Ladies and gentlemen, welcome to the AB Science webcast. I would like now to hand over the call to Alain Moussy, CEO of AB Science. Sir, the floor is yours. Thank you. Good evening and good afternoon for the participants in the United States. Thank you to join our web conference that will give a development update on the key topics of AB Science. With me for this presentation there is Laurent Guy, the Financial Director, and Olivier Hermine, who is the President of the Scientific Committee. Disclaimer as usual. Next slide. So the first topic—alors, the structure of the presentation is as usual, which means that we will deliver 30-minute presentations, and then we will leave it to your questions. We have received already lots of questions, so we'll try to address them in due time. And thank you to have sent us questions by writing even before this call. So the first topic is the most current one, which is the conditional approval status of masitinib in ALS with the two agencies, EMA and Health Canada. Next slide. All right. So, EMA, we press release already. What I'm going to say is a clarification or repetition of what has been said, but we'll try to make it extremely clear for the audience. So, for EMA, the application was filed in 2022, and then in January this year, 2024, we were invited to present our responses to pending concerns through an oral explanation. And CHMP proposed to AB Science a couple of days before the date, instead of going to the oral explanation, to submit a written response to the list of issues pending, which is very unusual, which we said in the press release. And we, of course, accepted this procedure, which gives more time for the sponsor and more time for the agency to look at the responses. So now, alors, why CHMP has decided to switch from an oral explanation to a written response news cycle, so to speak, is unknown. But if the responses of AB Science are satisfactory, there might be no need to go to the oral explanation anymore. That's the important point. So it adds literally one cycle within this phase of review. The decision, of course, is delayed and now is expected by the end of Q2 2024. Health Canada, as you know, we are also into a conditional rule process with Health Canada. And we press release that we have received recently a notice of non-compliance with rule. It's the formal letter saying that they still have concerns. And we also press release that we intend to submit a request for reconsideration. What does it mean? In fact, in the process of an approval by Health Canada, there is this possibility to ask for a reconsideration. It means that the process is not over. This reconsideration process is different from the two first cycles. Why? Because the assessors, the team of assessors, changed. Whereas in the second cycle that we have just finished, it was the same team. So now we are going to have a new assessor team. The second modification is that for the very first time, it gives the possibility to have an opinion of a panel of experts, which was not possible in the previous cycles. And we hope that this panel of experts will be used by Health Canada, but this is the decision of Health Canada. For a disease as serious as ALS, we hope it will be granted. Of course, the decision is delayed, and we've been informed that the process might take up to six months, which means that it might end now in the end of Q3 or even Q4 2024. Next slide. So we press release in detail what we think are the key major clinical objections, but also the intended arguments, I would say, possible answers from us. We thought it was important because we wanted to give to the public a good understanding of why we go to reconsideration. The reconsideration is done because we think that we have logical, credible answers to the concerns that we could not provide before. I know that some of you have asked by writing why we have not communicated those answers before. It's because we cannot. And why we cannot? Because the Canada process is working differently from the EMA or the FDA. There is a submission, and then sometimes you receive some Clarimail. It's called a Clarimail, which is a clarification email. But if you do not receive any Clarimail, then you cannot answer to any possible concerns that the agency has, and you'll discover the objection at the end. Whereas, for instance, at EMA, you have intermediary cycles where you receive the concerns, and so you have an opportunity to respond to them. So that's why, actually, it might come at the end, and then you have to engage in a new cycle if you want to respond to those concerns. Anyway, we have two cycles, and we resolved some concerns, but still there are some concerns left, and we think that reconsideration through a new cycle is useful to try to answer those concerns. So let's go into the details. The first key major clinical objections is on the amendment. There is no surprise that there has been an amendment. It's publicly known we have solved, I would say, some very critical aspects of that concern. For instance, Health Canada agreed with us that for a disease which is orphaned and withdrawn, it's not unusual to move from a phase 2 to a phase 3, which was not obvious at the beginning. Health Canada also agreed that multiple amendments is not unusual. Health Canada agreed that the amendments are not data-driven, which is very important, of course. And Health Canada also agreed, we said it in the press release, that the number of amendments we did, which is, in fact, three amendments when we transitioned from phase 2 to phase 3 is not unusual since the average of the number of amendments for pilot studies is, in fact, 3.3 according to the publications. Health Canada also agreed that the inclusion criteria for our study were very broad, and so there was a need to limit heterogeneity. And also, Health Canada agreed that in the amendment, we distinguish fast progressor from normal progressor, and we use a cut-off that, in fact, may be relevant. So all that is important, of course, in the context of trying to solve this issue. However, it remains one point. And the point is that Health Canada considers that the timing of this amendment was maybe late and maybe still not sufficiently justified. So what are the possible answers to those two sub-objections? First, we think that the amendment was not too late. Why? Because it was two and a half years prior to the study completions, but also it was not too late in terms of data accrual because only 12% of the enrolled patients could have reached the time point of the primary analysis, meaning that 88% of the data needed to remain to be acquired. And when we remove the first 12%, the study is still a success statistically, which means that the first 12% do not behave differently than the remaining of the study, the 88%. And also, since the key amendment was to distinguish normal from fast progressor, it's important to know how many fast progressor there were at the time of the amendment. Only 8 spread across three arms, which means that, of course, you cannot deduce nothing with only eight fast progressors. Also, another point is that at the interim analysis, the study was positive in the population normal plus fast. It's only because the EMA asked us to continue that we continued. There was no amendment after. We think that the amendment was justified because in distinguishing normal from fast progressor and removing the fast progressor from the primary analysis, because it was expected that fast progressor could not meet the week 48 time point for a large part of them. That was the recommendation from the principal investigators. In fact, it's exactly what happened. You know that the guideline recommends to minimize missing data at week 48. So that was that expectation. That was the primary driver of the amendment. In fact, it's exactly what happened in the study since normal progressor, in average, could reach at 25%-30% week 48, but fast progressor discontinued for more than 50%. And when you have more than 50% of missing data, it becomes extremely complicated to interpret this missing data. So these are the arguments that we would like to share with Health Canada for reconsideration. Next slide. The next slide is technical. That's why we are doing this call, is to try to explain very technical arguments that most of you might not understand through the form of the press release. And I will try to be as clear as possible so that you can share, I would say, the logic of the argument. So Health Canada said that the primary analysis was based on what they call LOCF, Last Observation Carried Forward, which potentially creates a bias. Let me explain. Last Observation Carried Forward is, in French, la dernière data avant discontinuation, the last data before discontinuation. If you consider that data before discontinuation and you say, "That's the one I'm going to use at week 48," it's going to create a bias because we are talking about a neurodegenerative disease. And so we expect the symptomatic score to decline and not to stay the same as the time of discontinuation. Okay? So that's why it might be a bias unless there is the same percentage of discontinuation as the second timing between the two arms, which was more or less the case, by the way, for our study. But still, methodologically, Last Observation Carried Forward is not the best methodology to treat the data. And alors, how do we respond to that? First, they have criticized, let's say, what we call, and it's very technical again, the linearity of the distribution of the data points of ALSFRS-R. What does it mean? It means that because there is some deaths before week 48, it is not linear. You can see that the score of ALSFRS-R can be 20, 30, 48, up to 48, all right? But when there is a death, the score becomes zero. And that creates a big distortion in the distribution causing nonlinearity. Now, it becomes very technical. When the distribution is linear, you can use some form of calculation, which is called nonparametric. And when it's nonlinear, then you cannot, so it's not recommended by statisticians, and you have to use another form of calculation, which is called CAFS, right? Now, although our distribution is nonlinear at the end, they have accepted one of our arguments, which is very technical, called re-randomization. I'm not going to detail that, which makes the nonlinearity acceptable, so to speak. It's important because it means that we are not criticizing a nonlinearity. For the ones who know very well this industry, you will see that, for instance, Amylyx was criticized on that as well by FDA in its registration process. So we have solved one of the key arguments, which is very technical. Now, we are left with LOCF. Okay? So we use LOCF, and of course, Health Canada does not recognize LOCF, but we never actually stressed LOCF. We stressed, and we want to provide this information again to Health Canada. We actually said that beyond LOCF, in the study, there was some pre-specified non-LOCF analysis, sensitivity analysis, that are successful, like, for instance, an imputation model based on cluster. F or most of you, it will not mean anything, but it means non-LOCF, and it's positive that it is significant. Then there are some additional analyses, which are even more conservative, like what we called a jump to reference. It means a penalty in case of discontinuation for masitinib, where we treat the missing data as a placebo, including not only the decline of the placebo but even the data of the placebo at the time of the discontinuation, which is a massive penalty. And we did another sensitivity analysis, which is called copying CREMOS reference. Those methodologies, which are super technical, are recognized by the agencies in the world as being very conservative and robust if successful, which is the case. The CAFS, which is a recognized methodology of calculation by Canada and by FDA as well, has a trend. Okay? This trend is T-value 0.07. It's not a win, but the study was not designed to be a win under CAFS because it requires more patience, all right? However, that is a good sign of the efficacy of masitinib. Health Canada told us that the CAFS cannot be actually considered because it encompasses some LOCF points of calculation, which, in fact, is not the case. No CAFS can be calculated using LOCF. We don't understand, by the way, why they said that, but we are going to provide this correction, I would say, or clarification in the reconsideration. So all that is very technical, and we understand that most of you could not understand the technicity and technicality behind statistical calculation to treat missing data. But trust us, the missing data treatment is paramount in registration in any neurodegenerative disease. And we think that the sensitivity analysis that we have is robust enough to convince agencies that the data are acceptable. Sorry, I have a tracheitis and a bronchitis, so if I cough, I would answer to your apologies. Next slide. So the next slide is on a third objection, which, again, is technical. What is it? It is the application of a guideline on subgroup. Most of you know that our study is positive, but in some subgroups, it's even more positive or even very strong. So we are using a guideline from EMA, which is called a guideline of subgroups, where we apply this guideline strictly, and we try to convince agencies that the product can have a reduced claim on this subset of patients but with, I would say, stronger benefits and even better safety. So alors, the point is to see if we can apply the guideline, yes or no. And at that stage, Health Canada considered the guidelines, of course, good. It's an EMA guideline but could not apply to our case. And the argument they use is that they consider that that guideline of subgroup is applicable only to subgroups that are pre-specified, which means it's already written somewhere in the protocol. And in fact, the guideline says something opposite. And we actually have literally stated what the guideline says. And it says it might be of interest to identify subgroups that have not been pre-specified. So in fact, the argument of Health Canada is contradicted by the guideline itself. So that's a point we would like to bring for reconsideration. And of course, once we have done that, which is pure methodology, we have to look at what is this subgroup. In fact, the subgroup is all patients except the one we have already lost, functions, which means motor neuron. And we know masitinib cannot regenerate motor neurons, so this subgroup makes sense. And in this subgroup, we have exceptionally strong data. The CAPS is statistically significant, the most preferred calculation of ALSFRS, but the survival is significant. And you know that in the extension phase, some placebos switch to masitinib. Because masitinib is effective on survival, apparently, the fact that placebos switch to masitinib creates a penalty on masitinib. So there is a methodology which considers to censor the data at the time of the switch. And that actually is a classic. So when we censor the data at the time of the switch to try to neutralize the penalty that we have because the placebo switched to masitinib, in fact, we observe that the additional survival is 22 months, almost two years, which is considerable in this disease. So we think those arguments are very important and should be brought to the agency for reconsideration. So I hope that those three slides, although very technical, help you to understand better why we engage into reconsideration. It's because we think it's worth doing it. We'll have six months to talk to them, a new assessor's team, and possibly a panel of independent experts. Next slide. Now we go to operational program, starting with masitinib platform. We have two platforms, masitinib and microtubule destabilizing agent. Let's talk about masitinib first. So masitinib has, in fact, eight programs active: three in neurodegenerative disease, two in mast cell disease, one in hematological disorders, sickle cell, one in COVID, and one in oncology, which is prostate cancer eligible to the Taxotere. And we'll go very shortly to tell you where we stand in each of the programs. Next slide. ALS, which is the key program among the eight programs, what can we see recently? First, we are not alone. So we observe what's happening for the other projects from other companies with other mechanisms of actions. We have seen, for instance, that Amylyx, which is a drug that has been approved by FDA, has been rejected by CHMP, so Europe, even after an appeal. We know that Amylyx has a confirmatory study which will end, will be done on which is designed on 48 weeks, whereas the first study was on 24 weeks. You have seen the impact of missing data, which is increasing with time because there is more and more discontinuation and death, which is not obvious at all to convert the data at week 24 into data at week 48. We will see what will be the confirmatory data from this program. Edaravone. Edaravone, there are two drugs, in fact. The first one from Mitsubishi Tanabe, which has been registered at FDA but not in Europe. They've been refused. There has been another formulation of edaravone, oral formulation, a second one, developed by a Spanish company called Ferrer. They have done a phase 3 for registration in Europe because, I would say, the Japanese Mitsubishi Tanabe stopped the investigation there. But their study failed with a primary endpoint at week 48. Then, more recently, there has been a competitive program led by Sanofi based on RIPK1, which is a kinase as well, which also targets microglia like masitinib. This program failed its primary endpoint, which has been released recently tofersen, it is the product from Biogen, is an antisense which targets the SOD1 mutation of this disease. It is an oligonucleotide antisense. This one failed its study in terms of improving ALSFRS-R versus control but reduced neurofilament, which is a biomarker. It has been registered conditionally both by FDA and EMA, although it's a failed study. The agencies think that the reduction of neurofilament is enough despite the fact that there is no clinical benefit. It's a little bit like in Alzheimer, where there is a reduction of the beta amyloid plaque, but there is no benefit in some studies. By the way, Biogen registered a study like that in the United States. Here, it's a little bit the same. No clinical benefit on the LSFRS but a success on the biomarker, which was a secondary endpoint. They registered. This concerned only 5% of the patients. What we can see is that besides Dr. Sen, which is very peculiar, the other programs are failed, like edaravone, like RIPK1. Amylyx, we don't know. We will see. But there is no clear winner in this and clear, I would say, breakthrough in ALS, unfortunately, which remains an unmet clinical need. Now, where do we stand with our masitinib program? Our confirmatory study is ongoing, and the study enrollment is slow and slower than the previous study, AB10015. We received many questions on that. So again, it's slow. And why it is slow? Because it is slowed down by its design. In fact, in the design, which was actually we followed the recommendation of EMA through scientific advice. They recommended to do a three-month running period. What does it mean? That for three months, the patients will take only riluzole before being able to have their treatment, which is masitinib or placebo. Patients don't like that. They want to be treated immediately with a drug and not wait three months in a disease where the median survival is only 18 months. So that is, of course, a deterrent to the recruitment. Then we chose moderate in severity patients because you have seen that and you know that the benefit is higher for those moderate. Of course, it's more difficult to recruit because there are rare ones. Also, EMA recommended not to allow, not to make eligible, the alternative drugs registered in the United States, edaravone and Relyvrio. And of course, it does not facilitate the recruitment, at least in the United States. And the fourth point is that the extension is blinded, whereas if you want to make it more friendly for the patients, it should be open label. But because EMA wants a time-to-event endpoint, a blinded extension was necessary to try to get a, let's say, a trend at least in either survival or progression-free survival. So you see, it's technical, but that slowed down the recruitment. But that has been the choice made initially. Next slide. Multiple sclerosis, progressive forms. What is happening about the landscape? First, there is only one drug which is approved, which is called Ocrevus from Roche, in part of the progressive forms, which is the primary progressive forms. There is a second form, which is called secondary. Then what? There are three drugs which are in phase 3. You have two drugs, and they are tyrosine kinase inhibitors. The first two are called BTK inhibitors, Bruton tyrosine kinase inhibitor. The two drugs, tolebrutinib, which is developed by Sanofi, and fenebrutinib, which is developed by Roche, have not finished their program, but they've been put on hold by FDA, public information, due to liver injury, which means that BTK inhibitors have at least one toxicity sign. Another drug called evobrutinib, which is developed by Merck Serono, Merck Germany, which merged with Serono, has announced its failure in a phase 3, not in progressive form but in relaxing forms, which does not give a good signal of efficacy of these Bruton tyrosine kinase inhibitors. Masitinib is a challenger. So some analysts or journalists said the situation potentially paves the way for masitinib to emerge as a standout oral option. We completely agree with these journalists. We think that there is a scarcity of potential drugs in progressive forms, and masitinib has its own merit and not the problem that we see for BTK inhibitors. We call that positive read-across. So we, of course, focus on our development, but we are also observing the development of others. And when the programs' alternatives do not match their expectation, it might be positive for masitinib. So where do we stand with the masitinib phase 3 program? As you know, the phase 2 B was positive and published. Confirmatory phase 3 is authorized by FDA and key European agencies. And we expect initiation of this program in 2024. And I will tell you how. With partnerships, of course, it's public. We announced the strategy, and I will come back to the partnership later. Next slide. So the next slide is on Alzheimer's. What needs to be known is that masitinib stands out because it's positioned in a part of Alzheimer where there is nothing, which is the mild and especially the moderate forms of Alzheimer. In fact, you have three forms of Alzheimer, which are classified by their, I would say, advance in the disease. The first one is called early Alzheimer. The second one is mild, and the third is moderate. And there is even a fourth one which is called severe, but nobody is going there with any drug. And that is measured by a scale called MMSE. Okay? So what do we have? We have two drugs which have been approved by FDA and are antibodies, one belonging to Biogen Eisai, the other one to Eli Lilly, and they are in early Alzheimer and a part of mild but not all of mild. And these are the winners. But there are others, lots of others with the same mechanism of action that failed. Recently, one called gantenirumab. In fact, two drugs from Roche failed recently in Alzheimer's in this position. You have different strategies. You have the antibodies, again, the beta-amyloid plaque. That's the one I just described. And some are approved, but not all of them, of course, because they failed. There is another strategy targeting the tau protein. You know that there is also aggregate of tau protein. We don't have data yet of late-stage phase 3. And then there is a third avenue, which is our avenue, which is to target the environment of the neuron and to target the immune response and, in particular, the neuroinflammation. Here, you have two drugs. You have a drug from Anavex, which is in early Alzheimer's and mild but not in moderate. Then there is our drug, which is in mild and moderate. So that's the picture. When you look at that, who is in moderate? Only masitinib. Who is in mild? Lots of people but not exactly at the same positioning of the mild. So masitinib stands out as a potential drug for moderate Alzheimer's and also full mild. Where do we stand in our program? The phase 2b was positive and published. The confirmatory phase 3 has been discussed with scientific advice. By the way, it was the same for MS and has been authorized both by FDA and key European countries. And we expect initiation in 2024 with the same strategy of partnership that we made public. Next slide. Next slide is on mastocytosis. Mastocytosis is a long, well-known indication, of course. There has been some novelty here. In fact, there are two companies. One is called Blueprint Medicines. The other one is called Cogent. They are developing KIT D816 inhibitors because in mastocytosis, you have this mutation, which is the driver of the activation of mast cells. Masitinib doesn't target this mutation. It targets other kinases but with efficacy as well. So those compounds are different mechanisms of actions. It seems they have benefit on different symptoms of mastocytosis. KIT D816 is good on urticaria pigmentosa, which is the spot dead on the skin, and GI symptoms. Masitinib is more effective on neurological symptoms for a distant flush. So to some extent, they might be complementary. In terms of efficacy, you can see a difference between the response. The response is not defined the same. 50% for the competitors, 75% for us, published. The difference between the treatment and the control is 15% for avapritinib, 12% for masitinib, which looks about the same. It's not the same endpoint, though. And the long-term safety is well-known for masitinib, less well-known for the other ones. And it's technical. But when you press on the mutation, the KIT D816, there is a risk to emerge clones. Since we do not press on PIT816, there is no emergence of clones possible with masitinib. For the other programs, we don't know yet to be monitored. Where do we stand? We're still there. We're doing the ongoing study. Okay? If we take some more time, of course, we're still there. And we have a phase 2 in MCAS, which is another subset of myeloid disease where there is no mutation. We are doing a phase 2. And if the phase 2 is positive, we would continue the program. So that myeloid diseases continue and the appearance of competitors makes it more challenging. But still, the position with masitinib is differentiating from the other ones. That's the point. Next slide. The next slide is on sickle cell disease called in French, drepanocytosis. Drepanocytosis is a hematological disorder with some mutation of the hemoglobin gene, which leads to problems that can go the patient does not produce enough hemoglobin and can die from them in severe forms. And the lifespan there is one third of the patients, they have severe forms. And these severe forms, they die before in average, I think they die around 50. So they shorten the lifespan considerably. It's the broadest, I think, genetic disorder in the world. Now, what's happening in the landscape? You have two companies which have used the latest technology called CRISPR that you have certainly heard of. They have come with two products which are very effective and cure the patients, which is beautiful in the field of the industry. Still, there are some problems. The problems need unique donors. The second problem is that sometimes toxic because there are side effects. The very key problem is that they price it at a price of $2 million or $3 million because it's a cure. Based on that, analysts estimate that the number of patients insured enough to pay that would be 5%, probably even less in Europe, which is a progress, of course, but does not solve the issue for all the patients. You have new drugs which have been registered, and we have given there some. All of them are used but not massively, like less than 5%. I do not get into the details of each of one. So it leaves room for some. Our co-founder and key scientist, Professor Olivier Hermine, who is on the call here, he has discovered something that we patented with him showing the involvement of mast cells in what is the main problem of this disease, which is the vaso-occlusive crisis that can kill ultimately the patients. That is new, completely new. The only product that targets mast cells in the SCD, the sickle cell, would be masitinib. It's the first one of its kind. Now, based on that discovery, we submitted with Olivier in fact, Olivier submitted with us, rather, a request for financing from the government called RHU. There have been hundreds of projects. Our project has been one of the winners, and it's been awarded by a grant of EUR 10 million, which will go to AP-HP, the Parisian hospital, who would be the academic leaders of the program, would receive a part of that budget. But the sponsor will be AP-HP. So they will implement the phase two with their team, with our product. Okay? And there will be two parts. The first part is a research of a biomarker to detect the signature of the sickle cells because maybe not all patients will have sickle cells involved that would lead to or force a vaso-occlusive crisis. And then we'll do a part two, which will be the phase two by itself. And you know a biomarker increases the chance of winning and being registered ultimately. Let's look at the product from Biogen called tofersen in ALS. The good news is that once this phase two is finished, AB Science, we're free to continue the development, of course, there will be a licensing with AP-HP. We'll let them part of the job. But we can continue, and this is fully financed. So that's the message for sickle cell. Next slide. Next slide is the oncology. So we did a lot in oncology to explore with masitinib. At the end of the day, we selected the data showed that the most promising is metastatic prostate cancer, eligible to do Taxotere. And in that setting, there is an unmet clinical need because there is only the Taxotere, and no drugs could combine with the Taxotere to improve survival or progression of survival in metastatic prostate cancer. There are lots of drugs, but they are positioned before the CET XL in what we call prostate cancer metastatic, sensitive or refractory to hormonal therapy but not advanced enough to be eligible to do chemotherapy. When it comes to chemotherapy, only the CET XL. And masitinib stands out because we succeeded in the phase 3. That's not enough to register. We need to do a confirmatory phase 3. Now, what we did is that we asked the scientific advice through EMA and FDA. We received it. And we validated the primary endpoint. But most important, we received the information that we don't need in the confirmatory study to prove benefit on survival. That is important part because if we had, then we need to recruit then it's more risky, and we need to recruit more patients, and the study will take more time. For all drugs that are before the CET XL, you need to provide evidence of benefit on both the PFS and the survival, which is challenging. Here, you just have to do radiographic PFS. Knowing that, we think the confirmatory study has a chance of success, which is higher. So we want to do it. Now, where do we stand in this program? We plan a submission for authorization in the coming months. And so we expect we have authorization in 2024 and to be able to start this program in 2024. Next slide. Next slide is COVID. So as you know, we have received a grant from the European Investment Bank to develop one study in COVID, which is the first one, which is patients suffering from COVID and being hospitalized and in need of oxygen, having moderate or severe COVID. In fact, we did two. We did this one, and we did a second study for patients who are infected. We use masitinib as an antiviral. But the patients are not necessarily hospitalized. They are in ambulatory status, or they're hospitalized but not in need of oxygen. But all of them have a comorbidity, which is a risk to develop severe symptoms. So we did two instead of one. As you know, it's much more difficult to recruit. In fact, there were lots of cases that, no, it can by waves. So it's super difficult to recruit patients. However, we are going to finish those two studies late, of course, but we're going to finish those studies. We're going to read them in 2024. We have to thank the European Investment Bank. People might think that it's over. I would disagree respectfully with this statement because it might come back. It might come back not as COVID. It might come back as another disease but a viral disease. As you know, masitinib is published as a broad antiviral activity. Even if it's not hot anymore, as hot as it used to be, it might come back. It's important to have antiviral in your portfolio that in case viral infection come back, might be useful for the next disease to come. There will be next disease to come. Even if it is late, not late for potential new disease that can strike on the planet anytime. Next slide. Alors, key, of course, is masitinib partnership. Next slide. Alors, as you can understand, this is something which is very sensitive and covered by confidentiality agreement with everybody. So I cannot tell you a lot, but I can share with you some information. The first information is that we're into discussions, and the discussions are ongoing. The second information I can share, which is very important, is that we expect the process to be completed by 2024, which was the objective. We started in 2023. We said it would take 12 months to 18 months. And we hope to complete this process by the end of 2024. Now, very important, those discussions that we have today are with companies which do not condition the signature of a binding offer to a positive opinion from EMA and Health Canada on the conditional approval of ALS. That's important to say because we have, of course, validated with them that they do not invest for an opportunistic conditional approval that might take two years or less. And we need something like a more long-term view. Okay? So we carefully watch that with them. We can tell you that we are serious, and they are serious about that. The risk is neutralized. Now, the scope of the license, which has been one of your questions that I have read that you have, is on alors, it's not only on neurodegenerative diseases, but it's mainly on that. Okay? And among those diseases, it's on ALS included. Alors, we said in the strategy that we expect a license, we want to focus on ALS, and we expect partners to do bigger diseases like MS and Alzheimer's. True. But the partners are interested by ALS. And it's very logical because it's the most advanced program. So we have to report here that the license is likely to be on NDD and likely to include ALS. Is it a problem? No, it's not a problem. It's just the way it is. Okay? So you know that. That's the only thing we can share with you. But it's already a lot because we have not communicated a lot because we have this confidential agreement. The rest will come in due time. And when it comes, it will be the first one to know. And everybody will know at the same time. Next slide. Next slide is important for the partnership and for the future of the masitinib. We want to develop a new formulation of masitinib, which is a liquid formulation of masitinib for two reasons. The first reason is because after some time, patients cannot swallow the tablet anymore. And it's a problem in our clinical studies because they cannot benefit from masitinib. Right? And it's a problem for the patients because they would like to continue, and they cannot. So a liquid formulation will solve this problem. The second benefit is that we have different possibilities of success, and the price will be different. We know the price of Relyvrio is $140,000 in the USA, whereas the price for a multiple sclerosis drug is $80,000 in the USA. The price for an Alzheimer's drug is $30,000. We know that because some of the products are registered. How to manage that with the same formulation is very difficult. But if we have two different formulations, one specific for ALS, which would be the liquid formulation, then we can maybe certainly maintain high price. Okay? And not have to reduce the price because the tablet will be for ALS and MS. That is logical, and that is important for the partnership. To do that, we need to do a bioequivalence study and develop the liquid formulation. So it's an effort that takes years. Next slide. Then we go to the second platform, the microtubule destabilizing agent called MDA, to use an acronym that will simplify the communication. Next slide. We have two drugs in this second platform. One is an injectable and is developed in hematology, in particular in acute myeloid leukemia. The other one is an oral formulation that is developed and will be developed in oncology. Next slide. T he important thing to understand is that we have strong and valuable differentiations through this program on three things, which are technical, but I try to make it clear. The first one is that the microtubule destabilizing agent, and we have, it already exists. There is Taxol, Taxotere, vincristine, vinblastine, etc. Those drugs are metabolized by an enzyme produced by the disease acute myeloid leukemia, which is called myeloperoxidase. Because of that, the drugs have reduced efficacy or no efficacy at all. Now, we report that 8939, but also the other drug, which, by the way, has the code name of 12319, those drugs are not metabolized by this enzyme, making it possible for the first time to use a microtubule destabilizing agent in AML. It has not been tried effectively so far. So that's a key advantage. Second advantage, you have heard of a terminology called multidrug resistance. What is multidrug resistance? It's the ability of an oncogenic cell to wash out the drug from the cell because nature has had millions of years to invent some ways of surviving. And how does it does that? It does that through a protein called P-gp. And so this P-gp is produced this protein is produced by the cell itself. And the more you put the chemotherapy, the more the cell produces P-gp. The chemotherapy will bind to the P-gp, and the chemotherapy will exit the cell, will be washed out, reducing the efficacy of the chemotherapy. Now, we report that our drugs do not bind to P-gp, and they can avoid drug resistance. What does it mean? It means that we can treat with our drugs refractory or relapsing patients, which are the ones who have the utmost medical need in this disease. And the third differentiating advantage is the synergy between our drug and another drug registered called Vidaza or azacitidine. That's on the spot that you can see on the diagram below. And the red is, the black is no treatment. So you see a lot of oncogenic cells. The red is our drug. The green is the Vidaza. And the super green on the right-hand side is, in fact, a combination. You can see there is no more bad cells. It kills all cells. This is super synergistic effect. Vidaza is registered. It's registered for patients who are not eligible to high-dose chemotherapy. It's almost 50% of the patients. So we expect our drug to be developed maybe ultimately in combination with Vidaza. There is one drug which did that called venetoclax, completely different mechanism of action from our drug. They've been very successful. Next slide. Next slide is where do we stand? We are in phase 1, and there are four steps, as you can see. The first step is a treatment of three patients, the objective of the phase 1 is to reach what we call maximum tolerated dose, not to produce any efficacy, just to see what the maximum dose takes that can be used in patients. There are four steps. The first step is a treatment of three days. Three days cannot be effective. It's too short. Still, we take minimum risk, and we treat patients three days, and we try to reach the NTD. Then once we reach the NTD, we actually reduce even the dose. But we go to step two where we treat patients 14 days. Then once we reach the NTD in 14 days, we go to step three, which is the combo, as we have seen because of the synergistic effect. And we do also 28 days in parallel. So there are four steps. Now, the news is what? We've finished step one. And in fact, I'm on our protocol because we plan some doses based on the animal that were too low. And the product was not toxic enough, I would say, to reach the NTD. And so we had to find new dose and took more time than expected. But we have finished step one. And agencies, key agencies, already did that. And they gave us green light to go to step two. Now, we're going to start step two. That's where we stand. And we expect to finish the phase 1 by the end of 2024. And then, alors, we do not expect efficacy from that, maybe some signs of activity, but not efficacy demonstrations. Once we finish that, we'll see if we prefer to go combination with azacitidine or single agent or both. Then we will engage into phase 2. And in phase 2, we'll try to design the phase 2 to be compliant with a possibility of fast track approval that FDA offers. Now, the two additional information I'd like to share with you is what? Our product, which is a cytotoxic, it's a chemotherapy. We observe that the neutrophils, which are key white cells, are not reduced by our compound. So it's not so cytotoxic. And in fact, neutrophil counts are stabilized or even increased afterwards, after a few days, and even at day 28. What does it mean? It means that first, we don't observe high toxicity hematologic for our product. But it means that we could use our product maybe in a chronic fashion, not in an acute, I would say, two weeks, and then we cannot go on, but chronic. And if we can go chronic, we can treat another disease which is close to AML, which is called high-risk myelodysplastic syndrome, which gives another opportunity for this drug. So that's important. And we have also observed a response in the MECOM rearrangement. What you have to know is that it's a very negative prognosis where people die very quickly. And here, we had an unexpected response, which is always a good sign, of course, to have in your development. Next slide. Next slide is intellectual property. It's important because we know masitinib is an old product now. But it has been rejuvenated by use patent strategy. And this use patent strategy gives us a lot of time to develop our indications. It has been, by the way, granted in ALS. It's not even pending. It has been granted in most of the countries. And ALS is protected worldwide up to 2037. MS will be protected until 2041, Alzheimer's 2041, mastocytosis 2036, sickle cell, where we patented as well, 2040, and prostate, metastatic, 2042. Plenty of time to develop the drug and sign partnerships because they look at that, of course. Plus, we have a fundraise status in ALS, but also in mastocytosis and possibly in sickle cell. Next slide. And the patent for the second platform is 2036. But we took patents for the MECOM and other rearrangements that could protect in 2044. And I think we finished there. Yes. So it has been long, but I think it was necessary. You have a probably better picture than before. And it's global. You can see what's on the highlights. I just would like to summarize in one sentence the milestone expected in 2024 for the conditional approvals, both EMA and Canada, which will come end of first semester for EMA and end of the year, I would say, or Q4, end of Q3 for Canada. And we are doing everything to get registered. And we know it's difficult. And we know it's technical. But it's the way it is. And the second milestone is a partnership that we're working on very actively. The rest continues. And with the partnership, we'll continue all programs that were described in this presentation. Thank you for your listening. And I know you have lots of questions. So you might have to stay another 30 minutes. Laurent is going to take, hopefully, most of the questions. I would like to know if Olivier is there in case there is a question for you, Olivier. Olivier, are you there? Yes, I'm here. Okay. Excellent. Everybody knows Olivier. Thank you, Olivier, for your presence. I know you're very busy. So Laurent, first question, I take them in the order received. Is masitinib ready for industrial production? How long will it take after granting of marketing authorization? It's an important question for partnership. Yes, we're ready for production, for instance, in case of registration in ALS. However, as you have seen, we have a liquid formulation in mind, which will take two years. So we're not ready for liquid formulation. But we're ready for the other formulation. You had supply issues with Masivet in 2022. Is this resolved? And is there a risk of occurrence of such a problem with the potential marketing authorization? Okay. So we have not talked about all of that of the situation in Vet. We are continuing to commercialize in Vet, not the key, of course, but we are doing it in mast cell tumor. So yes, we have the shortage because of an unexpected problem with our supplier. However, that was purely on the Vet. The question, we never had shortage in humans. And of course, we'll do everything to avoid any shortage with the partner. Now, the question, I'd like to make one precision. Are we going to license the production of the masitinib? The answer is no. In case of partnership, we keep the production even if we have sourced it, and we sell it, which is a stream of revenues. So we'd better be good in production, as the question said. It was a good question. Next. Is the risk related to nitrosamine fully under control? O kay. So nitrosamine, we publicly shared this risk that it was a guideline coming from EMEA, which is new. It's not a problem on masitinib. It's a guideline. So they have to answer the question. It took us time to answer the question because it took us new little studies to do. Whether it's satisfactory or not, I cannot tell you because we have to wait for the end of the process. But from our perspective, yes, we had the answers to the questions. Last year or recently, you downsized the staff at AB Science and then reducing headcounts. Have you completed this process? Y es, it has been completed. We also publicly inform our change of strategy by saying that we go for licensing and that we will concentrate with our own money on ALS program and the second platform. And then given that new strategy, we would restructure the company to try to be more lean, which we did. It was tough to do, but we did it. And it was implemented at the end of mid-year last year, which has a benefit, which is the reduction of the cash burden. You have financing until end 2024. With what financing will you carry out the development in 2025? I t's a wonderful question. So Laurent, it's your jurisdiction. You might want to answer that question. For the second part of the questions, we are looking for partnerships, as you know. So partnerships can bring money, of course. And this is how we intend to continue. We can also raise money. But the partnership is there in 2024 to solve this problem. Now, how much money do we have, Laurent, if you want to respond to the question? I think we met some public announcements on this last year. Well, last figures we provided were when we released the accounts. As of June 23, we had EUR 14.8 million in cash. We expect to receive research tax credit. The outstanding amount prior to 2022 is EUR 11.1 million. The estimated amount for 2023 to be received in 2024 is EUR 2 million. As we have indicated in the past, we have reduced our cash burden. We approximately spend EUR 1 million per month. All right. We can refer you to the previous communication we did on this topic. You can work out the numbers easily to make your projections. Next question regarding the approval process with Health Canada. Health Canada is rejecting the application currently based on information which are known since the beginning of the application. Why did it took you so long to clarify those points? It's a good question. In fact, in the two cycles that we had, we solved problems. It's not visible. But I tried to explain in the first three slides. For instance, in the amendment, there were six or seven questions. At the end, there are still two remaining. But there were more at the beginning. The two remaining problems still hold. But we did it in the previous cycles. So that's what we did, plus some other questions that were solved, of course. But typically, you receive lots of questions. You reduce them. It's only when at the end there is no major objection that you are given and granted the conditional or an approval. That's how it works. So, let's try to take an analogy. Where do we stand now? If there are three possible steps, and there were three, okay, we are at the end of step two. It's two-thirds of the process, which has elapsed. Now, we engage into the third one, right? So it's not over. Remember, Amylyx we had a no at the end of the process of the FDA, and totally unexpectedly, had an extended thing where they finally got it from the FDA. So you see, ALS, difficult to register. We know that. If it takes another cycle, it takes another cycle, all right? And we will go through this other cycle. Excusing the real diseases, why not create a clinical partnership for one disease and commercial partnership for all the others to keep the most value? Alors, in the past, we mostly said that one partner is likely because it's difficult for pricing reasons. The information we delivered tonight that we are going to have two formulations now makes it easier to have potentially different partners. So that's one point. We can also have partners by regions, which are different, of course. So yes, it is possible that ultimately, we might have more than one partner. Could you clarify again the position from Health Canada on the distinction between normal and fast progressors? Can you repeat the question? Sorry. Could you clarify again what is the position from Health Canada regarding the distinction between normal and fast progressors? Health Canada told us that now they more or less agree with the fact that we have introduced an amendment trying to distinguish and sequence the analysis on the basis of fast progressor versus normal progressor, which at the beginning was not so clear for them, okay? So there is an interest to what they call dichotomize but sequence and remove the fast progressor from the primary analysis because they say it's heterogeneous. And, being heterogeneous is one thing. Saying that the fast is a logical or acceptable population to remove is another thing. But now they agree, okay, on the basis of the data that we provide to them. And then we have to agree on even the cut of fast because there was no clear consensus on how to define a fast. They agree now. Before, it was not so good. But during the cycles, we had opportunities to defend this position. So it's no more that. It's only it's late. But you have noticed, it's late, but it's not data-driven, which is kind of contradictory. If it is not data-driven, why late is a problem, okay? I don't know. But we will see by responding to this point into a reconsideration process. Next question. Health Canada has refused the statistical analysis for the clinical data. Will EMA take a different position on this technical issue? F irst, we have not shared with you with the same precision. We have not shared at all with you the objections of EMA. Why? Because we are into the process. So we don't have even the objections. We have to respond and we'll see. Let's wait, okay? We're not at the same level of the process between EMA and Canada. Now, your question is, in theory, EMA would have the same argument technically on how to treat missing data at cut points. The answer is no. I already explained. Canada is very much like FDA. They first look at the distribution of the LSFRS dataset. If it is nonlinear or nonparametric, which is the case, they would say, "Oh, but I'm going to look at only at CAPS." Here, we have more flexibility because we convinced them that linearity has not been violated. I tried to make it clear. I'm not so sure I was that I was clear enough. But so it means that in our case, they are not going to rely only on CAPS. That's what it means, which is good for us this way. And they have an argument on LOCF, but we have many other measures than LOCF. Now, that's Canada. Then what is the practice for EMEA? They don't care about enfin, they don't care. They don't ask CAPS. They look at it, but they don't ask for it. They ask for a penalty in case of discontinuation for your product. That's what they want for you. A penalty in case of discontinuation for your product. And that's their guideline. So definitely, yes, we have discussion with EMEA on that point. Definitely. That's the only thing I can share with you. We have a question regarding AB8939. First signs of activity were detected compromising with some results promised by end of 2023. Now we understand that you do not wait anymore for efficacy on step two, but step three in 2025. Okay. we should not over-expect from phase one. Phase one design is not to deliver any efficacy. Signs of activity, but not efficacy. It's not a design to demonstrate any efficacy. For instance, if some patient respond, we are happy. But we cannot say the product is effective at all, okay? That's only phase two or phase three that can say that. But still encouraging, of course. And we are always happy to have some signs of efficacy. And we have one in the MECOM, as you have seen, which led us to take it happen. Now, we have those signs. It's encouraging. Let's be modest. Now, when do we finish phase one? Yes, it's not in 2023. It's in 2024. Why? Because we took more time since the product was not, as I said, to kick enough and not reach the MTD, okay? So we had to increase. You also have to know that we go very slowly, almost one by one in terms of the patients because we minimize risk for the patients. It's a phase 1. It's a cytotoxic. It's not cytostatic. So it takes what it takes. So far, so good. We have finished step one. Now, it's going to accelerate a little bit now that we have some measures of the maximum tolerated dose. Now, we are just going to add a number of days of treatment. That's relatively the same dose and combine with azacitidine, which is another thing, okay? But all in all, phase 1 should be finished by the end of the year. I think we are reaching the end of the questions. Are you waiting for response from EMA and Canada to sign a license? That's the question I already answered in the presentation. We anticipated it. No, the answer is no. And a license, if it is MS and Alzheimer's obvious. But if it is ALS, is not impacted by the decisions, positive or negative, from both Canada and Europe. And that's good news because we are clear about the strategy. Any other questions, Laurent? I think we covered all topics. All right. I hope that this presentation has given you first a more, I would say, integrated vision of the company. We have 10 programs. Some are late stage. That's where we stand. We have two innovations, which can be very beneficial to the patients. We treat a medical need. We are not fast follower. We are front-runner in innovation. The other companies and some very big have spent EUR billions. And they have not been able to find a cure or even make significant progress in the disease that we try to treat. So masitinib remains competitive, even if it is slow, because, one, the strategy is good. And there is no better in Alzheimer's, in MS, in ALS. We are not seeing things breakthrough emerging that would outdo completely masitinib. We are not seeing that in none of the indications that we are pursuing. The new platform is totally innovative, as I tried to convince you. We are going to continue those 10 programs. They are extremely valuable. We cannot continue alone. That was a clear strategy change that we informed publicly last year. We are executing this change of strategy next time, okay? We expect this change of strategy to be implemented and finished by the end of the year. We are into volatility because of two conditional rules that are everything but obvious. If you have not tried it, most of you today would have reported to us that we have lack of courage, strong data, and we will not have dared. At least keep something in mind. This is due to the patients. If we had not tried, it would have been really detrimental for the patients. I hope it will be a win at the end of the effort, okay? We are doing the job very seriously. The data are good. It's difficult, true. We have not chosen the easiest indications in the world. It takes volatility, but we will finish the job. Now, I would like to. I know Olivier was there. Olivier, are you still there? Yeah, I'm still there. Alors, thank you to have stayed so far. Do you want to conclude? No, I think it's very important to know that what we are doing is based on very strong and robust science. And as you know, clinical development is not always very easy. But clinical results are also in line on what we are doing in preclinical and on basic science. So I'm very confident that these drugs and all of the mechanisms that we have discovered are very new and very difficult to be acceptable by health authorities because we are far out through the science. But I'm very confident that we will succeed, hopefully, soon. Thank you, Olivier. You have inspired us from the very beginning. We just follow you, okay? Thank you for the audience to have stayed extended time. Hope it helped you. Thank you. Thanks.