AB Science S.A. (AB.PA) Earnings Call Transcript & Summary

Good evening and good afternoon for the people who connect from the United States. Welcome to the web conference on the clinical development update that will be focused on masitinib. My name is Alain Moussy. I'm the CEO of AB Science. And with me, there is Olivier Hermine. Hello, Olivier, we can see him.

Hello?

And he is the Chairman of the Scientific Committee of AB Science. Olivier, you can interrupt me any time during this presentation to add your comments, which are always useful. And this presentation will last approximately 1 hour. At the end, if you have any questions, we recommend that you send them to Alexis Bernard and you certainly know his email, otherwise, it's [email protected]. This is the usual disclaimer. And we're going to talk, as I said, about masitinib and masitinib in the 3 indications that we call the platform. Masitinib is -- brings in innovation in the industry. AB Science has been probably the first company to I would say, hypothesize that the innate immune system plays a key role in neurodegenerative disease, and we are pioneering the route to try to get a drug on this hypothesis. And today -- and we started, in fact, in 2012. And today, 11 years later, microglia and mast cells are the 2 targets of masitinib are recognized as very valid targets and I would say those programs are now cutting edge in the field of neurodegenerative disease. Masitinib has brought pieces of evidence one after another in nonclinical and then in clinical. And today, masitinib is a very credible asset, so it's still a drug candidate, that I hope one day a drug, and it's a very credible asset for 3 indications, which are amyotrophic lateral sclerosis, Alzheimer's’ disease and progressive MS, and it's a pleasure to update you about where this program is. So let's start with ALS. ALS, what happened? Unfortunately, we have seen many, many sellers despite many, many attempts and riluzole, which was approved first in 1995, 30 years ago by FDA is still a drug of reference. Radicava, edaravone, a drug brought by Mitsubishi Tanabe has been registered by FDA, but not by EMA and as a list of failed study, I think there are indeed 6 studies and 5 failed and 1 was successful, the 1 that brought the registrations. In particular, edaravone was developed by Ferrer in a similar, I would say, formulation and failed. Tofersen brought progress in the sense that it has been registered, but it targets only the patients who have the SOD1 mutations, which represents only 2% of the patients. And in fact, the study failed in all its clinical endpoint, but just broad benefit in a surrogate endpoint, which is the reduction of the marker called neurofilament which marks the disruption of the neuron. Masitinib represents today the most advanced program. And the list of the failure is long, and it's actually longer than the 1 on this screen. But among the different failure in the last 12 months, 16 months, there has been drugs that brought hope that finally felt like the drug of [indiscernible], for instance, and most recently, the 1 from Denali. Denali and Sanofi, the previous failure with the RIPK1 drug, but there was another failure recently 2 weeks ago. And we are still facing a considerable unmet medical need that masitinib could fill. Next slide. So masitinib targets are mast cells and microglia and both play a critical role in this disease in the sense that the microglia are recruited and activated and they proliferate and they reach the motor neuron sites and then they contribute to the disruption of the motor neuron. So if you block the microglia, you protect the motor neuron. And mast cells activates the microglia and so it's good also to inhibit them. And also mast cells play a role at the junction of the nerves and the muscles, and they contribute to the destruction of this junction, and this is why the disease is a location centrally in the brain but also at the periphery where there are the nerves and the muscles. And masitinib brings a benefit -- potential benefit centrally, but also peripherally. So we have demonstrated this benefit in 2 animal models, which are completely different, one which is the SOD1 model, where there is this very specific mutation that we find in the familiar form of ALS. And there was an extension of the survival of the mice. And Olivier, by the way in his lab, the second experiment in a completely different model, which is zebrafish, where there is a mutation on a very important gene called TDP-43 and the zebrafish lose the motor neuron function whereas with masitinib that we put not in the zebrafish, but in the water where the zebrafish swim, the -- so they swallow so to speak, while they dive -- they swim into the masitinib, they are protected. And these 2 experiments separately prove the effectiveness at least in animals of masitinib. We have a third experiment that is not very well known but critical. Probably some of you have heard that the biomarker are extremely important because it's difficult to benefit directly on the clinical benefit. So that's why we're using biomarker because we think it might be early signs of efficacy. And one is the neurofilament because neurofilament is released when neurons die. So if you reduce the neurofilament, the drug is supposed to have protected the neuron. And here, we have an experiment still in animals. It's not in ALS model. It's in multiple sources model, but it's quicker to execute as an experiment. And here, we have demonstrated that in this model, masitinib could reduce significantly the number of neurofilament after day 8, which is rather quickly. So we have evidence of the neuroprotective effect of masitinib, which contributes to commencing the scientists that this drug is promising. Next slide. So you have heard, of course, of the first study called AB10015, and I would like to come back to it to tell you more about this study. So this study was successful in its prespecified endpoint at week 48, which is a long endpoint, and we observed a slowing down of the decline of the function of the patients measured by the score of ALSFRS. And we used a methodology which is called modified observation carry forward. Now this methodology is not the best. And so we did some sensitivity analysis to take care about the what we call missing data, which are the patients that could not reach week 48 and this is a complex question because there is no gold standard to calculate what would be the data at week 48, why the patient discontinued or died, and we need to impute the use, so to speak, the value at week 48. So the publications said that there are 2 methodology, more than 2, but those 2 methodology are recognized. The first one is called Copy Increment, where there is a penalty, which is imputed to the discontinuation under your treatment group, which is masitinib here. And the model, it's the computer, will hypothesize a progressive return to placebo. So the patients will lose the efficacy of masitinib and progressively return to placebo. That's the first model called Copy Increment in Reference. The second model is a Jump to Reference, it's a jump so it's brutal, it directly goes to the placebo. Think of a painkiller. For instance, if you have pain, you take a painkiller. You have no more pain and then you stop the painkiller and back to pain immediately. So in the first hypothesis, it's a slow return, which is probably most compatible with what we call a disease modifier, which is masitinib because it protects the neuron, whereas the other one is more symptomatic. But in the 2 cases, you can see that the data is significant because the p-value is less than 5%. And so we can conclude that the data obtained in the first study is robust for its primary analysis. The next slide is the -- an information, which we are happy to bring here. In fact, in the first study, there was a disbalance against masitinib. And this disbalance was in a subset of patients, which is the most problematic patients because we enrolled them at baseline with what we call a loss of function already. So the score of ALSFRS measures 12 function. And there is a score from 0 where there is a loss of function to 4 where the function is normal. When there is a loss of function, it means that a group of motor neuron is dead. And when a group of motor neuron is dead in at least 1 function, the patients usually collapse. The other set of motor neuron dies and then the patient die usually 6 months later. So if you enroll these types of patients, they will not reach week 48. They are very likely to die in the first 12 months. And you better make sure that there is no disbalance in this subset of patients because they are the worst patients with the worst prognosis, and they will, so to speak, influence your primary analysis. So let's look at how many patients they were in the 2 arms between the placebo and masitinib. And in fact, we discovered that there were 20% in masitinib group and 8% in the placebo, so a disbalance. And it wasn't expected because we try to avoid the situation by using what we call a minimization of the severity at baseline. So we -- the study was designed so that in average, the severity is the same in the 2 arm. But it's not because it's the same in average, that there was no disbalance in a subset of patients. And in this case, bad luck in the patients which have the worst prognosis. And if you look at the table below, you can see that it represented 21 patients in the masitinib group and 9 patients in the placebo. The 9 patients in the placebo, 8 is at 1 function loss, 1 item and 1 at 4 item loss -- 4 function loss. But in masitinib, you can see 10 patients had 1 loss of function, but 7 at 2, 3 at 3 loss of function and 1 at 4. So you can see that there were a number of patients who unfortunately were close to death. Now what is interesting is to see what is the data that masitinib is able to generate if you remove this subset of patients, which represents, as you have seen, A plus 20 divided by 2 is 14% of the patients. So we're left with 86% of the patients. Now on the left column, you have the data of the study. And on the right column, you have the data of the study once you remove this 14% of the patients and -- let's look at the endpoint one by one. So in ALSFRS, the prime analysis, it was significantly improved with a delta of 3.39 in favor of masitinib. Now it's 4.04, much better. Now the Copy Increment in Reference, which hypothesize a progressive return to placebo, had a difference of 2.67, now has a difference of 3.13. And the catch, the catch is complex calculation that FDA prefers. So it's the FDA endpoint and it's a ranking, to make it short. In our study, it was not statistically significant, but there was benefit from masitinib of 14.8% as compared to the placebo. Now it's 20%, and it is significant. That's an important data at least for FDA. Then the quality of life was significant, remains significant. The forced vital capacity, which measures the capacity to breath was at a trend but was not significant and now is significant. The p-value is less than 5%. The progression-free survival, which measures the earlier 2 events, death, or a decline by more than 9 points of the score of ALSFRS was significant with a delta of plus 4 months in favor of masitinib now has a benefit of 9 months, which is huge. And the overall survival, which at a trend, the p-value was close to 5%, but not below 5%, showed a benefit of 6 months, which was interesting. But now shows a benefit of a year, which is considerable and is statistically significant. So that data is important and set of data and represents the strongest hypothesis that our first study can tell us. Masitinib, if there is no disbalance in the population of the study, which excluded the fast progress, as you know, can generate, in fact, a huge benefit on all variables, including the benefit of survival of 12 months. Now that is the representation of this 12 months benefit in a curve called Kaplan-Meier curve, where you can see that the placebo dies faster, a long follow-up of more than 7 years. Now more interesting is that we followed the patients 7 years, both placebo and masitinib, but we continue to follow the patients because there was a program of compassionate use. And -- but this program has been extended. And so we continue to follow the compassionate use for an additional 3 years. So altogether, we have 10 years now of follow-up of the patients. And what do we see? We see that -- we'll take the masitinib arm, 4.5 milligram, which had 128 patients at baseline. And we can see that 55 patients out of 128, which represents 43% of the patients, survived, in fact, more than 5 years. And that is unexpected because this disease is known as, unfortunately, making patients die in the first 2 to 3 years. So 43% of the patients survived after 5 years, that's a good performance from masitinib. Now we said maybe it's changed, maybe it's explained by the baseline characteristic that maybe we're biased in favor of masitinib. So we try to analyze if it was possible to rationalize the survival with the baseline characteristic. So we used a model called ENCALS model, which has been published. And ENCALS model gives you the survival -- expected survival depending on the baseline characteristics. And in fact, ENCALS creates 3 groups and 1 of the group, group number 5, is the super long-term survival. So we thought that our survival where the group 5 survivor of the MCAS model. So we applied our baseline characteristic and we asked ENCALS model, how many months those patients would have survived, and ENCALS model said 45 months. In fact, in our study, we observed 87 months on these 55 patients, which is a benefit of 42 months, which is 3.5 years more than the ENCALS model that predicts survival in the baseline characteristics. Now these 42 months additional survival, not extendable by baseline characteristics, could be changed, but huge change if this is changed or can be masitinib. We think and we hope that a large part of this additional 42 months could be explained by masitinib effect. But that's important data that we show here because a steady measures the decline -- the slowing down in functional decline at 12 months but doesn't tell you nothing about the long-term survival. You have to follow the patients really long term, which we need 7 years and even now 10 years, and we can obtain this kind of result, which is very intrigue. We have patients, in fact, that are surviving now under masitinib more than 10 years. Some are reaching 15 years, and it seems they are -- they stabilized. And even some improved 15 years later, they seem to be in better shape as they used to be 15 years before, that proves that at least in some patients, mast cells and microglia play a critical role. This set of data is called real life or real-world data. You might have heard that in the United States, they are going to rely on real life data to even register some drugs. So we are going to bring, of course, this set of data because we think they are important data that are in extension of a clinical study but could tell a lot about the potential of the product. So we are happy to share that with you. Now you have heard that -- you have read that EMA has rejected, unfortunately, the conditional approval of masitinib in ALS. It's a news that, of course, is still painful to us and to you, probably because you're close to AB Science. So we have to pass that negative news and go on. But the message here is that this first study was not recognized as robust enough for a conditional approval, it's considered as a hypothesis-generating study. And you have seen in the previous slide, the hypothesis that the drug can deliver. In the process, still, EMA is recognized that safety is fine, which is good because there is no problem now for the safety. So we have a strong hypothesis, and the registration now will be based on a confirmatory study and ways to focus on that. Now the study AB19001 is slow to recruitment. And it's due to design of this study, which has been recommended by EMA. And among the main obstacle to this study, they were run-in, run-in is a term that says that the patients will be observed for 3 months before we can start treating the patient with masitinib. And why? It has been asked by EMA to do that because we exclude fast progressor, and we propose to expedite from the retrospective from the onset of symptoms. So saying we look back to the first signs of the disease and we can deduce whether the patient is fast progressor excluded or not fast progressor included, but EMA told us, no, we want to do that prospectively, so you have to observe them for a certain period, 3 months. Now nobody wants to participate to a study where you don't receive a drug for 3 months. 10 years ago, it was possible maybe, but now it's impossible because patients have choice in different studies, and they want to be treated immediately. So that was a serious penalty for the recruitment of the study. Also, we were very restrictive in the inclusion criteria, recruiting only patients with moderate severity. Also on the recommendation of EMA, all treatment registered in U.S.A. were probably [indiscernible] including analytics. Now it's no more problem but also edaravone. So we could recruit very little -- very few patients in the U.S.A. And also because EMA wanted time to event endpoint, as secondary endpoint, we had to continue with a blinded extension and the patients did not like that because if they have the placebo, they want to have access to the product as soon as possible, so at minimum after 12 months of treatment. And EMA asks us also to explore second dose or higher dose of 6 milligrams. So those 5 points together, cumulative was a serious problem for the recruitment of the study. So we discussed with FDA and EMA and ask if it was possible to remove those points through an amendment. And they said that they strongly discouraged to do any amendment. We amended, remember, this first study, AB10015, it was a problem for the registration. And instead, they said that we should start a new study, which was, of course, difficult because we don't want to spend too much time on that. But finally, after serious thinking, we said, yes, we're going, and we have to follow the recommendation of the agencies. We cannot take the risk to go against the agencies. So we are following the recommendation from EMA and FDA, and we will launch a new study, which would be called AB23005. This study will solve the problem of the previous study. There will be no run-in period. There will be not only moderate patients, but also severe. The only patients that would be excluded will be the one with a loss of function as you have seen to go back to the right-hand column of the previous slides. We are going to authorize in the U.S.A. whatever is registered, which is edaravone today. There will be an open-label extension that will give access to the patients at week 48. We will not explore 6-milligram anymore, it will be 4.5-milligram. And so the study will have to enroll around 400 patients. So that's the design. There will be a specific statistical analysis plan for FDA on CAFS and another one with -- for EMA with the methodology that they like to treat missing data. So this design also will be optimized in terms of population in the sense that the limitation of the first study will be treated upfront. For instance, the first study excluded fast progressors, but through an amendment, of course, it will be excluded from scratch. The first study discovered -- not discovered but enrolled patients with loss of function and it was disbalance. So we're going to exclude it from scratch. And the first study minimize the severity, but forgot to stratify it, of course, it will be stratified. So the limitations that we have observed in the first study will be solved additionally in this study. Also, we'll take zero risk in terms of the statistical hypothesis. In the first study, you have seen that in the population, there was a relative benefit of 14.8% with a p-value, which was close to significance. But when we remove the loss of function, which we will do in the confirmatory study, the benefit was 20%, and it was statistically significant. And with that, we add this significance with 92 patients per arm. So in fact, we could do a study with 2x 100 patients. And we are not going to do that, of course. And we're not going to take 20% as hypotheses. We're going to take as a hypothesis that hypothesis as if the loss of function are still there and we're going to put, as you have seen, 400 patients. So in fact, we double the sample size as compared to what masitinib has done in the first study, taking zero risk in the statistical hypothesis for the CAFS and also for the EMA statistical preferred analysis. Now where do we stand with that? We had discussion with FDA and EMA. And the design has been discussed and has been approved by FDA and EMA and it was very long, in particular, with EMA because EMA did not agree with us upfront because they had to somehow not recognize that the first design they proposed was bad, but accepted the second design was better, okay? And it took a lot of time. But we convinced them. And so we submitted to FDA and EMA after we discussed the design, and it was already approved by FDA. So we have got already the approval of FDA and we have got also the approval of EMA. There are 2 parts now when you submit a study. There is a first part which is called the design part, and it has been approved. And now we are moving towards the second step which is called the local part, if you want, part 2, where you submit to the different countries, but the design, which is strategic, has been approved by EMA. And so the study, currently the AB19001 will become supportive after EMA has approved the study at the end of the step 2, but will be presented at the time of registration and has at least 1 minute, which is to have explore the 6-milligram dose, which would not be explored in the study AB23005. Now the benefit of that strategy is what. It's essential for potential partners, and you know that AB Science's strategy is to partner on masitinib for the Phase III. It is essential that we follow the recommendation of the agencies and that we do not depart from the recommendation of the agencies, which we did. Also, it secured the pathway to registration. If we do that because it's what they want that we do, then we are at no risk for the registration of this -- of masitinib, provided, of course, that the study is successful. Also, the Phase III is much easier to enroll, and I will show you that the feasibility study in a moment. And there is also a force merit, which is since we have to do another one, the potential partner can do it on their own, whereas at that time, we are ongoing on a study that we have started, which is not completely their own. So to some extent, the situation is clear, vis-a-vis, EMA, FDA but also potential partners. Now in terms of feasibility, we have contacted U.S. sites and European sites. And we have, in fact, more than 86 sites between -- in the time we wrote those slides, and today we have more. We have more than 100 sites interested. But we have received feasibility from 86 sites and they can recruit roughly 700 patients, 683 in 12 months' time. We do not need 683, we need only 400 patients. So we can even be selective in the site. But I guarantee that we can do the recruitment in one year, whereas it was very tough in the previous study, and we have to wait 12 months for the last patients to be treated. So it's a study that can be completed in 2 years. Now the -- I would say a conclusion of that is that, yes, we have to spend another 2 years. But meanwhile, the other programs from competitors failed. So we have lost time, but we are the prime player. So we're still the most advanced program today. Even if we have to do a neuron, we can do it in 2 years' time, and we are in a much better position to register if we follow the recommendation of EMA and FDA. And also, we're in a much better position for partnering. Now I move to the multiple sclerosis things because we have things to say as well on this program. So the multiple sclerosis, as you remember, we are not in relapsing-remitting forms where it's graded in terms of number of drugs registered or in secondary progressive, active. Active in the sense that you have signs of activity and inflammation in the brain at the imaging. We are in the 2 other forms, which represent still 50% of the patients, which are primary progressive or secondary progressive, but inactive. And here, there is only one drug, Ocrevus but which has a mini level because it does not cover the full scope of primary progressive as you can see here in their label, they are registered for specific forms of primary progressive, defined as PPMS, which is a disease duration and level of disability early, okay? Early, this is duration in level of disability and with imaging features, characteristic of inflammatory activity, and most of the primary progressive have no inflammation because they are not active. Sure, it's like saying, it's active versus inactive primary progressive. So in fact, this level is very small. And so there is nothing and we are here. Now in terms of science, as we said, and it's true for the 3 disease in MS, likewise in Alzheimer, likewise in ALS, the neurons are dying and when the neurons are dying, the innate immune system, the primitive immune system is recruited, trying to repair. And in fact, instead of repairing, it switches phenotype, and it presents what we call pro-inflammatory phenotype of microglia, which contributes to the disruption of the environment, including the neuron itself and creating inflammation, of course. And this is why it's important to control this immune response. And mast cells just exacerbate and push further the microglia and also mast cells by degranulating can destroy, for instance, the needing that protects the neuron cell. So for all these reasons, there are very important target. So I passed the data that we obtained in mice, which proved that at least in mice, masitinib is protective and neurofilament in this model I've already shown. So I'm going to remind you some data and add some new information. So the study that we did, which was successful, tested 300 patients and 10 in escalating dose of 6-milligram, we stopped the 6-milligram flat and 7 proportion of patients, 300 randomized 2:1 in the 4.5-milligram. And it was successful on an endpoint, which makes 2 things. It makes worsening of EDSS, which is the score from the GCP, but also improvement. So both worsening and improvement. So there is a mix. And Here, you can see that the placebo deteriorates because the score increased and masitinib stabilize and then deteriorates a little bit, but there is a difference all over the 2 years, and it is statistically significant. So the study has reached its primary endpoint. Now to register, you do not register on a mix of improvement and worsening. You register on worsening and in fact, worsening confirmed 12 months apart or even 24 months apart. This is the slide. So it's called disease progression or disability progression. So you can see here, it's increasing because some patients progressed. And you can see that the placebo progressed more and the hazard ratio tells you the probability for the patients to do better, I would say than the placebo. And so when there is 0.58, it means that masitinib reduced by the 42% the probability of progression, and this is statistically significant. Now you still not register with that measure because you need to have a progression confirmed 12 months apart. And that is the right-hand side, confirmed 12 months apart. And you can see here the curves look very similar. The hazard ratio, so the probability to slow down the progression is 0.63, which means that masitinib reduced this probability by 37%, but we lose significance because, in fact, there are fewer events. And this study was not designed to show any statistical significance on that endpoint. But that is the endpoint that we need to focus on, because this is the one on which we rely to register in the confirmatory study. Now what is interesting is that last year in September 2024, there was a second data generated by a product called tolebrutinib, which also targets microglia, but do not target mast cells and through a different enzymatic target called BTK, Bruton tyrosine kinase, and that product, tolebrutinib, has been successful in secondary progressive. So secondary progressive is this one, non-active secondary progressive, okay? We did a study combining primary and non-active secondary progressive. But tolebrutinib was focused on that and they have been successful. And they have been successful, they recruited 1,200 patients, so much more than what we did, but our study was a Phase IIb and Phase III and their study was a Phase III. And this is the curve that they obtained in their study as compared to the curve that we obtained in our study. So we should not compare because it's a difficult to interpret comparison because it's not the same patients, and it's not the same study, and it's not the same time, but still we've try to do so. And you can see here on the right-hand side that on the progression confirmed 3 months apart, tolebrutinib reduced the risk by 24%. And you can see the curve here. And you can see the number of months of follow-up. And they have followed the patients rather 3 years, as you can see here, okay? And they have a reduction of the probability of progression of 24 months, and the study was statistically significant. Now when you compare that to our data, we followed the patients, in fact, 2 years, not 3 years. So if we have compared 2 years, we would have to take that part here at 24 months. And it would be a little not as good as the 24-month reduction risk and maybe not statistically significant. We don't know. So that's why it's not really comparable. However, we had a 37% risk reduction. They have a 24% risk reduction but it's not the same, that is not the same population as I said. So I don't want to be approached to have concluded anything between tolebrutinib and masitinib, just visually interesting to observe. Now in a table, I have put old figures, which is registered even with a small label, and you can see the number of patients, our data and tolebrutinib data. And you can compare the risk -- the reduction of probability of progression. And you can see that masitinib is competitive. It's still a hypothesis-generating study, but it's competitive. Now what is happening to tolebrutinib? They are a Sanofi drug, they are applying for registration. They filed to FDA and they've received a breakthrough designation, which they can because it's a Phase III. But it means what? It means that the agencies receive very well any, I would say, data which is significant in this unmet medical need of primary and secondary progressive. But that tells you one thing. It tells you that targeting microglia is, in fact, probably a very valid strategy. And immediately, the risk is decreased. So masitinib has more chance to succeed perceived by the industry because the target of masitinib is the similar target as tolebrutinib and in addition, masitinib targets mast cells. So the results of our study were endorsed by the KOL that you might have heard before, [indiscernible] with French, [indiscernible] with American, [indiscernible] with German. Interestingly, these KOLs, Key Opinion Leaders, are the same as the one of tolebrutinib. We have the same team who has pushed the two products. So the confirmatory study, as you know, is authorized already by FDA and key European countries, and it's a no surprise design where we do EDSS progression confirmed and where we will try to target both primary progressive and inactive secondary progressive. So the message here is tolebrutinib confirms, so to speak, that the hypothesis of targeting microglia is probably a very valid one, and so reduce the risk of failure in the confirmatory state. Now Alzheimer's disease. Alzheimer's disease things -- there were some things that happened that you need to know. So to get started, you have to know that Alzheimer is splitted by severity of the patients. That there is an early phase of Alzheimer's called prodromal, it's a technical term that is early, and this measure here from 30 to less than 10 is what we call MMSE and it measures the severity of the patient. So the higher the score, the less severe is the patient. But it starts with a prodromal phase and then patients become mild and then patients become moderately handicapped and then they become severely handicapped. Severely handicapped is total dementia. Nobody treats those patients too late. And so the studies are done between prodromal, mild and moderate. And in fact, there are two drugs which had been recently registered in the United States, which on biologics that targets the plaque of beta-amyloid that you have probably heard in Alzheimer, trying to reduce the plaque. And their studies have involved early Alzheimer and part of the mind, okay? That's how they've been positioned when you look at the inclusion criteria of the study. But they have not done moderate. In fact, masitinib is the only successful study that has recruited moderate patients in partly overlap. So we partly overlap with those drugs, but we do not overlap on moderate. And masitinib is the only data positive with moderate patients. Now what can we do with masitinib? We can do, of course, development as single agent and in particular, position on the moderate where there is nothing. We can also do a combination with the biologics. Now you have to know that there are two aggregates in the Alzheimer's disease. There is the aggregate of beta-amyloid, which is very well known. And there is also another aggregate, which is called tau protein. So there are two aggregates and the industry is striving to reduce those aggregates in hope that it will reduce the symptoms. Sometimes products can reduce the aggregates. There is no clinical benefit, which is very disappointing. But for those two drugs, there has been a reduction of the plaque of beta-amyloid and also a benefit, clinical benefit. That's why they have been registered. Now what we can do is combine with the biologics. Why not? In oncology, we combine. In virology, we combine, that's how HIV is treated. In neurodegenerative disease, well, in ALS, we don't combine because our drug is [indiscernible], but there is nothing to combine because there is no drug registered, right? In MS, there is no drug registered, nothing to combine. In Alzheimer, there is almost nothing, but it's still a little bit better than MS and ALS, because there are those 2 drugs. So now that there are those two drugs, you can combine. And we are going to try to combine. So we not only are hoping to do this confirmatory study here, but we would like to combine with this recently registered drug. By the way, those drugs are registered and accessible to patients in the U.S.A., they are not yet accessible to patients in Europe, okay? So we have to wait a little bit, but we can combine. And in fact, the mechanism of actions are completely different. One is to reduce the plaque, whereas our strategy, the approach of masitinib is to modulate, block the immune response that you have understood now, it's the net immune response that needs to be blocked because if it's not blocked, it will destroy, accelerate the disruption of the healthy neuron. So the combination might be synergistic. It might be the best way to treat Alzheimer disease and people are interested to combine, right? Okay. So there is a new way to develop masitinib, which is the combination. Also, there is another way to develop masitinib, which is what we call adjuvant. So once people have taken that, they see reduction of the plaque, the patients are not cured at all. They continue to deteriorate, but there is no more plaque. So to some extent, the deterioration is slower. But when the plaques are removed or reduced enough, there is no more interest to give this product. So what to give? Our product. So the third way to use masitinib would be in adjuvant, which is a technical word to say after. After what? After those products have cleaned the plaque. Some patients are not responsive, but some are. So for the patients who are, we can say, what's next? And what's next is masitinib. And so we have different approach that will be explored in the future. The future of Alzheimer is going to be a combination. And masitinib is well positioned to be one of the options to be combined with, because we are the only one to target the innate immune system. There is no other drug that clearly targets the innate immune system like masitinib through microglia and mast cells. So it's a very interesting drug to develop in Alzheimer and not only a single agent in moderate. But you can see the differentiation is clear in Alzheimer. Well, the mode of action of masitinib, once I have said microglia and mast cells, so microglia as I have already described, we have observed in rodents, the protection of the synapse, not only in the neuro-filament that we have seen in MS, but also directly in an Alzheimer's model that was done at the [indiscernible], where we have seen a recovery of synapse. It promotes a recovery of synapse, which is very promising. We also have an impact on tau with this drug. I told you that there is two aggregates, beta-amyloid and tau and masitinib has an impact on tau because masitinib inhibits a kinase called Fyn, and Fyn, phosphorylasing tau. So in fact, we also have a potential effect on tau and there is mast cell. So those microglia mast cell are known. Those one are less well known, but still can add up to the efficacy of masitinib. Now the study that we have done was a 700-plus patient study exploring essentially those 2 doses. Those ones have been stopped, so again 4.5 milligram, and escalating 6 milligram with 300 patients and more here, not the difference here. It was randomized 1:1 for 4.5-milligram, but 2:1 in 6-milligram with pure placebo. And the study was positive on slowing down the cognition deficit, which is the cog measure with a benefit between masitinib and placebo. Placebo worsen. We also have authorized [indiscernible] whereas there was even an improvement in masitinib. And for the daily function measured by the score of ADL, there was also a difference with a deterioration on placebo and even an improvement in average with masitinib at 6 months. And that gives this type of curve here. So you see the placebo shift. This is the curve. So the higher the curve, the higher the deterioration. But the placebo improved a little bit like it's often the case when you start a clinical study, then deteriorates after period of the 48 weeks. And here, you can see the masitinib, up to even 36. We have for 66 weeks, there was no deterioration and even an improvement in average with masitinib, which is spectacular. And for the Cog, you have to know one thing. The Cog is the cognition in mastocytosis, and we do specialize in mastocytosis where mast cells are activated, patients suffer from spectacular loss of memory and they do not have Alzheimer, they just -- so they don't have dying neuron. They just have activated mast cells in the brain. And activation in mast cells in the brain appearing in the hippocamp is enough to disrupt completely and even shut down the memory of the patients. So in fact, when you consider Alzheimer, and people say loss of memory, they immediately think of disruption of neuron. That's why we explain the loss of memory. But in fact, the loss of memory is explained by 2 things. First, an activity of mast cells that by itself is enough to lose memory, but this might be recovered, in particular, treated by masitinib. That's why in our study, we have seen patients recovering memory then continuing to decline because of the dying of the neuron and the second explanation is the dying of the neuron. So in fact, masitinib could be a drug of choice to treat the memory problem in Alzheimer, which is another distinctive feature of our drug in Alzheimer to be explored, so the confirmatory study is approved by FDA and key European agencies, similar to MS and ALS, ready to start. And so the key message here is there has been a registration of 2 drugs in MS. In MS, there is a success still not a registration, everybody failed. In MS, 1 drug succeeded, but is not registered yet, but gives hope on the targeting of microglia. And in Alzheimer, full registrations, but the position of masitinib is extraordinary complementary to those 2 drugs, okay? That's the message. Now the intellectual property because we have been developing masitinib for years. And there is a legitimate questions from you, but also from the potential pharma partners on the intellectual property. We never talk about intellectual properties. So I would like to share the situation with you. So what is happening is the following: First, in ALS, I'll start with ALS. ALS is an orphan disease, and we are protected by the orphan work status, which gives 10 years of protection at EMA and 7 years at FDA. So that is very strong. Then AB Science when it read the Phase IIb/III data, discovered things in those studies and filed, what we call a secondary patent called use patent is the use of masitinib in a special population. And that patent has extended the life of masitinib. And what you have to know and we communicated several time to press release, is that in ALS, this use patent, by the way, this use patent has been delivered already everywhere in the world in ALS, it's very robust. And it extends the life until 2037. And in MS and Alzheimer, it's not delivered yet, because they did not file. So it's normal, it's not delivered yet. But we protect masitinib until 2041, which gives plenty of time to us and potential partners to deliver and register masitinib. So the intellectual property, the patents, is robust enough for development. In addition to that, and it's not very well known, there were protection without patent called data exclusivity that I'm going to try to explain to you, and they are different in the U.S.A. and in Europe. And by the way, I'll start with Europe. So what is not very well -- the data protection is what? It's -- you have done a study, it's your data. And if somebody wants to, you know, for instance, generator, they want to register, they have to use your data because they just say I have another formulation, which is similar, bioequivalent and I want a registration. But in fact, they have to use the data, the clinical data, that has been developed by the sponsor before. So to get, they need to access the data, and that's where the data protection comes. So if you are protected by data protection, the generator cannot choose your data. Now what is not very well known is that in Europe, you have 10 to 11 years of data protection. It means that if we do not take any patent, we still have the protection of the data. Now if somebody wants to use masitinib and go in ALS, in MS and Alzheimer, they have to do the study again or wait 10 to 11 years to use the data. So they have to redo the clinical program, which generator will never do. A pharma might do, but not always. But the generator will never do, okay? So the double protection of data protection and this use patent in the orphan drug is very robust. In the U.S.A., it is a little bit less generous than Europe, but you are protected for 7-point years to 8 years and that exclusivity starts with 5 years, then it's extended. So altogether, we have 3 lines of protections. We have the orphan drug for ALS only. We have the use patent and we have the data protection. So that's robust enough. And even if we have lost years in the development of masitinib, which we recognize, the data protection, the use patent still gives us enough time to commercialize the product. And the fact that the, I would say, potential competitors failed is not a good news for the patients, but to some extent, put us still in a position where, ironically, we are the most advanced program. So the market, we also never talk about the market. We say it is big enough, but we never really prove it. So let's try to prove it. So here, you have the disease prevalence. So for instance, in MS, it's not the progressive forms of MS, it's all forms of MS. And here, it's all Alzheimer, and it's all ALS. We start with that, which is well known and measured worldwide, then we say what is the target of MS? It's not everything. For instance, in MS, it's primarily progressive and inactive secondary progressive. Here it's mild and moderate, but it's not prodromal. And so we deduce the percentage of patients, which is the maximum market we can reach. And then we said what would be the market share. So in ALS, it would be probably more than 50%. But even if there were drugs registered, which there is not and we are the most advanced. So if there were drugs registered that will be after us, 5 years after us, still, we think that patients will combine drugs because no drug will cure people in ALS, although with masitinib, often patients survive very long. So probably 50% here. And we use the well-known consultant, we cannot give the names, which backs up this data and completely just even push it to the higher end. Here, primary progressive, there is nothing except for figures. We target 10%. You have seen that there is a BTK inhibitor. There might be more BTK inhibitors, but still 10% is quite reachable. And in Alzheimer, where there are own biologics, we see mild overlap with 5% no more. But literally it is just nothing, we could put more than 20%. But here, let's put 20%, then we mix the 2, it would be 12.5% then not everybody is insured. We are talking about only U.S.A. and Europe. We use the price, which is the existing price of the product. That is the price that is used, for instance, for Darvon and it was used for Amylyx. Here in MS, we take the price of relapsing and remitting because there is no drug in progressive forms. And here, we take the price of the biologics that has been recently registered and we deduced the market. And as you can see, in each of the indications, including ALS, in fact here it's much more, we've been modest here, we can -- this product is the blockbuster. So we succeed one, it's a blockbuster for us and other partners. So summary of the message we would like to convey this evening is what? A new confirmatory study has been recommended by FDA and EMA and there is no way we are going to go against this recommendation. So we're going to follow it. And we are as advanced as possible in the sense that it has been -- the drug has been validated. The confirmatory study is already authorized by FDA, not completely by EMA, but we have passed step 1, which is the most critical one. We feel secure in the pathway to registration. It facilitates highly registration with partners now because we removed all uncertainty. And the hypothesis of the first study is actually better than what we probably had in mind because of the disbalance in the prior loss of functions. You have seen the very long-term survival, which proves certainly in real life that the product is effective. Some patients survive 2 to 15 years. That's what probably if there is one thing to retain, it's probably this one. Progressive forms of MS gave away, looks good, and the recent success of tolebrutinib, probably reinforced a hypothesis. We add mast cells, which BTK does not do. We -- the masitinib looks competitive in terms of hazard ratio to the EDSS progression confirmed. The KOLs are very supportive of our program, very supportive. In Alzheimer the targeting immune system is super differentiation and complementary to the anti-beta amyloid and anti-plaque strategy. We are alone on moderate, okay? we can combine. And there has been multiple failures of different programs, which still puts masitinib in the basket of the very visible and credible drug. And targeting the innate immune system is recognized every week as stronger hypothesis. The unmet medical need is immense for the patients, of course. It also represents billions markets. The Alzheimer's market is probably as big as obesity and will double in 10 years like the obesity and the IP rights is okay and the data protection also and the orphan drug also. And so all in all, masitinib is attractive. Sickle cell under the control of Olivier Hermine was there and it's his program and he has convinced the government -- not the government, but public to allocate EUR 10 million to the program. So this sickle cell disease called drépanocytose in France -- in French, is the largest genetic disease in the world. And there are some curative options on the basis of technology, but they are priced $2 million and $3 million and I think that one never sold even the first dose and the second one was minimum like less than 50 patients. And so it's very difficult to sell a drug at $2 million or $3 million because there is no insurance. And recently, there has been 3 products revoked or unapproved, but revoked the one from Novartis and Pfizer, they were registered under conditional approval and then their confirmatory study failed and they've been revoked. And so there is an unmet medical need in sickle cell. Olivier has proved the hypothesis of mast calls in sickle cells is real and even also macrophage microglia is also involved. So the mice survived longer in his hands, in his labs. And our hypothesis is considered credible enough and has convinced Olivier to be financed for this Phase II. So it will be the Phase II academic, but AB Science keeps the rights for further development. So we do that in cooperations. In one year, we will have the biomarker validated, hopefully, and in two years, we'll have the Phase II data or less if Olivier is quicker. So that's what we can say, but it's also a competitive, I would say, we are competitive and effective in this product. A few words on financing. So we presented you in December, the second platform, the value-added being the targeting of the stem cells, you remember through ADH in Phase I. And here, we talked about the -- what's happening from masitinib and we have new drugs and disclosed in nonclinical that we could discuss another day. Now in terms of financing, we raised EUR 5 million in Q4 and we have visibility of 12 months. And the strategy from masitinib remains partnerships, okay? We are still working on partnerships, so be patient, but that's really a priority. The clarity of the situation on ALS will help, okay? It took some time, but now it's clear. So it should help. And for the sickle cell, it's already financed by public loans. 8939 Phase I is financed through our ramp-up of equity and the recent capital increase helped, of course. The Phase II, which is the next step, should be financed through equity or partnerships. Partnerships now is embedded into the strategy of AB Science, and we are discussing. And unlike masitinib, we are not going to be too late to be in Phase III to start engaging into the discussion we learned, and we are going to take benefit about that. I think that today, partnering on the different programs is the best strategy we can have to create value as soon as possible for the shareholders and everybody wants that, so we're going to deliver that. And we are new drugs that we keep on disclose at that time. Now we have a debt of -- we have two debts, in fact. We have a debt with [indiscernible] but it's a long-term debt. And we have a short-term debt that we're paying every month that everybody did in the industry, which was at the time of the COVID called the Prêt Garanti par l’Etat. This debt represents still an amount of EUR 3.7 million. And as you have seen, many French biotechs have renegotiated this debt, which we have not done so far trying to obtain what we call a standstill. So a standstill is not an elimination of the debt, but just a pause in the reimbursement of the debt that we pay every month so that we prioritize the R&D, and we have programs in the R&D. So we have decided to start discussing with the bank that all this debt to see if they agree on standstill for how long, I don't know, and so we will start discussion with the bank. We think it's a better allocation in the R&D because we have programs and we want to deliver these programs, in particular in the second platform, 8939. So that closed the messages that we wanted to deliver. It was a little long, but you are fully informed about what's happening here. In 2025, the highlight is what? It's a hopefully partnership of masitinib on which we're working hard and the start of the Phase III program. And on the second platform is the end of the Phase I in its most interesting part, which is to combine AB8939 with the existing chemotherapy, where we expect efficacy. You remember that we had signaled in a subset of patients, which all died in 12 months' time will -- may come because it may come over expressed ADH which boost the resistance of the stem cells. So you have received a lot of information in December and also now in January, and hope it gives better visibility, clarifications about AB Science, which has wonderful innovations in the 2 platforms, masitinib-targeting mast cells and microglia in neurodegenerative disease, it's a major innovation that will go through the end. The science is there. It's just a question of execution and money, but we'll do it and this second innovation with the second platform based on stem cells that we'll deliver first in leukemia and then in solid tumors in sarcoma. Thank you for your attention. If you have questions, use Alexis Bernard e-mail, and we'll try to respond. Olivier, if you are still there, do you want to say a word? Olivier, I don't know if he's still there. I see you are there, but on mute.

Yes I am here.

Do you want to say a closing word for the audience?

I think the program on neurodegenerative disease is very important because we open a new field of investigation on the role of mast cells and microglia in all neurodegenerative disease with now a strong preclinical and basic science data and which are reinforced by the clinical data. So I think it's a very important findings, and we do need to confirm now in a confirmatory study or we have done and as explained before, the risk of failure is quite small because now we have better define the population of patients that we would like to treat. And also, we show this new program on mast cell and sickle cell disease because we found also that in this disease, inflammatory part is very important and is linked to mast cell activation also. And finally, the AB8939 platform is some kind of a new drugs which have a dual role of both to block the perforation through microtubule inhibition and also to block stem cell perforation and self-renewal, which is a new findings and very few drugs playing a role in this process. So I think we have a lot of new things and still very innovative program, which address all unmet medical need. I mean, the disease in which we have nothing much currently. So I think it's difficult, but it's very challenging and promising for the patients. So I think I will be open to respond to your question, but I think I summarized where we are now.

Thank you, Olivier. Thank you for the audience. And we are happy to again take your questions by writing and try to answer. We close now and wish you a good evening or a good day. Goodbye.