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

Ladies and gentlemen, welcome to the AB Science web conference. I will now hand over the call to Alain Moussy, Olivier Hermine, Laurent Guy. Gentlemen, please 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, the Financial Director of AB Science; and Professor Olivier Hermine, who is the President of the Scientific Committee of AB Science. The topic this evening is to walk you through the recent news on the recent Health Canada accessibility to file masitinib in the treatment of ALS under the NOC/c procedure. And also to walk you through the different updates across indications of the masitinib program and also the 8939 compound program. And 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. I'll share the disclaimer. And then we can enter into the first part of this presentation, which is a presentation -- a description of what it is this NOC/c procedure that has been recently authorized by Health Canada for masitinib in ALS. Next slide. And what is the 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. And the NOC/c status eligibility is restricted to new drug therapies intended for the treatment of serious, life-treating or severely debilitating disease for which there is no alternative therapy available in the Canadian market and where the new product represents a significant improvement in the benefit/risk profile over existing products. Very important is that the preassessment is performed by an Adjudicating Committee. It is necessary before being granted authorization to file under the NOC/c policy. And if granted, this NOC/c authorization to market comes with conditions and such conditions will be discussed during the procedure with Health Canada. Next slide. So what happened is that Health Canada has done the preassessment and concluded that masitinib fulfills the criteria for filing and advanced consideration under the NOC/c policy. This preassessment was based on the pre-submission package sent by us, including efficacy data on the study AB10015. The long-term survival data that was acquired after 75 months of follow-up from diagnosis and also all safety data concerning masitinib. The position from the committee, from Health Canada Educating Committee was that Health Canada considered that ALS is a serious life-threatening and severity debilitating disease with the median survival of 2 years. Health Canada considered the promising evidence for masitinib at the dose of 4.5 milligrams per/kg/day when added to riluzole therapy in the treatment of ALS. And then we just quote part of the letter that we received from Health Canada. So Health Canada, as I highlighted, has considered a clinical benefit on the primary endpoint study, AB10015 reported clinical benefit of the primary endpoint, change in ALSFRS-R from baseline to week 48. In ALS patients this disease progression less than 1.1 points per month, which we call the normal progressor prior to treatment initiations, masitinib at the dose of 4.5 milligrams per/kg/day, significantly decreased decline in ALSFRS-R at week 48 when added to background treatment riluzole with a between-group difference of 3.4 and p-value was significant equal to 0.016. In addition, Health Canada noted a significant delay in disease progression called PFS, the secondary endpoint called PFS, progression-free survival was defined as the earlier between death or disease progression corresponding on a deterioration of more than 9 points of ALSFRS-R from baseline. And this end point, PFS demonstrated a significant delay at the dose of 4.5 of 25% in the same category of patients called the normal progressor, and the p-value is 0.016. And 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. This came from a post-hoc analysis and overall survival that was assessed at the cutoff date of June 2020, corresponding to the end of a long-term post hoc follow-up with an average follow-up time of 75 months. And 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 0.036 that was observed at the same dose of 4.5 milligrams per/kg/day with 45 patients in the median group and 62 in the placebo in a cohort of normal progressor but with moderate ALS patients. Finally, Health Canada considered that there is no need of a head-to-head comparison with edaravone therapy because the guideline to prove that there is a significant improvement as compared to existing therapy registered in the edaravone was recently registered. But Health Canada considered that there was no head-to-head trial to assess the efficacy of masitinib compared to edaravone. Indeed, there is not. However, recently published article demonstrated the time to noninvasive ventilation and survival probability did not significantly different in patients receiving intravenous edaravone compared to matched ALS patients on standard therapy, and this is why they have not requested any data of masitinib versus the edaravone therapy. So we wanted to share the key considerations brought by Health Canada in delivering this authorization to file under the NOC/c policy. Next slide, please. Now, we would like to walk you through the process and the timing. So the final decisions of Health Canada is expected by the end of 2022. So the first step that we passed is the eligibility to the NOC/c procedure just being granted. And then we have to submit the dossier, and 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 this, but we'll do as quickly as we can, naturally. Then the guideline says that Health Canada has 200 days to review the applications with possible clockstop but quick clockstop that should not last more than 15 days. At the end of this 200 days review target, it could be quicker, by the way, it's the maximum. So we don't know if Health Canada is going to do it quicker, but it's a maximum of 200 days. At the end of this process, there will be either a noncompliance -- notice of noncompliance, meaning that the product is not registered or the opposite, a notice of compliance with conditions. And from that step, the sponsor should respond in 30 days to the conditions proposed by Health Canada. And then Health Canada can issue a notice of compliance under the NOC/c policy 30 days later. So 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 will be our target. Next slide, please. In parallel, we have to address and perform the market access activities so that we don't waste time and do things sequentially. So it could be done in parallel through the registration process so that we are ready to deliver masitinib to the Canadian patients after a potential NOC/c is delivered. First, we have to look whether we have enough product to supply masitinib to the Canadian patients. So we know that around 3,000 Canadian patients living with ALS with each year 1,000 patients unfortunately die 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. And so we will not be delayed by the, I would say, manufacturing activities. Then we have the market access itself. So it is specific to Health Canada. There are different bodies there, which we put here the acronym. So we have the PMPRB called the Patented Medicine Prices Review Board. This body sets a maximum price for a new drug. And so gives a sort of reference not to be passed. Then you have other bodies called CADTH and INESS. So CADTH is called Canadian Agency for Drugs and Technology in Health. And INESS is the similar body, but in Quebec, [Foreign Language] and they review clinical and economic data and then deliver recommendations. Then there is another body called Pan-Canadian Pharmaceutical Alliance, which helps to negotiate, in fact, streamline the negotiation process across Canada. And then we have to submit dossier to the different insurance companies called Manulife, Sun Life and Great-West Life to obtain private coverage. And so we have to negotiate with the public hospitals and the provinces of Canada and also with the private insurance. This takes time, of course, and this is why it should be anticipated and managed in parallel for registration process. Just for reference, since there is a product registered recently in Canada, Edaravone IV is priced CAD 190 before rebates, which gives a price for Edaravone of [ EUR 130K ] in Canada. And as you have seen, as Canada considered that there is no benefit in survival for Edaravone and we expect masitinib to be valued on the basis of its merits and benefit, including an additional median 25 survival, as you have seen. Next slide. So the next slide is about the, I would say, selling activities and commercialization strategy. So we have identified a number of centers, which are reference centers in Canada, which are below 20 and located in 11 cities. And at this time, we prepare a stand-alone commercialization strategy, which might change because we have a licensing strategy also in parallel on a more global basis. But at this time, it's a standalone and in-house sales force should be sufficient to service ALS centers in Canada at this time. So you can see the different locations of the centers which are located in New Brunswick in Fredericton and also, of course, in Quebec, Montreal, Laval, in Ontario, in the cities of Toronto, Hamilton, London and Ottawa and also in Alberta, Edmonton and Calgary, in Saskatoon, which is just before the Alberta and British Columbia and Vancouver. Next slide. So the next slide is the impact that it could have on EMA and FDA focus. Following this decision, we intend to open a discussion with both FDA and EMA on an accelerated approval and called conditional approval at EMA called accelerated approval at FDA. We need for that to show them new data as compared to what we have 3 years ago, where we stopped the discussions. And so what we have as new data or new ex-post analysis from study 10015 in particular, some statistical analysis with reference to [ edaravone ] which are actually conservative way to calculate missing data, where you impute actually a placebo effect to any patient who discontinued masitinib for lack of efficacy or toxicity. Obviously, we have the long-term survival data, which are ex-post but enlightening and correspond to the mechanism of action of masitinib. We have additional safety data that we have accumulated through compassionate use, but also outside of ALS. And we also have validated now and published masitinib mechanism of action, which was not the case 3 years ago, and there has been nice publications from independent groups, academic throughout the world to understand how masitinib works in this disease. Next slide. And then we would like to take this opportunity to update you on the situation in the other programs, but also in ALS on a clinical basis. Next slide. We'll start with ALS. So the study -- the status of this confirmatory study called the 19001 is that it's actively recruiting everywhere in the world. And the primary endpoint is the change in ALSFRS-R at week 48. And beside at week 48, the enrollment target is 550 patients. We actually had 3 arms, an arm, which is 4.5 milligram, which is the one which has been effective in the previous study, titrated this time to optimize the tolerability and minimize discontinuation and also a higher dose that has never been tested in ALS, which is reasonable since we expect a benefit in survival. This has been, of course, validated by authorities, FDA and EMA. We remind you that the publications, 2 publications have been done, the Phase IIb/III results -- sorry, 10015 has been published and also the long-term survival, which has been key in the analysis of Health Canada. And the impact of a possible registration in Canada of the timing to finish the study should be marginal. Of course, Canada is open, but we expect that in case it's registered, the recruitment should be close to the end or finished and should be a limited impact. Now in terms of market and competition, so this is what we observed. There are 2 registered drugs, as you know, riluzole also called Rilutek and the IV version of Edaravone and into developments in late stage, likewise, masitinib. You have the product from Amylyx called AMX0035, which also is under registration process in Canada, but also with FDA and EMA and edaravone in its oral version with a bioequivalent study, which has been done by Mitsubishi Tanabe in an effort to register the oral version of edaravone. So 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 no product increasing survival as long as there will be a product that can extend survival, the targeted number of patients should increase. Then to ensure -- to anticipate frequently asked questions about compassionate use, we report compassionate use, if not possible, indeed detrimental because it would put a risk on the confirmatory study since patients would prefer to do compassionate use rather than participate to our confirmatory study. And we have to wait until the last patient last visit before presenting the root cause is finished, as long as patients are under treatment, they would prefer to go to compassionate use than to take the risk to have a placebo and there is 1 chance of 3 to have a placebo in our study. So the compassionate use, we'll have to wait a little bit. We don't say it's impossible, of course, but we have to do it in a timely manner and effective manner. Next slide. So next slide, we like to give the key data of our study each time, and we think this is the key data at least for the patients. We know it's an exhaust data, but it has merit because it's a very long follow-up of 75 months. As you can see on this slide, the Kaplan-Meier curves distinguish -- differentiate themselves early and continue to differentiate. And there is a huge benefit of 25 months for the patients taking masitinib. Although after a while, patients could cross over for the placebo and they could take masitinib, which would penalize the benefit for masitinib all along because then it's a placebo and placebo with masitinib. But despite the possibility of the patients take masitinib after some time, still, we have a benefit that can be observed, but provided that the patients take the product early enough, so what we call the moderate patients before they become easier and we explain that because masitinib has not the capacity to regenerate the motoneuron, but to protect against destruction of the motoneuron rather and to slow down the disease progression or even if really taken at the time of diagnosis may be stabilized. We have some patients who are stabilized, but it needs to be proved, of course, in real life. Next slide. So next slide is the other -- I have to report that the key -- the core of the program of masitinib after we have read Phase IIb/III is clearly neurodegenerative disease with what we call the trilogy ALS progressive forms of MS and Alzheimer, where in this disease masitinib has efficacy data at the same dose of 4.5 milligrams per/kg/day consistence. And so we intend to focus on these 3 disease, of course, which we think brings maximum benefit and maximum value to the program. So the second indication is the progressive forms of MS, both primary and secondary inactive, secondary inactive forms, not secondary active forms because there are 2 secondary progressive forms of MS. So we have launched the confirmatory program. And this confirmatory program we announced has been already authorized by at least 2 countries, 2 agencies, France and Sweden, but in fact, more, but we are announcing them one by one. And the recruitment is imminent. The primary end point will be of at least EDSS over 96 weeks for all patients minimum and intend to enroll 800 patients. And though there will be only 1 dose, in which the masitinib 4.5 milligram titrated, which we didn't do in the first study where it was flat. And so we expect even a better tolerability with 4.5 milligram titrated. And the publication of the first study has been recently done. And so everybody now can access that, which is always nice to have because it's a peer review, of course, publication. In case of market and competition, this part of multiple sclerosis progressive forms is now more and more competitive. There is 1 drug registered called Ocrevus from Roche/Genentech in the primary progressive form but not in the secondary inactive forms. And there are 4 drugs at least in late stage development, all BTK inhibitors, which target microglia through BTK likewise masitinib, but masitinib targets in addition mast cells, and we do believe that the difference between mast cells and microglia is key and differentiate masitinib from other options. So it's not the same strategy also overlaps. It's going to be interesting to see the outcome of those 5 studies. So the one of Sanofi, Roche, Biogen, Merck with their BTK inhibitors and the one from AB Science with masitinib. The market is significant with 500,000 patients in Europe and in the U.S.A. And next slide is a visualization of the fact that there is a clear unmet medical need. As you can see only 1 drug in primary progressive forms ocrelizumab from Roche Genetech, but none in the non-active secondary progressive, which represents the largest part of this market. And all other drugs being registered in relapsing remitting or active secondary progressive. So clearly, the strategy is developed for [indiscernible] in progressive forms. And we think masitinib is key through microglia and probably even mast cells as well. Next slide. And next slide is the key data according to us for study. So 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 Phase IIb to try to have with fewer patients, a sign of efficacy, which we have. So you can see the 2 curves are clearly differentiating and the placebo is actually increasing in terms of EDSS, which means an increase in handicap, whereas with masitinib it flattens and so there is a clear difference between the 2 curves which enables us to say that the study was successful and there is a first sign of efficacy in our study. But what is very important for the agencies is the data on the right-hand side, which is the classic EDSS progression confirmed at 3 months where we can also see that the curve different shapes between masitinib and placebo. The p-value is not significant, but the study was not designed to be significant to the secondary endpoints. However, the hazard ratio is a reduction of EDSS progression by 37%, where as the only product registered in primary progressive forms has a risk reduction of 25%. And the 37% risk reduction applies to both primary efficacy patients and inactive secondary progressive. We don't see any difference in risk reductions. We think it's quite consistent with masitinib. And so if this data we can confirm in a confirmatory study, it will mean that we could register with masitinib, but in the 2 forms of progressive forms and also that we will need probably a fewer patients to demonstrate efficacy. So this data stands out, needs to be confirmed, of course, but is encouraging. And it is on this basis that we launched a confirmatory study. Next slide. Next slide is the Alzheimer's disease, which is the third neurodegenerative disease core program of masitinib. So 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 will follow, of course, the guidelines which is to have a significant statistically difference with the placebo on 2 clinical end points, one called COG to measure the committed 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 600 patients, probably to be confirmed. We will choose a short endpoint of 24 weeks because it has been the endpoint of Phase IIIa and also the Phase IIb/III, and so we don't want to change and take risk even if the level is more minimum as a symptomatic and not disease modifying level, but we prefer not to take risk, although this study will have the ability to test also an endpoint at 48 weeks, but which will be only secondary. But if we study the 2 targets, then level will change and will be disease modifying. We will focus on 1 dose, which will be Masitinib 4.5 milligrams titrated again, which was not the case in the first study. Again, it's an optimization in terms of tolerability. And the study -- the publication of the first study is pending today. Market and 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. And it's not the same positioning as masitinib because aducanumab is positioned in early Alzheimer's called also prodromal Alzheimer's disease which is not the same patients as what my team is trying to do, which is the classic mild and moderate. The market is huge with millions of people, 5 million of people, which is considerable, of course. Next slide. So next slide is visualization of the positioning of aducanumab versus masitinib. So what we call prodromal or only Alzheimer can be explained by a score called MMSE mini-mental state examination. When it's low, it's more severe. And 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 -- in 2 previous studies and in the confirmatory study includes mild and moderate Alzheimer's patients, which are not 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 effective in prodromal, but it's not what we have chosen as a primary target. We have to confirm in mild and moderate patients that masitinib could be effective. And again, what's important is that the primary endpoint with 24 weeks, meaning symptomatic treatment but with the merit, which will go a little quicker because it's a shorter end point. Next slide, please. So the next slide is the key data according to us of the first study and on COG and ADL. And the first study has shown that masitinib was able to significantly improve as compared to placebo. In fact, not placebo but memantine and oral anti-cholinesterase that could be taken as a background treatment. And COG is an impairment of cognition. So it actually increased. And when you do negative compared to placebo in terms of LSM which is [indiscernible] which means that it's a benefit for masitinib versus the placebo. So you can see that there is a LSM difference of 2.15 and it is statically significant. For at the end, the daily activity, it's known that it's more difficult to change the end point here the more activity you do, the better it is, so you must increase as compared to the control. And you can see there is a difference of EUR 1.82, which is also significant, but it is little less than COG. It's more difficult to move the ADL. But in the first study, masitinib was able to do both at the same time, which is very encouraging. And I stress the way we have calculated missing data, missing data have used multiple imputation as the guideline says. And we have done a sensitivity analysis where we penalized masitinib arm by imputing placebo in case of discontinuation for the masitinib patients, 4 reasons being a lack of efficacy of toxicity. And despite in the sensitivity analysis, highly conservative, both were still statistically significant, which proves that masitinib data is robust. And of course, we go to the confirmatory study program immediately to try to confirm that. We increased the sample size now that we know what dose is the correct one. And this study is not going to be too long to complete, and we will at the end of this study, maybe 6 months after we finish ALS or mastocytosis, by the way, we don't give time lines 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 be changed in the future. Next slide. Then we move to the inflammatory part of the program, starting with mastocytosis, indolent systemic, which is actively recruiting. This is a confirmatory study, which intend to enroll 140 patients on the duration of the primary endpoint of 24 weeks. Here, the dose is higher with a titrated 6 milligram, but again titrated, which was not done in the first study. So 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 skin problems, for instance, which was well known to be the characteristic of the toxicity or tolerability issue with masitinib. And here with the titration scheme we had a good, I would say, strategy and management plan to minimize severe skin tox and reduce really to a low, low, low, low percentage the serious skin tox, which was the problem of masitinib in the history of the development of this compound. So the first study has been published in the Lancet, as you know. Now the competitive landscape has evolved to the benefit of the patients. We have to distinguish aggressive systemic mastocytosis, which is a type of cancer, where there are 2 registered drugs avapritinib from Blueprint and midostaurin from Novartis. We don't compete on this segment of the disease, which is a fragment 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, but not marginal in terms of health problem for the patients and the big part is in indolent systemic mastocytosis. It's indolent as compared to aggressive systemic as compared to acute. Indolent systemic mastocytosis is the key thing, and there is no drug registered. And definitely, masitinib is the most advanced drug having already Phase III study published in the Lancet. But we have observed that the Blueprint is the same product developed in aggressive mastocytosis is in Phase II, and we are waiting for the data that they will publish probably. And they have also -- Blueprint entered into clinical development with a new compound called BLU-263, but the compounds have different mechanism of actions since the avapritinib and the other one blocks basically the mutations, which make the [ dose work ]. Masitinib is effective even for patients with KIT 816 mutations by bypassing the activity generated by the mutations, probably through the inhibition of Lyn and Fyn so to some extent, anyway, the strategies are complementary. It's going to be interested to see what it does. The big plus of masitinib is the safety with long-term safety data. You know that some patients have been taking the product for more than 10 years, I think, now in mastocytosis, which is a world record and completely control symptoms for some patients in extension. And so it is quite trusted in this program in mastocytosis, which has been the origin of AB Science for the ones who follow us for a long time. A number of patients here, it's the total mastocytosis, but the ones that could be targeted really by the product is less, it might be 1/3 of that because we have to restrict the label to severe indolent systemic mastocytosis. This is more indolent systemic, but the severe, which are the ones we target will be less like 1/3 probably of those patients. Next slide. Next slide is MCAS. MCAS is a relatively new indication for masitinib. It has been discussed with FDA, authorized by FDA actually the study and by -- in Europe by [ ISM ]. And MCAS is a sort of sister or cousin disease of mastocytosis. They have similar symptoms, except one, they don't have the spots on the skin and there is no [indiscernible] skin dwelling mutations. The activation of MCAS are not very well known. There are some publications, but they are not extremely well known. And what is interesting in MCAS is that the number of patients is literally 10x or more than the number of patients suffering from mastocytosis, and they are poorly diagnosed because they have some sort of symptoms. Since they don't have the spots, they are difficult to diagnose, except if they complain a lot. But 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 FDA, we have decided to enter into a program in MCAS. And in fact, some patients are severe. We estimate 10% of the patients to be severe, but there is no publication on that, where there are 33% of mastocytosis patients being severe. But since we estimate that there are 10x more MCAS than mastocytosis, the market is, in fact, higher. But nobody knows exactly how big is this market. So to register a product in MCAS, we have to do a Phase II and then a Phase III. So we have decided to launch a Phase II in Europe and in the United States, where we're going to test 2 doses, which are 6 milligrams titrated because it's the one which is effective in mastocytosis and a lower one because if we don't have to go to 6 milligrams, why we need to know. And so it's a dose range finding study with 62 patients, which is authorized on both sides of the Atlantic. And today, the market and competition is -- there is none. No drug registered and in development, I think, this is going to be the first study. One thing to mention, we did 2 Phase IIa in mastocytosis in 2 categories of patients genetically different. The K1T 816 mutations, and there is a fraction of the mastocytosis patients who do not bear the KIT 816 mutations, they are 1 type, but they are not MCAS because they have spots. You see the difference. So we think that it goes through a slightly different mechanism of actions. However, in the mastocytosis wild-type, masitinib is effective and as effective in the KIT 816s. And this we is a good sign of potential efficacy in the MCAS. And by the way, FDA was quite convinced by our data. So suppose that masitinib can capture the MCAS market in the future, that would be non-negligible and not a lot of drugs can do MCAS, in particular, the KIT 816 targeted drugs, cannot because there is no such mutation in MCAS. Next slide. Next slide is the 3 indications left, severe asthma uncontrolled by OCS oral corticosteroid or ICS inhaled corticosteroid. Pancreatic cancer locally advanced because it's where masitinib is potentially effective with pain and metastatic prostate cancer eligible to Docetaxel. These will be launched after sequentially after we launch Alzheimer because we cannot launch everything at the same time. And so we expect to launch probably 1 program before the end of 2022 and the rest in the beginning of 2023. So we don't give more details there, and we'll come back with more news a little later. Next. Next is COVID. On COVID we are doing with masitinib 2 studies, which are Phase II studies. The first one on the left-hand side of the presentation of the slide is in the patients being hospitalized and suffering from moderate and severe COVID. This study is actively recruiting. The endpoint is a clinical outcome at day 15. It plans to enroll 200 patients. They should -- they are treated with the standard of care, which is dexamethasone worldwide. And it explores only 1 dose, which is the 4.5 milligram titrated. And we expect the study results to come in 2022. We don't give any time line because we're highly dependent on the recruitment, which is fluctuant in the different parts of the globe. So 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 still some patients in the hospital, but those patients in the hospitals are already part of other programs that also have difficulties to finish their study. So it's not so 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. And 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 proved that masitinib in vitro and vivo in mice is an antiviral against the SARS COVID. But we don't know in humans. This is why we're doing this study. And this study is a dose range finding study that plans to enroll 77 patients and test 3 doses. And this study is very difficult to recruit. Let me explain you why. Because we have decided in this 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. And 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, Pfizer, which has registered its drug as an antiviral, as against like masitinib because we target the same mechanism of actions against the virus. As recruited patients like us with no IgG positive patients. And we think it's very difficult to do now, but still the best for limited number of patients in the study. So we don't give guideline or time line, but we expect the results to come in 2022 anyway. Now what is important is that if any of those 2 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 III study, which would probably has to include around 3,000 patients. And also not to be underestimated is the CMC scale-up problem because if you are registered in COVID, you need to deliver to potentially millions of people. And it takes 12 months to scale up, and we cannot wait the end of Phase III to scale up. So it will need to be anticipated, and it represents a significant amount of money that will need to be financed by somebody. And so we would probably partner with nations and/or bigger pharma on this program. But let's wait the Phase II studies, but it's clearly a potential game changer. Again, masitinib is an interesting compound because it's an unusual, atypical, let's say, direct anti-protease or indirect anti-protease drug. And even if COVID is less and less severe, the disease is still there and will still be there, and so we still need antiviral drugs. So that's where we continue this program. Next time. So next slide is not masitinib, but it's the second compound called 8939 in acute myeloid leukemia. So as you know, we have discovered, patented 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 destabilize the microtubule and [indiscernible] of the cells that replicate a lot like the cancer cells. But the differentiating factor is that 8939 does not bind to the Pgp, which is the mechanism of actions of resistance to the drugs from the cells. They are washed out through the Pgp and the drug is washed out from the cells using Pgp, and our drug doesn't bind to Pgp and should avoid multidrug resistance. And we have tested this in vitro, ex vivo and in vivo in mice where we have grafted PDX which is a real cancer cell lines -- cells coming from patients that we have drafted to deprive the mice that could tolerate them and then check the efficacy of this compound versus Ara-C and with Ara-C the mice could not survive and they have to be sacrificed because of tumor progress. But with 8939, the mice were completely controlled and some had complete disappearance of the tumors, which was very impressive. And this is why we engage in the clinical study. Now this clinical study in Phase I is authorized now in different parts of the world. So we enter into Phase I. And this Phase I will have different steps. The first step will be the compound 3 days in a row, then 14 days, then 28 days, and we'll also have a 14-day in combination with azacitidine because we have excellent data in combination with azacitidine, which we think is going to be very beneficial for the patients. And then we would enter into Phase II. Now it takes a lot of time because it's chemotherapy, so we need to go slow and step by step. So we think that the first step of the Phase I with 3 days will take the entire 2022. And then the 3 other cycles will take the entire 2023. It's only in 2024 that we can do a Phase II. However, if in the Phase II, once we know the maximum tolerated dose, we have -- we observed 30 patient response rate, hematological 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 FDA. So 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. So it sounds very slow, but it could accelerate through the Phase II. That's the benefit of hematological program. It's, of course, a very tough indication but the product is ready for that. Now what I can add on this compound is that which I have not put on the slide is that in nonclinical -- in the 2 species that we did, we have observed very low hematological toxicities, which is unusual for this kind of mechanism of action and gives us hope that this compound could be really different from all others that have been developed so far, which are limited by the hematological toxicities with toxicities on the bone marrow outside of the target itself, which is not the case of this compound. And so I would say the plus is that the plus is the low hematological toxicity to be confirmed, of course, in humans. Next slide. So next slide is the financing and the licensing strategy. Next slide. So this is important because investors always write the questions about the financial resources of AB Science. So here there is only public information that I will try to summarize. We have a commitment by historical 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 14 with warrants attached to that, but represent less than 10% of the shares that will be issued through the convertible at an exercisable price for the warrants of EUR 12.65, which was the price of the IPO. And so this comes with a premium, which is very fair. And then we have still the remaining part of this commitment, which represents EUR 17.5 million outstanding financing option. Then we have research tax credit. We have 2 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. Then we have 2 loans from the European Investment Bank. One is signed and is a facility to help us develop our program included, but the money so represents a loan up to EUR 15 million. The status is that this loan is signed, and there are 3 tranches or installments in this to be released at the initiative of AB Science that we have not used yet because it comes with interest rate, which merits that we do it, I would say, in a timely manner, but not too early. So the first installment is EUR 6 million and it came with operational conditions but which are already met. The second installment is another EUR 6 million. Again, the operational conditions are already met. So I would say AB Science can raise, I would say, in a manner which is warranted EUR 12 million on this loan. And there are another EUR 3 million, which conditions are 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 interest rate. Then 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. And it's always the case. So it has not changed in the public release. And so we intend to negotiate and sign if possible, the loan with the European Investment Bank. And this is a significant amount of EUR 30 million. And the status is we need to actually use the -- at least the first tranche of the first loan to be able to sign and close the second loan. This is why actually, we have not signed it yet because we have to use the first one, which is normal. And so there would be, I use conditional, but there would be 3 tranche, 3 installment of EUR 10 million with operational conditions. And we can report that if things do not change, of course, it's not signed, but if things do not change, the first installment has operational conditions, which are met. And the 2 other installments have operational conditions, which, in fact, we think, will be met in less than 12 months. And so in case we sign this loan, we think we are in a good position to be able to use, in case if we want those EUR 30 million, and it comes as mezzanine as well. So all in all, we have enough resource for minimum the next 12 months and so minimum the response of Health Canada, and that's the message we wanted to convey to you. And last slide, please, which is the update on the licensing strategy, which we announced publicly in July last year, where we said that now embedded into the core of our strategy in 2022 is the research of a license and so public. This execution is, however, confidential. So we don't expect to receive the information on that until the end, I would say, and for -- to help us, we have selected a financial service provider, but we don't give more information about that. And of course, any license today are available or we don't close any, I would say, options. So globally, indication by indication or region by region and all possibilities will be assessed over the current scenario, which is a stand-alone scenario. That's what I can say on the licensing strategy at this time. So I finished my presentation, and now I'm going to open it for all your questions.

[Operator Instructions] Well, it seems that we have no question by phone. However, I think we have some questions. on the webcast platform. So dear speakers, the floor is back to you.

All right. So we'll take the first question regarding the clinical data in amyotrophic lateral sclerosis, I think it relates to the survival data. And the question is how do you define early initiation of treatment in our clinical study? So we have defined moderate ALS patients and indicated that it's beneficial when patients start the treatment early.

Okay. So the moderate patients and the patients who are not severe. In fact, the score, the functional score called ALSFRS-R has 12 items that each item measure a function that will rank from 0 each item, a score of 0 to 4, 4 being normal and 0 being a total loss of function. So 0 is a loss of function, 1 is severe. I would say, 0 is even very severe, it's a loss of function. 1 is severe, 2 will be moderate, 3 will be mild and 4 will be normal. And so we define moderate as patients with no item at 0 or 1. It means that there is no loss of function and no close to loss of function. As long as patients have no 0 or 1 on any item, they are considered moderate or mild severity. So the product, masitinib is a maximum benefit to the patients as long as patients do not have a 0 or 1 on any item of the ALSFRS-R, meaning that there is no loss of function, which is logical because if there is a loss of function, it means some motoneurons are dead and masitinib will not repair them. And so it will be much more difficult for masitinib to make any difference with the placebo. Whereas if they are not, there is little function, motoneurons are not dead, then it can slow down or in the best case, stabilize patients. That's what we mean by moderate.

Okay. So we have a few other questions regarding the procedures with Health Canada. So first series of questions regarding the access to the drug. Does this mean when final decision is made by Health Canada that patients will be able to access the drug immediately after approval?

Hello. We are going to make everything so that patients could accept the drug after the NOC/c decision from Canada. Either we are in a position to deliver it immediately after because the market access has been anticipated and proved enough and the CMC and the quantity of product is available or we are -- we have to do more steps, okay? But in this case, we will absolutely work with Health Canada to build an access program to the patient so that they can access it, waiting for the classic market access program to be completed. So anyway, even if we -- the traditional process is not completed we will do everything we can so that patients can access masitinib in case the NOC/c is positive, of course.

And so we have another question ahead of this decision on 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 a 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, but there is this entity, this body from the Canadian administration with this objective, which is to set up the maximum price. So they will have to probably take some -- normally what they do is they take comparable price in other countries. We have price in other countries for other drugs, but they are not comparable. So that's their methodology, and they will check everything. What we can say for masitinib, which probably will be important is that, one, the benefit has been measured for the functional score at week 48 and not week 24. The other studies with products that compete with masitinib have a pivotal study, I would say, with an endpoint at week 24 and our study first study as an endpoint at week 48. So that's, I would say, point number 1 of differentiation. The second thing is this survival data, naturally, which is at first which is a subset of patients called the moderate, but still clinically very relevant and with a huge difference of 25 months in median that makes a lot of difference for the patients. And then there is a third data which is the quality of life where in our study, the quality of life was significantly increased as compared to the control with masitinib. And we have also another endpoint, which can make a difference, which is the PFS, a time-to-event end point, which is very classical in oncology, but not classical in non-oncology because rarely people die in the past, but in ALS people die. And so this PFS is a nice time to event endpoint, which also can be important when it comes to give price to the product. And altogether, what we can say is that there is a great consistency on 2 dimensions. The first is there is a consistency across all efficacy end points, whether ALSFRS-R or quality of life or PFS, survival and even force vital capacity, which is the breathing capacity. So all those endpoints have been positive. And also, there is a consistency across the severity of the disease at baseline. For instance, when patients are not severe, so they are moderate, mild or moderate, the benefit is maximum and its maximum on all those efficacy end points. And so we see a great consistency in the data of this first study. So altogether, with that, which might impact the price, and we hope should impact a potential registration.

Then 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 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, but it's not because they talk but they do the same. And so we should not imagine that because Health Canada has given access to a filing that EMA or FDA will readily do the same. No. But more logically, we should consider that we have new data. And those new data onwards being presented to EMA and FDA. If we don't have new data, we know the answer, but we have new data. And we have several new data. Again, the new data that we have that needs to be presented or 1 additional statistical analysis of the first study. Again, what is very difficult when it comes to an end point of week 48 is the treatment of missing data. Because when a study finished at week 24, the discontinuation rate is around 10%. It's true in the competitive follow ups of masitinib. It's true in our study. Masitinib is no different, same, but no more discontinuation at week 24. It's only 10%. And there are a few days, whereas when you take an endpoint at week 48, there are much more days and lots of discontinuation, up to 30% in our study. There was no difference in discontinuation rate between masitinib and the control. But it raises the question of how to treat at week 48, 30% of 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 have presented a multiple imputational model, which is, I would say, a classic and well recognized by the agencies, plus a very conservative treatment what we call jump to reference where we penalize the product efficacy by hypothesizing that once masitinib is discontinued, patients behave like a placebo -- if they have a placebo, which is not entirely true because there is a remnant effect of the timeline where patients had benefited from masitinib. So this is a key data we think. We don't know how competitors competitive studies treat missing data. In any way, the study at week 24. So that's 1 thing which is new. The other thing has been the long-term survival, that's obvious, and this is extremely important, but it's ex-post, it's not preplan, and it's also a subset of patients. So it's not a data that is I would say the same as if it was the overall population preplanned, but still it's extremely clinically relevant. Then we have this mechanism of action which on new data that might have their importance and all the safety data. There is no product with thousands of patients exposed but we have long-term data 7 years. And we have exposed now with the compassionate use, lots of hundreds of patients. And so we have a better idea of the safety of the product. So all this helps and deserve to be presented to FDA and EMA. And on the top of that, there is the urgency for the patients to have a new treatment is extremely difficult and patients want a new treatment, new effective treatment. So we hope that we could maybe have a possibility to file our dossiers at FDA and EMA, at least we will discuss with those 2 agencies.

We have 2 other questions regarding other products in ALS. First, regarding Riluzole, can masitinib replace Riluzole in ALS patient treatment? Or does it have to be prescribed in addition of Riluzole. That's the first question. And second question is Amylyx considered a direct and serious potential competitor in ALS?

No, masitinib does not replace Riluzole since our study is on the top of Riluzole. So Riluzole is still a background treatment. And we have no data of masitinib head to head against Riluzole. So we don't have data. We don't intend to replace Riluzole. Our competitors late stage development program competitive project? Yes, they are. And otherwise, they will not be late stage or they will not be in the phase of registration, different agencies. And by the way, it's not the same mechanism of actions anyway and so complementary. So we don't have a second product like masitinib targeting microglia and mast cells. And 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 -- we think that the academic people, they need more than 1 mechanism of action to control this disease. So it will not necessarily limit the sales or the potential of any drug registered, but rather maybe amplify it.

Now if we move to other program. Are there further discussions ongoing with Health Canada regarding Alzheimer's disease or MS for approval under NOC/c?

No. And we have to focus on ALS at this time.

Maybe one last question regarding Alzheimer's program. Alzheimer's Phase III confirmatory study is probably designed to go alone. Any chance to work with partners?

We intend to initiate the confirmatory study in Alzheimer's as soon as possible. And we don't give any time line for the licensing, so I cannot answer your question. But we do not wait for licensing to initiate confirmatory program.

So if there are no more questions, then we can stop here.

If you have any questions, additional questions, feel free to ask. Olivier, you are still there?

Can you hear me?

Olivier, would you like to add anything as the Head of Science of AB Science?

Can you hear me?

Yes.

Okay. So I think it's a great achievement that Canada Health care to examine our dossier because of data, I should say, spectacular. And also on the basis of a good science we have made before to understand by which mechanism masitinib is working. And interestingly, as we have said before that masitinib is working in 3 distinct neurodegenerative disease. And because it targets always probably the same mechanism of action and targets the mast cells and the microglia and all this attributes, this mechanism that's the reason why masitinib is working and by its unique mechanism of action. So I think it's a good opportunity for us to provide this therapy for the patient because we strongly believe in the raw data is quite astonishing when you see the entry of overall survival in ALS.

Thank you, Olivier. And so I would like to thank all the participants to this call whether in Europe or in the United States. And I will just close by saying that we think of the situation in Ukraine, where we have clinical studies there, and we hope that the situation will be treated rapidly and peacefully to an end because of course, we are concerned. So thank you, everybody.

Ladies and gentlemen, thank you all for your participation. This concludes the web conference. You may now disconnect.