Ladies and gentlemen, welcome to the AB Science Web Conference. I will now hand over the call to Alain Moussy, Olivier Hermine, Laurent Guy and Ivan Pican. Go ahead. Thank you. Good evening and good afternoon. This is Alain Moussy, CEO of AB Science. With me this evening there is Laurent Guy, who is the Chief Financial Officer of AB Science and Professor Olivier Hermine, Chairman of the Scientific Committee of AB Science. The topic this evening is to walk you through the recent news on the recent Health Canada authorization to file masitinib in the treatment of ALS under the NOC/c procedure. To walk you through the different updates across this indication, the masitinib program and also the AB8939 compound program. Naturally as usual, I will deliver a presentation and after this presentation you will have the opportunity to ask questions either by oral or by writing. Let me kind of share the disclaimer and then we can enter into the first part of this presentation, which is a presentation description of what it is this NOC/c procedure that has been recently authorized by Health Canada for masitinib in ALS. Next slide. Hello. What is NOC/c? Compliance with conditions and what are the criteria? The market authorization under the NOC/c procedure allows Health Canada to provide earlier market access to potentially life-saving drugs. The NOC/c status eligibility is restricted to new drug therapies intended for the treatment of serious life-threatening or severely debilitating disease. For which there is no alternative therapy available in the Canadian market. Where the new product represents a significant improvement in the benefit-risk profile over existing costs. It is very important to get the pre-assessment, which is performed by an executive testing committee. It is necessary before being granted authorization to file under the NOC/c policy. If granted, this NOC/c authorization to market comes with conditions. Such conditions will be discussed during the procedure with Health Canada. Next slide. What happened is that Health Canada has done a pre-assessment and concluded that masitinib fulfills the criteria for filing an advance authorization under the NOC/c policy. The pre-assessment was made based on the pre-submission data from clinical trials, including efficacy data, the study AB10015, the long-term survival data that was acquired after 25 months of follow-up from diagnosis and also safety data concerning masitinib. The position from the committee from Health Canada discussing committee was that Health Canada considered that ALS is a serious life-threatening and severely debilitating disease with a median survival of two years. Health Canada considered the promising evidence for masitinib at the dose of 4.5 mg/ kg per day when added to riluzole therapy in the treatment of ALS. We just quote a part of the letter that we received from Health Canada. Health Canada has highlighted and considered the clinical benefit on the primary endpoint. The AB10015 reported clinical benefit on the primary endpoint change in ALSFRS from baseline to week 48. In ALS patients with disease progression less than 1.1 points per month, which we call a normal progressor, prior treatment initiations may be seen at the dose of 4.5 mg/kg per day significantly decreased decline in ALSFRS at week 48 when added to riluzole result with a different group difference of 5.4. The P value was significant, equal to 0.016. In addition, Health Canada noted a significant delay in disease progression to TFF. The secondary endpoint called TFF, progression-free survival was defined as the time to death or disease progression corresponding to a deterioration of more than nine points from baseline. At this endpoint, PFS demonstrated a significant delay at the dose of 4.5 of 35% in the same category of patients with a normal progressor and the P value is 0.016. This is equivalent to a PFS of 20 months for masitinib versus 16 months median for placebo. Health Canada also noted a significant advantage of 25 months in median overall survival. You see, this came from a post hoc analysis on overall survival that was assessed at the cut off as of June 2020 corresponding to the end of long-term post hoc follow-up with an average follow-up time of 75 months. This follow-up gave a significant advantage of a median of 25 months from 69 to 44 months corresponding to a 44% reduction in the risk of death p-value 0.006. It was observed at the full dose of 4.5 mg/kg per day. With 45 patients in the group and 62 in the placebo, in a cohort of normal progressor, but with moderate ALS patients. Finally, Health Canada considers that there is no need of a head-to-head comparison with edaravone therapy, so the guideline to prove that there is significant improvement as compared to existing therapy registered and edaravone was recently registered. Health Canada considers that there was no head-to-head trial to assess the efficacy of masitinib compared to edaravone, which is the result. Different institutions have demonstrated that time to non-invasive ventilation and survival probability is not significantly different in patients receiving edaravone compared to matched ALS patients on standard therapy. This is why they have not requested any data of masitinib versus edaravone therapy. We wanted to share the key considerations both by Health Canada in delivering this authorization to file under the NOC/c piece. Next slide, please. Now we would like to walk you through the process and the timing. The final decision of Health Canada is expected by the end of 2022. The first step that we take is the eligibility to the NOC/c procedure, so just being granted. We have to submit the dossier. We have 60 days to submit the dossier, and we intend to file it in less than 60 days. We don't give an exact number of days, but we'll do as quickly as we can, naturally. The guideline says that Health Canada has 200 days to review the applications with a possible hard stop, but the hard stop that should not cross more than 15 days. At the end of this 200-day review target, it could be quicker, by the way, it's the maximum. We don't push it as Canada is going to be quicker, but it's a maximum of 200 days. At the end of this process, there will be either a Notice of Non-Compliance, meaning that that product is not accepted, or the opposite, a Notice of Compliance with Conditions. From that step, the sponsor should respond in 10 days to the conditions proposed by Health Canada and then, Health Canada can issue a notice of compliance under the NOC/c policy. That's it later. If we add up all that, it is likely that we have a final answer with the precise condition by the end of 2022, and this is our target. Next slide, please. Now in parallel, we have to address and perform the market access activities so that we don't waste time and do things sequentially. It could be done in parallel to the registration process, so that we are ready to deliver masitinib to the Canadian patients after potential NOC/c is delivered. First we have to look whether we have enough product to supply masitinib to Canadian patients. We know that there are 3,000 Canadian patients living with ALS. We ensure 1,000 patients through 2025 and 1,000 patients who are newly diagnosed with ALS. We report that AB Science has already the capability to supply those 3,000 patients per year without any difficulty. We will not be delayed by the, I would say, manufacturing activities. We have the market access itself. It is to Health Canada. There are different bodies there which we could hear the acronym. We have the PMPRB for the Patented Medicine Prices Review Board. This body sets the maximum price for a new drug. This is sort of a reference not to be passed. You have other bodies called CADTH and INESSS. CADTH is called Canadian Agency for Drugs and Technologies in Health, and INESSS is a similar body but in Quebec, Institut national d'excellence en santé et en services sociaux. They review clinical and economic data, and they can give recommendations. There is another body called pan-Canadian Pharmaceutical Alliance, which helps to negotiate, in fact, and streamline the negotiation process across Canada. We have to submit a dossier to the different insurance companies called Manulife, Sun Life and Great-West Life for private drug coverage. We also negotiate with the provincial people and the agencies of Canada and also with the private insurance, just like cancer ports, and this is why it should be anticipated and managed in parallel through the registration process. Just for reference, since there is a product registered with Health Canada, edaravone IV is priced CAD 190 before rebate, which is a price for edaravone of EUR 130,000 higher in Canada. As you have seen, Health Canada considers that there is no benefit in survival for edaravone. We expect masitinib to be valued on the basis of its merits and benefits, including an additional median 25-month survival that you have seen. Next slide. The next slide is about the, I would say, following activities and commercialization strategy. We have identified a number of centers, which are reference centers in Canada, which are below 20 and located in 11 cities. At this time, we prepare a standalone commercialization strategy, which might change because we have a licensing strategy also in parallel, on a more global basis. At this time it's standalone and an in-house sales force should be sufficient to service ALS and just in Canada at this time. You can see the different locations of the centers which are located in New Brunswick, in Fredericton, and also in Quebec, in Montreal and Laval, in Ontario, in the cities of Toronto, Hamilton, London, and Ottawa, and also in Alberta, in Edmonton and Calgary, in Saskatchewan which is just before Alberta and British Columbia and Vancouver. Next slide. The next slide is the impact on this basic takeaway of an EMA, FDA for us. Following this decision, we intend to open discussion with both FDA and EMA on an accelerated approval, like a traditional approval at EMA, so accelerated approval at FDA. We need a process to show them new data compared to what they have two years ago, where we start the discussions and what we have as new data are new exploratory analysis from study 10015, in particular some statistical analysis with the jump-to-reference, which are actually conservative way to calculate missing data, while doing two to actually a placebo effect through any patients who discontinue from azacitidine for lack of efficacy of CCT. Obviously, we have the long-term survival data, which are exposed but enlightening and for instance, the mechanism of action of masitinib. We have additional safety data which we have accumulated through compassionate use, but also all types of highlights. We also have a very significant institutional accumulation of interest, which was not the case two years ago. There has been a nice publication from independent groups, academics from around the world to understand how masitinib works in this. Next slide. We would like to take this opportunity to update you on the situation with the other programs, but also in ALS from the two studies. Next slide. We start with ALS. So the status of the post-ambulatory study 019001 is that it's actively recruiting everywhere in the world. The primary endpoint is the change in ALSFRS at week 48. To be precise, at week 48. The enrollment target is 550 patients. We actually have three arms. An arm which is 4.5 mg which has been effective in the previous study. Hybrid III design to optimize the tolerability and minimize discontinuation, and also a higher dose that has never been tested in ALS, which is reasonable, let's say, to expect a benefit to survival. This has been of course validated by authorities, the FDA and EMA. We remind you that two publications have been done. The Phase IIb/III results, AB10015 has been published and also the long-term survival, which has been key in the analysis of Canada. The impact of a possible registration in Canada on the timing to finish the study should be marginal. Of course, Canada is open, but we expect that in case it's registered, group of patients should be close to the end or finished, and it should be limited in time. Now, in terms of market and competition, this is what we observe. There are two registered drugs, as you know, riluzole and edaravone, the intravenous version, and two in development in late stage. Likewise, for ALS, you have a product from Amylyx called AMX0035, which also is under registration process in Canada, also with FDA and EMA. Edaravone in its oral version with a bioequivalence study, which has been done by Mitsubishi Tanabe in an effort to register the oral version of risdiplam. There is, of course, competition, the benefit of the patients we expect and the targeted number of patients has not changed and is estimated to be 30,000 patients in Europe, 20,000 patients in U.S. This is, of course, with new products increasing survival as long as they will be followed as an extended survival, the targeted number of patients should increase. To ensure to anticipate frequently asked questions about compassionate use, we will start compassionate use if not possible in the different also because it would put at risk on the confirmatory study, since patients would prefer to go to compassionate use rather than participate to our confirmatory study. We have to wait until the last patient start visit because then the enrollment quickly is finished. As long as the patients are on the treatment, they would prefer to go to compassionate use and to take the risk of the placebo. There is one chance in three to have a placebo in our study. For compassionate use, we have to wait a little bit. We don't say it's impossible, of course, but we have to have to do it in a timely manner, in an effective manner. Next slide. Next slide, I would like to give the key data of our study, fine, and we think this is the standard practice for the patients. We know it's an exposed data, but it has to be there because it's a very long follow-up of 75 months. As you can see on this slide, the data only shows distinguishable differences early and continues to differentiate. There is a huge benefit of 25 months for the patients taking masitinib. Although after a while, patients could crossover from the placebo, and they could take masitinib, which would penalize the benefit for masitinib all along. It's placebo and masitinib. Despite the possibility of the patients taking masitinib after some time, still we have a benefit that we observed. Provided that the patients take drug early enough, what we call the moderate patients, before they become severe. We extend that because masitinib has not the capacity to regenerate the motor neuron, but to protect the function of the motor neuron rather, and to slow down the disease progression. Even if early patient at the time of diagnosis, maybe advanced, we have some patients who are collapsed. It needs to be proved of course in a Phase III. Next slide. Next slide is the other. Hello. I have to report that the key, the core of the program of masitinib, after we address FTD-3, is clearly a neurodegenerative disease, with what we call the trilogy ALS, progressive forms of MS and Alzheimer's, where in this disease, masitinib has efficacy data at the same dose of 4.5 mg per day consistent. We intend to focus on these three diseases of course, which we think brings maximum benefit and maximum value to the program. The second indication is progressive forms of MS, both primary and secondary inactive, and secondary inactive forms, not secondary active forms, because there are two secondary progressive forms of MS. We have launched the confirmatory program. This confirmatory program we announced has been already authorized by ANSM to complete the confirmatory for some reasons. In fact more, we're not announcing them one by one. The recruitment is imminent. The primary endpoint will be EDSS progression over 96 weeks for all patients minimum. We intend to enroll 800 patients. Those with the one arm which is the masitinib 4.5 mg titrated, actually participants in the first study where it was flat. We take them flexibility, the masitinib with the 4.5 mg titrated. The publication of the first study has been completed as well. Everybody now can access that, which is always nice to have because it's a review, of course, and publication. In terms of market and competition, this part of multiple sclerosis progressive forms is now more and more competitive. There is one drug registered called Ocrevus from Roche/Genentech in the primary progressive form, but not in the secondary progressive forms. There are four drugs at least in late-stage development, all BTK inhibitors, which target microglia through BTK likewise masitinib, but masitinib has additional astrocytes. We do believe that the crosstalk between astrocytes and microglia is key and differentiates masitinib from other options. It's not the same strategy, although overlaps. It's going to be interesting to see the outcome of those five studies. The one of Sanofi about Biogen MS, if they're BTK inhibitors and the one from AB Science masitinib. The market is significant with 500,000 patients in Europe and in the USA. Next slide. It's a visualization of the fact that there is a clear unmet medical need. As you can see only one drug in primary progressive forms of ocrelizumab from Roche Genentech, but none in the non-active secondary progressive, which represents the largest part of the project and all other drugs being registered in late-stage for active secondary progressive. Clearly, the strategies developed for that community has failed in progressive forms and we think masitinib through microglia and probably mast cells as well. Next slide. Next slide is the key data coming to us for study. On the left-hand side, we remind that the primary endpoint was change in EDSS, which is not an endpoint considered for registration, but it's an endpoint which is logical for PPMS to try to have with fewer patients a sign of efficacy which we have, but you can see the two curves are clearly differentiating. The placebo is actually increasing in terms of PHF, which means an increase in handicap, whereas with masitinib, it flattens and so there is a clear difference between the two purposes which enables us that the study was successful, and there is a first signs of efficacy in our study. What is very important for the agencies is the data on the right-hand side, which is a classic EDF expression confirmed at three months, where we can also see that the curve differentiates between masitinib and placebo. The P value is not significant, but the study was not designed to be significant at the secondary endpoint. However, the hazard ratio is a reduction of EDSS progression by 37%, whereas the only product registered in primary progressive forms has done a risk reduction of 25%. The 37% risk reduction applies to both primary progressive patients and in active secondary progressive, we don't see any difference in risk reductions. I think it's quite consistent with masitinib. If this data we can confirm in a confirmatory study, which means that we could register with masitinib but in the two progressive forms, and also that we will need probably fewer patients to demonstrate efficacy. This data is pivotal, needs to be confirmed. Of course, that is encouraging. It is on this basis that we launched the Phase III. Next slide. Next slide is the Alzheimer's disease, which is the third neurodegenerative disease core program of masitinib. The confirmatory study still needs to be launched, so it's in preparation. We expect to initiate it as soon as we can in 2022. The primary endpoint we follow, of course, the guidelines, which is to have a significant statistical difference with the placebo on two clinical endpoints. One with COG to measure the cognitive impairment, and second, ADL, which is to measure the daily function of the patients. We have not launched it yet, but we plan to enroll around 100 patients, probably, to be confirmed. We will choose an endpoint of 24 weeks because it has been the endpoint of Phase II, and also the Phase IIb/III. We don't want to change and take risk, even if the level is more minimum as symptomatic and not a disease-modifying level. This is preferred not to take risk. Although this study will have the ability to test also an endpoint at 48 weeks, which will be only secondary. If the study hits the two targets, then level will change and will be disease-modifying. We will focus on one dose, which will be masitinib titrated again, which was not the case in the first study. Again, it's optimization and therapy ability. The publication of the first study is pending to date. Market competition, but you know, like me, that aducanumab from Biogen has been registered in the United States only with accelerated approval and needs to do a confirmatory study. It's not the same positioning as masitinib because aducanumab is positioned in early Alzheimer's for those with clinical Alzheimer's disease, which is not the same patients as what masitinib is trying to. This is the critical mild and moderate. The market is huge with millions of people, 5 million people considered now, of course. Next slide. Next slide is a visualization of the positioning of aducanumab versus masitinib. What we call prodromal or early Alzheimer's can be explained by a strong MMSE, Mini-Mental State Examination. When it's low, it's more severe. You can see that aducanumab is more for patients who have a high score of MMSE, whereas masitinib in its first study and in its two previous studies and in the confirmatory study includes mild and moderate Alzheimer's patients, which are the classic Alzheimer's patients, which are much more difficult to treat and to control because the disease is more advanced. It doesn't mean masitinib could not be effective in prodromal, but it's not what we have chosen as a primary target. We have to confirm with mild and moderate patients that masitinib could be effective. Again, what is important is that the primary endpoint will be 24 weeks, meaning symptomatic treatment, but with an ADAS which will go a little quicker because it's a short endpoint. Next slide, please. The next slide is the key data from the first study on COG and ADL. The first study has showed that masitinib was able to significantly improve as compared to placebo. In fact, not placebo, but memantine and all anti-cholinesterase that could be taken as background treatment. COG is an increment of cognition, so it actually increased. When you do negative, it's as compared to placebo in terms of ADAS-Cog, which is a score that means that it's a deficit from masitinib versus the placebo. You can see that there is an 18 difference of 2.15. And it is statistically significant. For ADL, the daily activity, it's known that more difficult to change than pain here. The more quickly you do, the better it is. You must increase as compared to the control. You can see there is a difference of 1.82, which is also statistically significant but only borderline significant. It's more difficult to move the ADL. In the first arm, like, it was able to do both at the same time, which is very encouraging. I stress the way we have calculated missing data. Missing data have used multiple imputation as the guideline says. We have done a sensitivity analysis where we penalized masitinib arm by imputing placebo in case of discontinuation for the most depleted patients for reasons being a lack of efficacy or toxicity. Despite in the sensitivity analysis, highly conservative, those were still statistically significant, which proves that masitinib sensitivity data is robust. Of course, we go to the confirmatory study program immediately to try to confirm that. We increase the sample size now that we know what dose is the correct one. This study is not going to be too long to complete. We will, at the end of this study, maybe six months after we finish ALS or mastocytosis. By the way, we don't give timelines for the end of the study because it depends on the speed of recruitment, and we don't want to give information to the market that could change in the future. Next slide. We move to the inflammatory part of the program, starting with mastocytosis, indolent systemic, which is actively recruiting. This is a confirmatory study which intends to enroll 140 patients on a duration of primary endpoint of 24 weeks. Here, the dose is higher with a titratable 50 mg that became titrated, which was not done in the first study. With titration, we intend to improve tolerability and minimize discontinuation with excellent data on the titration in terms of showing that this scheme protects patients from severe symptoms, for instance, which was well-known to be the characteristic of the toxicity or tolerability issue with masitinib. Here, with the titration scheme, we have a good, I would say, strategy and management plan to minimize severe symptoms and reduce really to a low percentage of the severe symptoms, which was a problem of masitinib in the history of the development of this compound. The first study is published in The Lancet, as you know. Now the competitive landscape has evolved to the benefit of the patients. Now we have to distinguish aggressive systemic mastocytosis, which is a type of cancer, where there are two registered drugs, avapritinib from Blueprint Medicines and midostaurin from Novartis. We don't compete on this segment of the disease, which is a segment of the disease. You have to know that aggressive systemic mastocytosis is 5% or less of all systemic mastocytosis, so it's really, really marginal. Not marginal in terms of high problem for patients. The biggest part is in indolent systemic mastocytosis. A lot is indolent as compared to aggressive. It's systemic as compared to cutaneous. Indolent systemic mastocytosis is the key thing. There is no drugs registered. Definitely, masitinib is the most advanced drug, as in already a Phase III study published in The Lancet. Glaxo have also got blueprint with the same product developed in aggressive mastocytosis is in Phase II, and we are waiting for the data that they will publish probably. They have also a Blueprint entered in Phase II for development with a new compound called BLU-263. Different compounds have different mechanisms of action, since the avapritinib and the other one block particularly D816V mutations, which masitinib does not. Masitinib is effective even for patients with D816V mutations by titrating the activity generated by the mutations, probably through the inhibition of Lin28. To some extent, the strategies are complementary. It's going to be interesting to see where it goes. The big plus of masitinib is the safety, long-term safety. It's remarkable that some patients have been taking the product for more than 10 years actually now in mastocytosis, which is our readout. Typically controls symptoms in patients and extension. We feel quite trusting this program in mastocytosis, which has been the regime of Evance for the ones who follow us for a long time. Number of patients. Here it's the total of the mastocytosis, but the ones that could be targeted really by the product is less. It might be one third of them because we have to restrict the label to severe indolent systemic mastocytosis. This is more indolent systemic. The severe which are the ones we target will be less, like one third probably of those patients. Next slide. Next slide is MCAS. Now, MCAS is a relatively new indication for masitinib, which has been discussed with the FDA, right by FDA actually, this study, and in Europe by ANSM. MCAS is a sort of sister or cousin disease of mastocytosis. They have similar symptoms. Except one, it doesn't have the spots on the skin and there is no D816V variant mutations. The activation of mast cells in MCAS are not very well-known. There are some publications but they are not very well-known. What is interesting in MCAS is that the number of patients is literally 10 times or more than the number of patients suffering from mastocytosis. They are fully diagnosed because they have some sort of, you know, symptoms, but since they don't have the spots, they are difficult to diagnose, especially they are concerned a lot. There are efforts from the Mastocytosis Society throughout the world to consider those patients and now it has captured the attention of the agencies in the world, and through our discussions with the FDA, we have decided to enter into the program in MCAS. In fact, some patients were severe. We estimate 10% of the patients to be severe, but there's no partition on that. Whereas there are 33% of mastocytosis patients being severe. Since we estimated there are 10 times as many MCAS than mastocytosis, the market is in fact high. Nobody knows exactly how big this market is. To register a product in MCAS, we have to do a Phase II and then a Phase III. We have decided to launch a Phase II in Europe and in the United States, where we are going to test two doses which are 6 mg/kg/day, because it's the one which is effective in mastocytosis and a lower one, because if we don't have to go to 6 mg, why we need to know. It's a dose range finding study with 62 patients which is authorized, so on the side of the agencies and the market and competition is very small. No drug registered in development. I think this is going to be the first study. One thing to mention, we did two Phase IIa with mastocytosis in two categories of patients genetically different. D816V mutations and there is a fraction of the mastocytosis patients who do not bear the D816V mutations. They are wild type. They are not MCAS because they have spots. This is the difference. We think that it goes through slightly different mechanism of actions. However, in the mastocytosis wild type, masitinib is effective and as effective in the D816Vs. This we hope is a good sign of potential efficacy in the MCAS. By the way, the FDA was quite convinced by our data. Suppose that masitinib can capture the MCAS market in the future, that would be non-negligible and not a lot of drugs can do. Just in fact, without the D816V targeted first, cannot, because there is no such mutation in MCAS. Next slide. Next slide is the three indication sets. Severe asthma, moderate to severe ulcerative colitis in adults on steroid, pancreatic cancer, locally advanced. Since masitinib is potentially effective with brain and metastatic prostate cancer plus ipi/pembrolizumab. These will be launched sequentially after we launch Alzheimer's, because we cannot launch everything at the same time. We expect to launch probably one program before the end of 2022, and the rest in the beginning of 2023. We don't give more details here and we'll come back with more news a little later. Next is COVID. COVID, as you know, we are doing with masitinib two studies. We have two studies. The first one on the left-hand side of the presentation of the slide is for patients hospitalized and suffering from moderate and severe COVID. This study that we are recruiting, the endpoint is a clinical outcome at day 15 and involves 200 patients. They are treated with standard of care which is dexamethasone worldwide. It explores two new compounds which is 0.5 mg cyclically. We expect the study results to come in 2022. We don't give any timeline because we're highly dependent on the recruitment, which is fluctuant in the different parts of the globe. It's not so easy to recruit. As you can imagine, even if you can read in the newspaper that there are still a lot of patients with COVID and some patients in the hospital. These patients in the hospital are those hospitals that are already part of other programs which also have difficulties to finish their studies. It's also obvious to recruit patients in this disease. On the right-hand side you have the second study, which is a study in ambulatory and hospitalized patients, but with not severe COVID, mild and moderate. This study has a different objective, which is to see if masitinib is an antiviral in human. As you know, there has been a publication done by the University of Chicago, which prove that masitinib in vitro and in vivo in mice is an antiviral against the SARS-CoV-2. But we don't know in human. This is why we are doing this study. This study is a small groundbreaking study that plans to enroll 77 patients and test three doses. This study is very difficult to recruit. Let me explain to you why. Because we have decided in the design to recruit patients who do not have the IgG antibodies, which means they have not been infected or that they have not been vaccinated. Most of the people have been vaccinated, and now because of the Omicron variant, are infected. Now, if we relax this criteria of inclusion, it will be easier to recruit the patients, but more difficult to show efficacy with a limited number of patients. For instance, [inaudible], which is remdesivir, [inaudible] is good as an antiviral, as an anti-polymerase like masitinib because we carry out the same mechanism of action against the virus. As recruited patients like us with no IDD-positive patients and we think it's very difficult to do now, but still best for limited number of patients we study. We don't give guideline or timeline, but we expect the results to come in 2022 anyway. Now, what is important to say, if any of those two studies is positive, then we will try to enter into a licensing agreement and/or an agreement with countries or nations like EMA, for instance. Because we need help to do and finance to execute and finance the Phase II study, which could probably have to include around 3,000 patients. Also, not to be underestimating, it is the CMC scale-up problem because if you are registered with COVID, you need to deliver to potentially millions of people. It takes three months to scale up and we cannot wait the end of Phase III to scale up. We need to be anticipated and it would represent a significant amount of money that we need to be financed by somebody. We would probably talk with nations and/or bigger pharma on this program. Let's wait the Phase II studies. Clearly potential in [inaudible]. Again, masitinib is an interesting compound because it's an unusual atypical, let's say, direct anti-protease or indirect anti-protease drug. Even if COVID is less and less severe, the disease is still there and will still be there. We still need antiviral drugs. That's where we continue to look for that. Next slide. Next slide is not masitinib but it's the second compound to AB8939 in acute myeloid leukemia. As you know, we have discovered, synthesized a new drug that is promising because it's a synthetic drug first, not coming from the nature. It targets microtubule, which is a highly well-known and effective chemotherapy drug that destabilizes the microtubule and so kills the division of the cells that replicate a lot like the cancer cells. The differentiating factor is that AB8939 does not bind to the P-gp, which is the mechanism of resistance to the drugs from the cells. They are washed out through the P-gp and the drug is washed out from the cells using P-gp and our drug doesn't bind to P-gp and should avoid the multi-drug resistance. We have tested this in vitro, ex vivo and in vivo in mice where we have grafted PDX which is real cancer cell line cells coming from patients that we have grafted to immunodeficient mice that could tolerate chemo and then check the efficacy of this compound versus Ara-C. With Ara-C, the mice could not survive. We had to sacrifice because it's not progress. With AB8939, the mice were completely controlled and some had a complete disappearance of the tumors which was very impressive. This is why we engage in a clinical study. Now, the clinical study in Phase I is authorized now in different parts of the world. We enter into Phase I. This Phase I, we have different steps. The first step should be the compound three days in a row, then 14 days, then 28 days. We'll also have a 14 days in combination with ZD6474 because we have excellent data and combination with ZD6474 which we think is going to be a very beneficial for patients. We would enter into Phase II. Now, it takes a lot of time because it's a chemotherapy, so we need to go slow and be very careful. We think that the first step of the Phase I in three days would take the entire 2022. The three other cycles will affect the entire 2023. Early in 2024, that we can do a Phase II. However, if in Phase II, once we know the maximum tolerated dose, we observe 30 patients response rate, a metabolic response rate, let's say in a series of less than 100 patients or close to 100, then it's possible to have accelerated approval with the FDA. By the end of 2024, we might be in a position to discuss with FDA an accelerated approval while we do a confirmatory Phase III. It starts very slow, but it could accelerate through Phase II. That's the benefit of hematological one in AML. It's a very tough indication, but good product is a good product. Now, what I can add on this compound that I would have not put on the type is that in non-clinical, in the two species that we did, we have observed very low hematological toxicity, which is unusual for this kind of mechanism of action. It gives us hope that this compound could be really different from all other so far. It's only limited by the hematological toxicities with toxicities on the bone marrow outside of the targeted cells, which is not the case of the compound. I would say the plus is that. The plus is the low hematological toxicity. To be confirmed of course, in humans. Next slide. Next slide is the financing and the licensing strategy. Next slide. Now this is important because investors always raise questions about the financial resources of AB Science. Here there is only a bit of information that I will try to summarize. We have a commitment by three co-shareholders to inject EUR 25 million up to June 2022. We have just used EUR 7.5 million of debt facilities that we announced this morning through the issuance of convertible bonds with a conversion price of EUR 13 with warrants attached to that represent 10% of the shares that we issued through the convertible. I can use the price for the warrants of 12.65, which was the price of the IPO. This comes with a premium which is very clear. We have in the remaining part of this commitment, which represents EUR 17.5 million of financing function. We have research tax for this. We have two to be received in 2022. The one of 2022 that we still have not received, and the one of 2021, which represents altogether EUR 6.5 million, which is a guaranteed resource to come. We have two loans from the European Investment Bank. One is signed and is a facility to help us develop our program in COVID. But the money represents a loan up to EUR 50 million. The status is that this loan is signed, and there are three tranches, or installments in English, to be released at the initiative of EIB that we have not used yet because it comes with interest rates which merit that we do it, I would say in a timely manner, but it's too early. The first installment is EUR 50 million, and it came with operational conditions that were already met. The second installment is another EUR 50 million. Again, the operational conditions are already met. I would say EIB can raise, I would say in a manner which is warranted, EUR 20 million on this loan. There are another EUR 2 million which conditions were not met because it means the study should be successful and leads to a sort of reference of the product by some agencies. The loan should be viewed not as a classic loan, but rather as a mezzanine financing with some warrants and an interest rate. We have a second loan where we publicly announced that the European Investment Bank is willing to negotiate in good faith with us this second loan. It's always the case, so it has not changed since the public release. We intend to negotiate and sign, if possible, the loan with the European Investment Bank. This is a significant amount of 30 million EUR. The status is we need to actually use the first tranche of the first loan to be able to sign close this second loan. This is why actually we have not done it yet, because we have to use the first loan which is normal. There would be I use conditional, but there would be three tranches, three installments of 10 million EUR with operational conditions. We can report that if things do not change, of course that's fine, but if things do not change, the first installment has operational conditions which are met. The two other installments have conditional operational conditions, which in fact we think will be met in less than three months. In case we sign this loan, we think we are in a good position to be able to use, if we want, those 30 million EUR, and it comes as a mezzanine in itself. All in all, we have enough resources for minimum the next three months and minimum the results of Phase III. That's the effect we wanted to do. Last slide please, which is the update on the licensing strategy, which we announced briefly in July last year, where we said that now embedded into the core of our strategy in 2022 is the resort to licensing, and this is to publish. This execution is, however, confidential, so we don't expect to receive information on that until the end, I would say. For to help us, we have selected a financial service provider, but we don't give more information about that. Of course, any license today are available or we can show the options. Globally or indication by indication or region by region. All the possibilities will be assessed over the current scenario, which is a standalone scenario. That's what I can say on the licensing strategy this time. I finish my presentation, and now I'm open to all your questions. Thank you, ladies and gentlemen. If you wish to ask a question by phone, please press zero-one on your telephone keypad. You can also submit a question on the webcast platform. Once again, ladies and gentlemen, if you wish to ask a question by phone, please don't hesitate to press zero-one on your telephone keypad to receive a queue for the question and instruction. Well, it seems that we have no question by phone. However, I think we have some questions on the webcast platform. Dear speakers, the floor is yours to you. All right. We take the first question regarding the clinical data and amyotrophic lateral sclerosis. I think it relates to the survival data. The question is how do you define early initiation of treatment in your clinical study? We have defined moderate ALS patients, and you indicated that it's beneficial when patients start the treatment early. Okay. The moderate patients are the patients who are not severe. In fact, the score, the functional score from ALSFRS is 12 items that each item measure a function that will rank from zero, each item scored zero to four. Four being normal and zero being a total loss of function. Zero is a loss of function. One is severe. I would say zero is even very severe. It is a loss of function. One is severe, two will be moderate, t hree will be minor, and four will be normal. We define moderate as patients who have no item at zero or one. It means that there is no loss of function and no close to a loss of function. As long as patients has no zeor or one on any item, they are considered moderate or mild severity. The product masitinib has a maximum benefit to the patients as long as patients do not have zero or one on any item of the ALSFRS, meaning there is no loss of function. Which is logical because if there is a loss of function, it means some motor neurons are dead and masitinib will not repair them. It will be much more difficult for masitinib to make any difference with the placebo. Whereas if they are not, there's no loss of function, motor neurons are not dead, then it can slow down or in the best case stabilize patients. That's what we mean by moderate. Okay. We have a few other questions regarding the procedure with Health Canada. First series of question regarding the access to the drug. Does it mean when final decision is made by Health Canada that patients will be able to access the drug immediately after approval? We are going to make everything so that patients could access the drug after the NOC/c decision from Canada. Either we are in a position to deliver it immediately after it's approved. The architecture has been anticipated and through the NOC/c and CMC, the country product is available. Or we have to do more steps. In this case, we will absolutely work with Health Canada to build an access program to the patients so that they can access it waiting for the classic market access program to be completed. Anyway, even if we... The patient process is not completed. We will do everything we can so that the patients can access masitinib if the NOC is positive, of course. We have another question ahead of this decision on the NOC/c. Is there a plan to launch a special access program in Canada, allowing Canadians living with ALS to access the drug through this special access program while the evaluation is under review by Health Canada? For the same reason as what we already talked. It's always difficult to do that in the middle of registration process. But these questions will be evaluated and discussed with Health Canada. I think we already addressed this point in the presentation, but we have a question regarding the pricing. Is there an idea on the maximum price Health Canada may advise? No. There is this entity, this body from the Canadian administration with this objective, which is to set up the maximum price. They will have to probably take some. Normally what they do is they take comparable price in other countries. You know, we have price in other countries for other drugs, but they are not comparable. That's their methodology, and they will everything. What we can say for masitinib, which probably will be important, is that one benefit has been measured for the functional for ALSFRS week 48 and not week 24. The other studies with product that compete with masitinib have a pivotal study, I would say, with an endpoint at week 24. Our first study had an endpoint at week 48. That's I would say point number one of differentiation. The second thing is the survival data, naturally, which is exposed, which is a subset of patients with moderate but still clinically very relevant. With a huge difference of 25 months in median, it makes a lot of difference for patients. There is third data, which is the quality of life, where in our study, the quality of life was significantly increased as opposed to the control with masitinib. We have also another endpoint which can make a difference, which is the PFS, the time to event endpoint, which is very classical in oncology, but not classical in non-oncology because rarely people die that fast. In ALS, people die. This PFS is a nice time to event endpoint, which also can be important when it comes to give a price to the product. Altogether, what we can say is that there is a great consistency in two on two dimensions. The first is there is a consistency across all efficacy endpoints, whether ALSFRS or quality of life or PFS, survival, and even physical capacity, which is the breathing capacity. All those endpoints have been positive. There is a consistency across the severity of the disease at baseline. For instance, when patients are not severe, so they are mild or moderate, benefit is maximum, and it's maximum on all those efficacy endpoints. We see a great consistency in the data of this first study. Altogether, with that, which might impact the price, and we hope should impact the registration. We have a series of questions regarding the impact the decision from Health Canada may have on the decision by FDA or EMA to access the data for conditional or marketing authorization or accelerated approval. It's something we already discussed in the presentation. We can elaborate on that, but not speculatively. Each agency is independent, even if they talk to each other. That's not because they talk that they do the same. We should not imagine that because Health Canada is given access to findings that EMA or FDA will readily do the same. No. More logically, we should consider that we have new data. Those new data are worth being presented to EMA and FDA. If we don't have new data, we know the answer. We have new data, and we have several new data. Again, the new data that we have that needs to be presented are one additional statistical analysis of the first study. Again, what is very difficult when it comes to an endpoint of week 48 is the treatment of missing data. Because when a study finish at week 24, the discontinuation rate is around 10%. It's true in the competitive products of masitinib, it's true in our study. Masitinib is no different. 10 but no more discontinuation at week 24. Only 10%. There are few deaths. Whereas when you take an endpoint at week 48, there are much more deaths and lots of discontinuation, up to 30%. In our study, there was no difference in discontinuation rate between masitinib and the control. It raised the question of how to treat at week 48 30% of the data that are missing, and it's not insignificant on the primary analysis. This is what we have done in new data set of analysis where we've used a multi-computational model, which is, I would say, a classic and well-recognized by the agency. Plus a very conservative treatment, what we call jump-to-reference where we penalize the product efficacy by hypothesizing that once masitinib is discontinued, the patients behave like a placebo. That if they have a placebo, which is not entirely true because there is a remnant effect of the time where patients had benefited from masitinib. This is the key data we think. We don't know how competitors from the key studies treat patient data. Anyway, this is a key control. That's one thing which is new. The other thing has been the long-term survival with BLU-263, and this is extremely important. It's exposed. It's not a pre-planned, and it's also a subset of patients, so it's not data. That is, I would say the same as if it was the overall population plan, but still it's extremely clinically relevant. We have this mechanism of action, which on new data that masitinib is very important and all the safety data. There is no product with thousands of patients exposed. We have long-term data, seven years. We have exposed now with the compassionate use, hundreds of patients and so we have a better idea of the safety profile. All this helps and this shall be presented through the FDA and EMA. On the top of that there is the urgency for the patients to have new treatments. It is extremely difficult, and patients want a new treatment, new effective treatment. We hope that we could maybe have possibility to file our dossier at the EMA. At least we will discuss with those two agencies. We have two other questions regarding other products for ALS. First regarding risdiplam. Can masitinib replace risdiplam in ALS patient treatment or does it have to be prescribed in addition to risdiplam? That's the first question. Second question, is Amylyx considered a direct and serious potential competitor in the ALS? No, no. Masitinib does not replace riluzole since riluzole is on top of riluzole. Riluzole is still the background treatment. We have no data of masitinib head to head against riluzole. We don't have data. We don't think masitinib does not compete with riluzole. Are all competitors late stage in second-line program in this competitive project? Yes, they are. Otherwise they will not be late stage or they will not be in the phase of registration different agencies. By the way, it's not the same mechanism of action anyway. Complementary. We don't have a second product like masitinib targeting microglia and macrophages. We think that's what matters because even if ultimately there are several products registered, which is always good for the patients. Anyway, I think. So we think that the academic people, they need more than one mechanism of action to completely ease. It will not necessarily limit the sales or the potential of any drug registered, but rather maybe amplify it. Now, if we move to our program, are there further discussions ongoing with Health Canada regarding Alzheimer's disease or MS for approval under NOC/c? No. No, we have to focus on ALS at this time. Maybe one last question regarding Alzheimer's program. Alzheimer's has three confirmatory studies. Is it already decided to go alone? Any chance to work with partners? We intend to initiate the confirmatory study in Alzheimer's as soon as possible. We don't give any timeline for the licensing, so I cannot answer your question. But we do not wait for licensing to initiate confirmatory program. I think we covered most topics. If there are no more questions verbally then we can conclude. If you have any question, additional questions, feel free to ask. Olivier, you are still there? I'm here. Can you hear me? Yes. Olivier, would you like to add anything as the head of the Scientific Committee? Can you hear me? Yes. I think it's an achievement that Canada has allowed to examine our dossier because our data are spectacular and also are on the basis of a good science we have made before to understand by which mechanism masitinib is working. Interestingly, as we have said before that masitinib is working in three different neurodegenerative disease. Because it targets always probably the same mechanism of action and targets the macrophages and the microglia, and in all the neurodegenerative disease this mechanism are the common. It's for the reason why masitinib is working and by its unique mechanism of action. I think it's a good opportunity for us to provide the right therapy to the patient. We are strongly believing that our data with our compound and we see the increased overall survival in the ALS. Thank you, Olivier. I would like to thank all the participants to this call, whether in Europe or in the United States. I will just close by saying that, thinking of the situation in Ukraine, where we have people studying there, and we hope that the situation will be treated rapidly and peacefully to an end because we of course are concerned. Thank you, everybody. Ladies and gentlemen, thank you all for your participation. This concludes the web conference. You may now disconnect.