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 anytime during this presentation to add your comments, which are always useful. And this presentation will last approximately one 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 alexis.bernard@ab-science.com. This is the usual disclaimer. And we're going to talk, as I said, about masitinib and masitinib in the three indications that we call the platform. Masitinib 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 have 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, which are the two 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 non-clinical and then in clinical. And today, masitinib is a very credible asset. It's still a drug candidate, but I hope one day a drug. And it's a very credible asset for three 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. Alors, ALS, what happened? Unfortunately, we have seen many, many failures despite many, many attempts. Riluzole, which was approved first in 1995, 30 years ago by FDA, is still the drug of reference. Radicava edaravone, a drug brought by Mitsubishi Tanabe, has been registered by FDA, but not by EMA. As a list of failed studies, I think they did six studies and five failed, and one was successful, the one 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. In fact, the study failed in all its clinical endpoints, but just brought benefit in a surrogate endpoint, which is the reduction of a marker called neurofilament, which marks the destruction of the neuron. Masitinib represents today the most advanced program. The list of the failure is long, and it's actually longer than the one on this screen. Among the different failures in the last 12 months, 16 months, there have been drugs that brought hope but finally failed, like the drug of Amylyx, for instance, and most recently, the one from Denali. Alors, Denali and Sanofi had a previous failure with a RIPK1 drug, but there was another failure recently, two weeks ago. We are still facing a considerable unmet clinical need that masitinib could fill. Next slide. Masitinib targets our 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 destruction of the motor neuron. If you block the microglia, you protect the motor neuron. And mast cells activate 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 has 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 at the periphery. So we have demonstrated this benefit in two animal models which are completely different. One, which is the SOD1 model, where there is this very specific mutation that we find in the familial form of ALS. And there was an extension of the survival of the mice. Olivier, by the way, in his lab, did the second experiment in a completely different model, which is zebrafish, where there is a mutation on a very important gene called TDP-43. 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, so they swallow, so to speak, or they swim into the masitinib, they are protected. These two experiments separately prove the effectiveness, at least in animals, of masitinib. We have a third experiment that is not very well known, but critical. You know, probably some of you have heard that the biomarker is extremely important because it's difficult to prove 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 a multiple sclerosis 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 eight, which is rather quickly. So we have evidence of the neuroprotective effect of masitinib, which contributes to convincing the scientists that this drug is promising. Next slide. So you have heard, of course, of the first study called AB10015, and we would like to come back to it to tell you more about this study. So this study was successful in its pre-specified endpoint at week 48, which is a long endpoint. We observed a slowing down of the decline of the function of the patients measured by the score of ALS-FRS. We used a methodology which is called modified last observation carried forward. Now, this methodology is not the best. So we did some sensitivity analysis to take care about what we call missing data, which are the patients that could not reach week 48. This is a complex question because there is no gold standard to calculate what would be the data at week 48 while the patient discontinued or died. We need to impute and deduce, so to speak, the value at week 48. The publications say that there are two methodologies, more than two, but those two methodologies 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 reference. The second model is the 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 two 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 information which we are happy to bring here. In fact, in the first study, there was an imbalance against masitinib. And this imbalance 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 ALS-FRS measures 12 functions. And there is a score from zero, where there is a loss of function, to four, where the function is normal. When there is a loss of function, it means that a group of motor neurons is dead. When a group of motor neurons is dead and at least one function, the patients usually collapse. The other set of motor neurons dies, and then the patients die usually six months later. So if you enroll this type of patients, they will not reach week 48. They're very likely to die in the first 12 months. And you'd better make sure that there is no imbalance 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 there were in the two arms between the placebo and masitinib. And in fact, we discovered that there were 20% in masitinib group and 8% in the placebo. So it is balanced. It was unexpected because we tried to avoid that situation by using what we call a minimization of the severity at baseline. The study was designed so that, on average, the severity is the same in the two arms. It's not because it's the same on average that there is no imbalance in a subset of patients. In this case, bad luck in the patients which had the worst prognosis. If you look at the table below, you can see that it represented 21 patients in the masitinib group and nine patients in the placebo. The nine patients in the placebo, eight had one function lost, one item, and one had four items lost or four functions lost. In masitinib, you can see 10 patients had one loss of function, but seven had two, three had three loss of function, and one had four. 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, 8 + 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 ALS-FRS, the primary 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 Reference, which hypothesized a progressive return to placebo, had a difference of 2.67, and now has a difference of 3.13. And the CAFS, the CAFS is a complex calculation that FDA prefers. So it's the FDA endpoint, and it's a ranking, so to make it short. In our study, it was not statistically significant, but there was a benefit for 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 measured the capacity to breathe, was at a trend but was not significant, and now is significant. The p-value is less than 5%. The CAFS, which measures the earlier of two events, death or a decline by more than 9 points of the score of ALS-FRS, was significant with a delta of + 4 months in favor of masitinib, now has a benefit of 9 months, which is huge, and the overall survival, which had 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 the set of data represents the strongest hypothesis that our first study can tell us. Masitinib, if there is no imbalance in the population of the study, which excluded the fast progressors, you know, can generate, in fact, a huge benefit on all variables, including a benefit of survival of 12 months. Now, that is the representation of this 12-month benefit in a curve called Kaplan-Meier curve, where you can see that the placebo dies faster along a long follow-up of more than seven years. Now, more interesting is that we followed the patients seven years, both placebo and masitinib, but we continued to follow the patients because there was a program of compassionate use, but this program has been so extended, and so we continued to follow the compassionate use for an additional three years, so altogether, we have 10 years now of follow-up of the patients, and what do we see? We see that, well, we'll take the masitinib arm, 4.5 mg, 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 five years. That is unexpected because this disease is known as, unfortunately, making patients die in the first two to three years, so 43% of the patients survive after five 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. We use the model called ENCALS model, which has been published, and ENCALS model gives you the survival, expected survival, depending on the baseline characteristic. In fact, ENCALS creates three groups, and one of the groups, group number five, is the super long-term survival, so we thought that our survivor were the group five survivor of the ENCALS model. We applied our baseline characteristic, and we asked ENCALS model how many months those patients would have survived. 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 on the baseline characteristics. Now, these 42 months additional survival, not explainable by baseline characteristic, 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 a masitinib effect. That's important data that we show here because a study 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 very long-term, which we did seven years, and even now 10 years, and we can obtain this kind of result, which is very intriguing. We have patients, in fact, that are surviving now under masitinib in more than 10 years. Some are reaching 15 years, and it seems they're 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, and 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 that could tell a lot about the potential of the drug. So we're happy to share this 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 has 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 we have to focus on that. Now, the study AB 19001 is slowed to recruitment, and it's due to the design of this study, which has been recommended by EMA. Among the main obstacles to this study, there were a run-in, well, a run-in is a term that says that the patients will be observed for three months before we can start treating the patients with masitinib. And why? It It has been asked by EMA to do that because we exclude fast progressor, and we propose to exclude it 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 the patient for a certain period, three months. Now, nobody wants to participate in a study where you don't receive a drug for three months. Ten 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 treatments registered in the USA were forbidden, including Amylyx. Now it's no more problem, but also edaravone. We could recruit very little, very few patients in the USA. And also, because EMA wanted time to event endpoint as secondary endpoint, we had to continue with a blinding extension, and the patients don't 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 asked us also to explore a second dose or higher dose of six milligrams. So those five points together, cumulative, was a serious problem for the recruitment of this study. So we discussed with FDA and EMA and asked if it was possible to remove those points through an amendment. And they said that they strongly discouraged doing the amendment. We amended, remember, the first study 10015, and it was a problem for the registration. 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. 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. We are following the recommendation from EMA and FDA, and we will launch a new study, which will be called AB 23005. This study will solve the problem of the previous study. There will be no running period. There will be not only moderate patients, but also severe. The only patients that will 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 USA 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 mg anymore. It will be 4.5. 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 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 enrolled patients with loss of function, and it was imbalanced. So we're going to exclude it from scratch. And the first study minimized 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 two times 100 patients. And we are not going to do that, of course. And we are not going to take 20% as a hypothesis. We're going to take as a hypothesis that hypothesis as if the loss of function was 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 accept that the second design was better. Okay? It took a lot of time. We convinced them. We submitted to FDA and EMA after we discussed the design, and it was already approved by FDA. We have got already the approval of FDA, and we have got also the approval of EMA. There are two parts now when you submit a study. There is a first part, which is called the design part, and it has been approved. Now we are moving towards the second step, which is called the local part, if you want, part two, where you submit to the different countries. The design, which is strategic, has been approved by EMA. The study, currently the 19001, will become supportive after EMA has approved the study. At the end of the step two, but will be presented at the time of registration and has at least one merit, which is to have explored the 6 mg 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 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 secures 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 masitinib, provided, of course, that the study is successful. Also, the phase III is much easier to enroll, and I will show you the feasibility study in a moment, and there is also a fourth 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-à-vis EMA, FDA, but also potential partners. Now, in terms of feasibility, we have contacted USA sites and European sites, and we have, in fact, more than 86 sites between the time we wrote the 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. In 12 months' time, we do not need 683. We need only 400 patients, so we can even be selective in the sites, 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 two years. Now, the, I would say, conclusion of that is that, yes, we have to spend another two years, but meanwhile, the other programs from competitors failed, so we have lost time, but the other program failed, so we are still the most advanced program today. Even if we have to do a new round, we can do it in two years' time, and we are in a much better position to register if we follow the recommendation of EMA and FDA. 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. The multiple sclerosis, as you remember, we are not in relapsing remitting forms where it's crowded in terms of number of drugs registered or in secondary progressive active. Active in the sense that you have signs of activity on inflammation in the brain at the imaging. We are in the two other forms, which represent still 50% of the patients, which are primary progressive or secondary progressive, but inactive. Here, there is only one drug, Ocrevus, but which has a mini label 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 disease duration and 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. Here, it's like saying it's active versus inactive primary progressive, so in fact, this table 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 three diseases, in MS, likewise in Alzheimer's, 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. It presents what we call pro-inflammatory phenotype of microglia, which contributes to the destruction of the environment, including the neuron itself, and creating inflammation, of course. This is why it's important to control this immune response. Mast cells just exacerbate and push further the microglia. Also, mast cells, by degranulating, can destroy, for instance, the myelin that protects the neurons. For all these reasons, they are very important targets. I passed the data that we obtained in mice, which proved that at least in mice, masitinib is protected. The neurofilament in this model, I have already shown. I'm going to remind you of some data and add some new information. The study that we did, which was successful, tested 300 patients and 10 in an escalating dose 6 mg. We stopped the 6 mg flat and same proportion of patients, 300 randomized two to one in the 4.5 mg. And it was successful on an endpoint, which makes two things. It makes worsening of EDSS, which is the score of handicap, 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 increases, and masitinib stabilizes and then deteriorates a little bit. But there is a difference all over the two 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 progress, and you can see that the placebo progresses 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 reduces by 42% the probability of progression. And this is statistically significant. Now, you still do 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 reduces this probability by 37%. But we lose significance because, in fact, there are fewer events. 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 does not target mast cells, and through a different enzymatic target called BTK, Bruton's 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 II-B/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 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'll try to do so, and you can see here on the right-hand side that on the progression confirmed three 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 three years, as you can see here. Okay? They have a reduction of the probability of progression of 24 months. The study was statistically significant. Now, when you compare that to our data, we followed the patients, in fact, two years, not three years. If we had compared two years, we would have to take that part here at 24 months. It would be a little, you know, not as good as the 24-month reduction risk, and maybe not statistically significant. We don't know. That's why it's not really comparable. However, we have a 37% risk reduction. They have a 24% risk reduction. It's not the same data. It's not the same population, as I said. I don't want to be reproached to have concluded anything between tolebrutinib and masitinib. Just visually interesting to observe. Now, in a table, I have put Ocrevus, which is registered even with a small label. You can see the number of patients, our data, and tolebrutinib data. You can compare the risk, the reduction of probability of progression. 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 synthetic 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. 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. That tells you one thing. It tells you that targeting microglia is, in fact, probably a very valid strategy. Immediately, the risk is decreased. Masitinib has more chance to succeed perceived by the industry because the target of masitinib is a similar target as tolebrutinib. And in addition, masitinib targets mast cells. The results of our study were endorsed by KOL that you might have heard before, Patrick Vermersch, who is French, Robert Fox, who is American, Paul Friedemann, who is German. Interestingly, these KOL, key opinion leaders, are the same as the one of tolebrutinib. We have the same team who has pushed the two products. 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 a EDSS progression confirm and where we will try to target both primary progressive and inactive secondary progressive. The message here is tolebrutinib confirms, so to speak, that the hypothesis of targeting microglia is probably a very valid one and so reduces the risk of failure in the confirmatory study. Now, Alzheimer's disease. Alzheimer's disease, there are some things that happen that you need to know. To get started, you have to know that Alzheimer's is split by severity of the patients, that there is an early phase of Alzheimer's called prodromal. It's a technical term that says early. And this measure here from 30 to less than 10 is what we call MMSE. And it measures the severity of the patients. The higher the score, the less severe are the patients. 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. The studies are done between prodromal, mild, and moderate. In fact, there are two drugs that have been recently registered in the United States, which are biologics that target the plaque of beta-amyloid that you have probably heard in Alzheimer's, trying to reduce the plaque. Their studies have enrolled early Alzheimer's and part of the mild. Okay? That's how they've been positioned when you look at the inclusion criteria of the study. They have not done moderate. In fact, masitinib has the only successful study that has recruited moderate patients and part of the mild. We partly overlap with those drugs, but we do not overlap on moderate. Masitinib has the only data positive with moderate patients. Now, what can we do with masitinib? We can do, of course, a 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 would 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, a clinical benefit. That's why they have been registered. Now, what we can do is combine with the biologics. Why not? You know, 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 in an advantageous position, but there is nothing to combine because there is no drug registered. All right? In MS, there is no drug registered, nothing to combine. In Alzheimer's, there is almost nothing, but it's still a little bit better than MS and ALS because there are those two 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 USA. They are not yet accessible to patients in Europe. Okay, so we have to wait a little bit, but we can combine. 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 innate immune response that needs to be blocked because if it's not blocked, it will destroy, accelerate the destruction of the neuron. The combination might be synergistic. It might be the best way to treat Alzheimer's disease. People are interested to combine. Right? Okay? 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. Once people have taken that, they see a reduction of the plaque. The patients are not cured at all. They continue to deteriorate, but there is no more plaque. To some extent, the deterioration is slower. But when the plaque is removed or reduced enough, there is no more interest to give this product. So what to give? 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? What's next? Masitinib. Okay? And so we have different approaches that will be explored in the future. The future of Alzheimer's 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 ones 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. It's a very interesting drug to develop in Alzheimer's, and not only a single agent in moderate. You can see the differentiation is clear now in Alzheimer's. The mode of action of masitinib, once I have said microglia and mast cells, so microglia I already described, we have observed in rodents a protection of the synapse, not only in the neurofilament that we have seen in MS, but also directly in an Alzheimer's model that was done at the Institut du Cerveau et de la Moelle, 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 are two aggregates, beta-amyloid and tau. Masitinib has an impact on tau because masitinib inhibits a kinase called Fyn and Fyn phosphorylates tau. In fact, we also have a potential effect on tau. There are mast cells. Those microglia mast cells are known. Those ones are less well known, but still can add up to the efficacy of masitinib. Now, the study that we have done was a 700+ patient study exploring essentially those two doses. Those ones have been stopped. Again, 4.5 and escalating 6 with 300 patients and more here. No difference here. It was randomized one-to-one for 4.5, but two-to-one in 6 mg with for placebo. The study was positive on slowing down the cognition deficit, which is the COG measure, with a benefit between masitinib and placebo. Placebo worsened. We also have authorized memantine and anticholinesterase, whereas there was even an improvement in masitinib. For the daily function measured by the score of ADL, there was also a difference with a deterioration in placebo and even an improvement in average with masitinib at six months. And that gives this type of curve here. So you see the placebo here. This is the COG. So the higher the COG, the higher the deterioration. Well, the placebo improves a little bit, like it's often the case when you start a clinical study. Then deteriorates over a period of 48 weeks. And here you can see the masitinib up to even 36. We have, you know, for 66 weeks, there was no deterioration. And even an improvement in average with masitinib, which is spectacular. Now, 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's. They just have, so they don't have dying neurons. They just have activated mast cells in the brain, and activation mast cells in the brain, apparently in the hippocampus, is enough to disturb completely and even shut down the memory of the patient, so in fact, when you consider Alzheimer's and people say loss of memory, they immediately think of destruction of neurons. That's why it explains the loss of memory, but in fact, the loss of memory is explained by two things. First, an activity of mast cells that by itself is enough to lose memory, but 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. 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's, which is another distinctive feature of our drug in Alzheimer's, 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 registration of two drugs. In MS, you know, in MS, there is a success, still not a registration. In MS, everybody failed. In MS, one drug succeeded, but it's not registered yet, but gives hope on the targeting of microglia. And in Alzheimer's, two registrations, but the position of masitinib is extraordinarily complementary to those two drugs. Okay? That's the message. Now, the intellectual property, because we have been developing masitinib for years, and there are legitimate questions from you, but also from the potential pharma partners on the intellectual property. We never talk about intellectual property, 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 drug status, which gives 10 years of protection at EMA and seven years at FDA. So that is very strong. Then AB Science, when we read the phase II-B/III data, discovered things in those studies and found what we call a secondary patent called use patent. It's the use of masitinib in a special population. And that patent has extended the life of masitinib. What you have to know, and we communicated several times through press release, is that in ALS, this use pattern, by the way, this use pattern has been delivered already everywhere in the world in ALS. So it's very robust, and it extends the life until 2037. In MS and Alzheimer's, it's not delivered yet. It has been found, 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 patent, is robust enough for development. In addition to that, and it's not very well known, there are protections without patent called data exclusivity that I'm going to try to explain to you. They are different in the USA and in Europe. By the way, I'll start with Europe. What is not very well known, 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, generic drug, 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 that, they need to access the data. And that's where the data protection comes. So if you are protected by data protection, the generic drug cannot use 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, in Alzheimer's, 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 generics never does. A pharma might do, but not always. But the generics will never do. Okay? So the double protection of data protection and this use patent and the orphan drug is very robust. And the U.S. is a little bit less generous than Europe, but you are protected for 7.0 years to 8 years in data exclusivity. It starts with 5 years, then it's extended. So altogether, we have three 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's 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's. And it's all ALS. We start with that, which is well known and measured worldwide. Then we say, what is the target of masitinib? It's not everything. For instance, in MS, it's primary 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 say, what would be the market share? So in ALS, it would be probably more than 50%. But even if there are drugs registered, which there is not, and we are the most advanced, so if there are drugs registered, there will be after us, five years after us, still we think that patients will combine drugs because no drug will cure people in ALS, although with masitinib, certain 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 we use this, even push it higher to the higher end. Here, primary progressive, there is nothing except Ocrevus. We target 10%. You have seen that there is a BTK inhibitor. There may be more BTK inhibitors, but still 10% is quite reachable. And in Alzheimer's, where there are biologics, we see mild wear and overlap, we put 5%, no more. But moderate, there's nothing. We could put more than 20%. But here, let's put 20%. Then we mix the two. It would be 12.5%. Then not everybody is insured. We are talking about only USA and Europe. We use the price, which is the existing price of the product. That is the price that was, that is used, for instance, for edaravone, and it was used for Amylyx. Here in MS, we take the price of relapsing remitting because there is no drug in progressive forms. Here we take the price of the biologics that has been recently registered, and we deduce the market. As you can see in each of the indications, including ALS, in fact, here it's much more. We have been modest here. We can, this product is a blockbuster. If we succeed in one, it's a blockbuster for us, other partners. 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're going to go against this recommendation. We're going to follow it. We are as advanced as possible in the sense that it has been, the design has been validated. The confirmatory study is already authorized by FDA, not completely by EMA, but we have passed step one, which is the most critical one. We feel secure in the pathway to registration. It facilitates highly the discussion with partners now because we remove all uncertainty. And the hypothesis of the first study is actually better than what you probably had in mind because of the imbalance 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 two to 15 years. That's what probably if there is one thing to retain, it's probably this one. Progressive forms of MS, the MOA looks good, and the recent success of tolebrutinib probably reinforced that hypothesis. We add mast cells, which BTK does not do. 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's, targeting the immune system is super differentiated and complementary to the anti-beta-amyloid anti-tau plaque strategy. We are alone on masitinib, okay? We can combine. There have been multiple failures of different programs, which still put masitinib in the basket of the very visible and credible drug. Targeting of the innate immune system is recognized every week as stronger and stronger as a hypothesis. The unmet medical need is immense for the patients, of course. It also represents billions of markets. The Alzheimer's market is probably as big as the obesity and will double in 10 years like the obesity. The IP rights is okay. The data protection also, and the orphan drug also. So all in all, masitinib is attractive. Sickle cell under the control of Olivier Hermine, who is there, and it's his program, and he has convinced the, you know, the government, not the government, but the public to allocate EUR 10 million to the program. This sickle cell disease called drépanocytose in France, in French, is the largest genetic disease in the world. There are some curative options on the basis of CRISPR technology, but they are priced $2 million and $3 million. I think that one never sold even the first dose, and the second one was minimum, like less than 50 patients. It's very difficult to sell a drug at $2 million or $3 million because there is no insurance. Recently, there have been three 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. There is an unmet medical need in sickle cell. Olivier has proved the hypothesis of mast cells in sickle cell is real, and even also macrophage microglia. It's also involved. The mice survive longer in his hands, in his labs. Our hypothesis is considered credible enough, and he has convinced Olivier to be financed for this phase II. It will be the phase II academic, but AB Science keeps the rights for further development. We do that in cooperation. 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. That's what we can say, but it's also a competitive. I would say we are competitive and attractive in this program. Few words on financing. So we presented you in December this second platform, the value added being the targeting of the stem cells, you remember, through LDH, and we're in phase I. And here we talked about what's happening from masitinib. And we have new drugs and disclosed in non-clinical 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 for masitinib remains, the 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 funds. AB8939 phase I is financed through our own funds or 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're not going to be too late to be in phase III to start engaging into the discussions we learn, and we're 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. Everybody wants that, so we're going to deliver that. We have new drugs that we keep on disclosing at that time. Now, we have two debts, in fact. We have a debt with a Banque Européenne d'Investissement on COVID, but it's a long-term debt. We have a short-term debt that we're paying every month, debt everybody did in the industry, which was at the time of the COVID, called the PGE, Prêt Garanti par l'État. This debt represents still an amount of EUR 3.7 million. 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. 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. We have programs in the R&D. We have decided to start discussing with the bank that holds this debt to see if they agree on a standstill for how long, I don't know. 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 on masitinib, on which we are 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 8939 with the existing chemotherapy where we expect efficacy. You remember that we had signal in a subset of patients which all die in 12 months' time called MECOM because this MECOM overexpressed LDH, which boosts the resistance of the stem cells. You have received a lot of information in December and also now in January. I hope it gives better visibility and clarifications about AB Science, which has wonderful innovations in the two platforms. Masitinib targeting mast cells and microglia in neurodegenerative disease. It's a major innovation that will go to the end. The science is there. It's just a question of execution and money, but we'll do it. Now the second innovation with the second platform based on stem cells that we will deliver first in leukemia and then in solid tumors and sarcoma. Thank you for your attention. If you have questions, use Alexis Bernard's email, and we'll try to respond. Olivier, if you're still there, do you want to say a word? Olivier, I don't know if you're still there. I see you are there, but unmute. Yes, I'm 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 strong preclinical and basic science data and which are reinforced by the clinical data, so I think it's a very important findings. We do need to confirm now in the confirmatory study all we have done, and as Alain explained before, the risk of failure is quite small because now we have a better defined population of patients that we would like to treat. Also, we chose this new program on mast cells and sickle cell disease because we found also that in this disease, the inflammatory part is very important and is linked to mast cell activation also. Finally, the AB8939 platform is some kind of new drugs which have a dual role, both to block the proliferation through microtubule inhibition and also to block stem cell proliferation and self-renewal, which is a new finding and very, very few drugs playing a role in this process. So I think we have a lot of new things and still a very innovative program which addresses all unmet medical needs. I mean, the disease in which we have not seen 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 summarize where we are now. Thank you, Olivier. Thank you for the audience. 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.