patients with NASH anti-2 diabetes. Where and why we work a lot on the anti-diabetic properties of Lani is because we look at competition, and when we look at competitors, we believe we are the only one that have this direct insulin sensitizer properties. 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 2b, those patients during the course of the trial had 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 data we will be generating with Professor Cusi, I think, will help position the drug among endocrinologists. Now, maybe for the GLP-1, I'll let Michael up here answer. Just one comment just to point out that in the current native three, the phase three, we are allowing patients under GLP-1, under a stable dose of GLP-1 for three months. And so we are including patients with GLP-1 in the trial. And that will help us, of course, generate data about combining GLP-1 Lani and GLP-1. Maybe, Michael or Pierre, do you want to add something about PLEDGEN in combination with GLP-1?
spk05: Yeah, so I think, you know, in these diseases, it's also known in cardiovascular disease and diabetes, treatment paradigms change as new treatments become available. And semaglutide specifically, so GLP-1 receptor agonists suddenly have or are changing that paradigm. And now that GLP-1 receptor agonists have become first-line treatment in type 2 diabetes. So I think that's something that we adapt to. I think that's actually an opportunity. We do allow patients who are on a stable dose to be enrolled in Native 3. We may also, since Frederic referred to that, consider to use that opportunity to update Legend, if you wish. That's something that we are discussing. I think lanofibrinol remains a very distinct drug from the other compounds in that as a PAMP paragonist, it does have this effect on metabolism as well as on inflammation as well as on fibrosis. And so, you know, 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 over type 2 diabetes, many of those have pre-diabetes, which the diabetology community also recommends to treat. So this is an advantage, I think, that we have in the NASH field. And the fact that the treatment field for type 2 diabetes is changing is something that we use regularly. to our advantage to position lanofibrinol in combination with these newer treatments as well. So I think that's how our studies are currently designed, and I think that lanofibrinol will have an attractive position in this field.
spk02: Okay, great. Thank you.
spk01: We are now going to proceed with our next question. The questions come from the line of Ed Alt from HC Wainwright. Please ask your question.
spk00: Great. Thanks for taking my questions, and congrats on the continued progress. A few for me. Firstly, just wanted to ask if you can disclose how many patients are currently enrolled in Native 3. And then turning to the outcomes trial, I think you mentioned 900 patients is the total target, but 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 follow-ups.
spk06: Okay, so let's see the first two. I think the outcome trial is correct. We will disclose the number of patients that we have randomized and enrolled. No, we have not. We have not done the practice. Of course, we monitor the situation daily, and we're very pleased with the results. enrollment with the screen failure I mentioned We have let's say battles or anyway had to concentrate in the screen failure which was higher than what we expected something General in the industry, but we've been you know really working hard and we see the screen failure going down for the past regularly for the past several months, so that's very positive and As I mentioned, we have quite a large number of sites that are screening, inactive screening, so that gives us confidence that we can meet our target of end of enrollment for the second half of this year. Then on the third question, on the dose, maybe Michael, you want to give an highlight of the discussion we've had with FDA.
spk05: Yeah, if I understand the question correctly, correct me if I'm wrong, it was about the total number of patients that we enroll in the outcome study. So our estimate is 800, about 800, with two arms, one dose of lomofibrinol and placebo. And the 950 or 960 is for the native tree, the study that we are currently running that is providing the data for accelerated approval. So did I answer your question?
spk00: Actually, Michael, the question, the other part of the question was which dose would you be using, intend to use for the outcomes study? Which dose?
spk05: We have not decided yet, but we will choose one 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 NativeTree, depending on where we are.
spk00: 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 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? Thanks so much.
spk06: Okay, so on the biopsy process, so it's been many activities going on and improving that process that helped 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 speed up and optimize that process. And then secondly, the big change we made is that we follow the FDA guidelines to have biopsy reviewed by three pathologists with a tiebreaker. We started the trial with two pathologists involved. And if one of these two pathologists disagreed or did not evaluate in the same way as the other one, the biopsy of the patient would be excluded. And now we have introduced a tiebreaker also for the baseline. And so now when There is a disagreement between the two biologists. There is a tiebreaker for pathology that has a tiebreaker. So that also has been introduced. And all along the way also, we have introduced training, alignment training between these three pathologists so that they really work as a team. That's also something that has taken us some time and we see now good alignment between these three pathologists. Then on cash, And all of that led to Jean's answer about the ATM and the cash.
spk03: So, 88 million, as we've seen, end of 23, and very important, without considering the second tranche of the EIB, which represents, as they say, a cartridge of 25 million euros. And we have still 58 plus million US dollars on the shelf for the other market programs.
spk00: Great, thanks so much.
spk01: We are now going to proceed with our next question. And the questions come from the line of Frederic Gomez from Farmium Securities. Please ask your question.
spk07: Frederic Gomez, your line is open.
spk04: Thanks for taking my questions. One of the, on the legend study, yes, can you hear me? yes yes yes i'm not on you no no we hear you very well can you hear me yes yes yes okay perfect uh yeah perfect so the first question is on on the legend study the the primary will be the hba1ac can you maybe clarify a little bit the the statistical analysis plan how you will perform the the analysis between the combo arm and the Lani arm. I'm just wondering how you will say that the study is positive because we should expect an effect on the primary with the Lani alone 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 two, now it's three pathologists. I'm curious to hear about the potential impact on the outcome and also the baseline data because this shift may have an impact overall on the trial itself if more patients have been looked at by three pathologists. Can you maybe elaborate a little bit more on the potential impact of this change?
spk06: Sure. So, for the legend, we can start with that, and maybe even for the tiebreaker, maybe, Michael, you can address that. Sure.
spk05: Yes. I think to start with legend, we actually have based the sample size calculation on the power. on the data that we have from Native 2 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 four large randomized trials that give actually a consistent picture that you have an additional benefit on on the decrease of hpa1c after half year of treatment or longer but most of these studies was half a year and and that that provides the basis you know to to uh define an effect size that we should see and uh 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 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 may need it and also on weight for those patients who may find this important. I can only repeat that the weight gain with P-paragon 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. We really see the value of this 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. The physician will start with an treatment and then see how the patient evolves and may add another treatment if necessary in certain patients. With regard to the biopsy, it was always our intention to start with three expert pathologists and we have started with two and have, as soon as the third one was on board contractually, made the time breaker 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 two 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 72-week treatment period, all histology will be rereads. So the histology at inclusion and the histology at the end of treatment will be evaluated again by the three pathologists according to this pattern. So for the entire study, if you look at the evaluation of efficacy, the reading will be consistent.
spk01: We have no further questions at this time. I hand back the conference to Mr. Crenn for closing remarks. Thank you.
spk06: well thank you very much for for attending we have in front of us 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 they're going to be quite a lot of events this year especially with the fda the antiseptic and the magical submission and concerning you know lani fibrino will remain know 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 give it to deliver native three and as i mentioned uh it seemed that we are on the right track and then we also be looking forward with you know optimism let's say the cautious optimism to uh to the data that will be generated by uh by Professor Cusi in the type 2 diabetes study and also of course in the legend study. I think 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.
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