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

Good evening and good afternoon for the audience attending our web conference on AB Science development update. And with me this evening, I have the pleasure to welcome Co-Founder, Professor Olivier Hermine, who is a member of the French Academy of Medicine and also Professor of Hematology at Necker Hospital. This web conference will last approximately 1 hour. And we can take the questions by -- after the meeting, not during the meeting, where we -- you can write to us, and we will have a pleasure to answer your questions. This is the usual disclaimer. And as you know, AB Science has 3 platforms, which -- and we don't have the opportunity to give you a presentation of those platforms. So we will try to do it this evening. The first platform is well known and it's focused on masitinib, essentially in neurodegenerative disease. But we have also the second platform, which is in hematology and oncology, where AB Science is developing an innovation that we will try to explain tonight. And you have to know that AB Science has now a third platform, which is a drug discovery platforms with today undisclosed targets, but which aim to be developed in neurogenerative disease, which is the focus of the first platform to renew and to give new drugs for future generations. So we'll start with this second platform focused on this compound called AB8939. Now we talked about it before, but shortly. Now we would like to get into more details and give you an update of the development of this platform. The compound is called 8939. And we previously presented it as a microtubule destabilizer. But in fact, our compound is more than that. There are 2 mechanism of actions in one in this compound. The first one is microtubule destabilization that I will explain. And the second one is to target a new target called ALDH, which is strategic in leukemia, in acute myeloid leukemia, and I will explain that. And all the presentation this evening is a little technical, but that's what you want. You want to understand the value of the product and the platform. And this is why Professor Olivier Hermine is with me, is to also add maybe some comments when it becomes very technical. So I will try to do it, I would say, in an understandable way, and Olivier might add his technical and medical comments. So our compound has two mechanism of actions in one. The first one is classic microtubule is a sort of skeleton of the cells. And when a compound destabilized microtubule, you end up blocking the division or the proliferation of the cells. It's a well-known mechanism of actions used in compounds like Taxol, Taxotere. The only problem is that in acute myeloid leukemia, the disease produce an enzyme called myeloperoxidase, which will degrade the microtubule destabilizer and so shorten their half-life. And this is why those products have never been used in AML. Here, we have a compound which is not metabolized by myeloperoxidase and so can be used in AML. And the second problem of microtubule destabilizer is that they are evacuated from the cells it's called the multidrug resistance through an efflux, it's the movement to get out of the cells, where the chemotherapy will bind to a protein called PGP and leave the cells through this binding and efficacy mechanism. And our compound escape that because it doesn't bind to PGP. So already there, we have the first innovation, which might be strategic. But -- and that's why we would like to share with you tonight, our compound has a second mechanism of action. It targets ALDH. An ALDH, and I will get back to that in the presentation, is a strategic target on the stem cells, the very primitive cells that when they are mutated can give cancerous and they're extremely difficult to remove. That's why the cancers are resistant. And here, we have with this compound, the possibility to not only target the stem cells, but maybe to destroy them by inhibiting ALDH, which the product is doing. And that this mechanism is targeted to the stem cells, and it's completely new. And these two mechanisms in one can be very powerful. So we think that our compound can be positioned in refractory relapsing leukemia. And we know that unfortunately, when patients are refractory or relapsed after high-dose chemotherapy, unfortunately, they will die sometimes very quickly, sometimes less quickly, but everybody, every patient unfortunately will die. And this is what we're going to try to delay or prevent -- also our compound has a very low hematological toxicity. So that's the target product profile, but this compound is even better than what we thought before because of the second mechanism of action. Next, so we want to position this compound, as we said, when it relapse or when it's refractory. We call it relapsed/refractory AML. And you can see that there are more or less 2 categories of patients. Either the patients are young, they call it fitted and eligible to high-dose chemotherapy. So they take high-dose chemotherapy to try to, I would say, remove the cancer from the bone marrow and then to do a transplantation. 40%, 50% of the patients can tolerate that and survive. And then the other one, they will relapse. And then you give high dose or low-dose chemotherapy and then clinical studies because there is no approved drug or best supportive care. When patients are aged, they cannot go to the stem cell transplantation and high-dose chemotherapy. So the standard of care is a combination of azacitidine, venetoclax plus/minus targeted drugs. And then if it relapse and it does, then you do best supportive care and then there is nothing in clinical setting. So in the pink boxes, that's where we would like to position the drug or even in this gray box here in line 2 in relapse. That's where we would like to position the drugs, and there is a high unmet medical need there. So in terms of business, what are we talking about? The incidence case of AML for U.S.A., Europe and the rest of the world is a little lower than 100,000 cases. And as I said, 50% of the patients will be refractory or with relapse. And then the price of the product can be between EUR 60,000 and EUR 100,000 for a market of EUR 2 billion. That's the market of refractory relapse that we're targeting because there is the pink box and so nothing or very little. And in this category, you have a subset of patients that we will describe later in this presentation, which is the worst patients in AML. They all die in less than 12 months. They are called the MECOM rearrangement. And I will come to that because we think our product has an advantage in the MECOM. There are very limited number of patients. They represent roughly 5% of the AML, and so they represent a EUR 100 million market, which is okay, it's not great, but those patients might become extremely important for our compound and for AB Science. I will come back later, try to explain why we think our compound can have a good results on MECOM. Now let's go to the pharmacology data. I've tried to explain why our compound has a value and a high potential in AML. So we said that we would like to position our compound in refractory relapse. Let's try to prove it. So here is an experiment that we say is ex vivo. So it's not in an animal, it's in the labs. But what have we done? We have taken 100, I would say, cell lines, which come from the patients. And these cell lines extracted from the patients, we are trying to -- try to kill them with our drug, 8939. And as a comparator, we have put azacitidine, and I'll show you again what is azacitidine, azacitidine is, in fact, cytarabine, and it's a product which is given here in first line. And so you can -- and here, you have the concentration. So 1 micromolar you have 100 cell lines, you have roughly 2/3 of the cell lines which are refractory to azacitidine, which is a gold standard in first line. And by contrast, you can see 1 micromolar is there. This is 89 -- sorry, this is -- this part here, which is sensitive to Ara-C. And all those cell lines, they are refractory to Ara-C. So it's 90%, 95% of the cell lines which are refractory to Ara-C. And here, the black of the browner 8939, you can see that below 1 micromolar, you have 2/3 of the cell lines which are killed below 1 micromolar. So in fact, we prove here that in 67% of the cases, our compound will be able to kill the cell lines, which Ara-C cannot do. And so we can prove through this first experiment that we have a compound that can be used in refractory relapsing AML, but that's ex vivo. Now let's do it in vivo in mice. What do we do? We treat mice from week 2 to week 4, and we use our compound. And again, we use azacitidine as a control because it's a gold standard. And this is the control. It's not treated. So -- and we are going to look at the cancer cells either in the blood, as you can see here, or in the bone marrow, as you can see here. And what do we see? We see that these mice treated with the cell lines are resistant to Ara-C, but they are sensitive to 8939. And you can see here, there is no more cancers. We can see it here on the right-hand side by luminal cells, red spot means that there are still cancer cells. So you can see that at day 28 in the control and the azacitidine mice treated mice, you still have cancers, whereas in the 8939 mice, you have no more cancers. So that's a nice experiment that shows that our compound is able to cure in fact the mice, which has been transplanted with a cell lines, which is coming from patients suffering from acute myeloid leukemia. So second experiment showing the benefit of our compound in relapsing remitting end. Now we continue, and we will try to combine our compound with a gold standard called -- in fact, it's not yes, it's not assay, it's azacitidine also called Vidaza. Let me explain position Vidaza. So Vidaza, azacitidine is one of the gold standard here that we're using in the aged patients and fit patients here. Let's go back to the experiment of Vidaza. So here, I will simplify, we're looking at normal cells here in this graph, normal cells, not the cancer cells. And you can see that Vidaza is toxic on normal cells because it kills them. So we have a chemotherapy, which is toxic on normal cells. And here, our compound is not toxic, which is a big surprise because our compound is also known as being a chemotherapy. But you can see the advantage. We have a nontoxic destabilizer of microtubule. And that's an advantage because it means you can give our compound chronically, whereas Vidaza is more toxic and the use of Vidaza will be more limited. So it gives us an advantage in the treatment of AML. That's for the normal cells. Now on the right-hand cells on the right-hand sorry, side of this slide. We are looking at the efficacy in a combined manner. So you can see that each point is a mice treated. She has the control, so they have a lot of cancers there. So 8939 and Vidaza are kind of effective, but the combination is much better, true in the blood, even better in the bone marrow, you can see the mice are almost cure. So when you see that, you have the willingness to use, in fact, our compound in combination with Vidaza and that's what most of the compounds that are developed do. They have a development in monotherapy, but they have also a development in combination. And here, you can see the advantage of using our compound in combination with Vidaza with a good results in the blood, in the bone marrow and also in the sleep. Now we are doing that again, but with this time with another gold standard called venetoclax. What is venetoclax. Venetoclax is the second compound sorry, that you can see here that, by the way, is given in combination with Vidaza. The name sound difficult to remember, but now we are with venetoclax. Venetoclax, same story. What do we know about the toxicity of venetoclax? It's not very toxic. As you can see, it doesn't kill the normal cells here, like our product. And venetoclax, which has been a big success from AbbVie has been known to be a surprising drug, nontoxic, but that is very effective when it is used in combination with other drugs. So we share the same characteristic as venetoclax, very low toxicity. Now let's look at the efficacy of venetoclax alone, our compound and the combination in this mice model. So you can see venetoclax is not effective because it's no more effective than the control. That is known venetoclax however, gold standard cannot be effective alone. And you can see our compound can be effective alone, as you can see through the red spots. Now when you look at the combination -- I'm sorry, when you look at the combination, you can see a nice additive effect showing about 2 in the blood, 2 in the spleen and 2 in the bone marrow, showing that the combination makes sense. So this is very securing because in the experiment that I have showed you, [indiscernible] show the potential of the compound in monotherapy, but [indiscernible] show the potential of the compound in combination, and it seems to be even better. So we will have a choice. But in fact, our compound is suited for refractory relapsing AML. Now I'm going to walk you through this innovative and new second mechanism of action of the compound, which is the targeting of ALDH. In fact, in science, it's always more complicated than what we think. There are different ALDH, 1 and 2 and even several receptor 1. But we -- to summarize, we have to know that our compound is an inhibitor of ALDH 1 or 2. This is a very complex slide. Just trust me, we have a nice inhibitor of ALDH in different, what we call isoform. But the very important thing is to show you why we think based on our data and based on the literature that the targeting of ALDH is strategic in AML and in particular, in removing the stem cells. That's the experiment that I will explain. So we take some mice and we're going to treat the mice with our compound, 8939, but also with the gold standard azacitidine. And we are going this time to treat them at low dose because the objective is not to cure the mice, but to leave in the bone marrow some cancer cells still left that we call blast. And this is what's happening. So you can see here on the right-hand side that there is still blast in the bone marrow, as you can see here, treated with 8939 and with our assay and with the combination. And what we don't know in this bone marrow is if you still have a stem cell or not, you have cancer cells, but do you have stem cells. And the goal is to remove the stem cells. Now why it's very difficult to know? It's because stem cells are isolated. So in a sample, you might have 1 out of 100,000 cells as a stem cell, and it's very difficult to detect them. So that's why we have -- we take what's left in the bone marrow. We don't know if there are stem cells there. But to know, we're going to reimplant these cancer cells in new mice, and we are going to see if the disease restarts. If there are stem cells left, the disease will restart. If there are no more or very low stem cells left, then the disease will not restart. And here, what do we see in the reimplanted mice, we can see that from that sample assay the disease restarts rapidly, meaning that there are stem cell there, meaning that assay has no capacity to remove the stem cells, whereas with 8939, you have no restart of the disease, which means, yes.

Yes. Just to summarize what you have said very clearly, is that when you have a population of leukemic cells maybe 1% or 1 out of 10,000 sometimes 1 out of 1 million cells what we call the stem cells. And these cells usually are not sensitive to classical chemotherapy. So you can have a very efficient chemotherapy, which kill all cells except 1 out of 1 million. And these cells, when you stop the chemotherapy, they will go back and we start to announce a new tumor. And what we have here with AB8939 is that we have a mechanism of action which kills the dividing cells by disorganizing the microtubule and then kills also what cells are sleeping and what we call out of the cycle, not sensitive to chemotherapy. And these cells, if you kill them, you can never start and relapse in the disease. So I think it's because of this dual activity, you can see exactly the experiment we show here that the cells that remains here are not able to engraft the new mice, meaning that we keep what enhance and what produce the secondary tumor.

Thank you, Olivier. And so that is new, and that might have a huge impact in the future of the development of that drug. So let's continue, and let's share more data with you. So where do we stand in the program? We are in Phase I. And this Phase I is step by step because it's a toxic drug that we're giving to the patients -- that we are giving to the patients. So the step -- sorry, the step 1 was to give the drug for 3 days and no more and then to find the maximum tolerated dose. And as you can see, there has been 9 substeps and we found the dose which is acceptable for the patients. Then we moved and it was -- it took us 28 patients to do that. Then we move to the step 2, which is to give the drug for 14 days. Just I would like to be clear, in 3 days' time, you cannot really show any efficacy or observe any efficacy in the patients. Now we move to the step 2 and the step 2 is 14 days. And 14 days is beginning to be a little bit more interesting for the patients who are still in the safety designs. And we have started with the dose below the safe dose here and then we increase and we are finishing -- in fact, we finished the step 2 this month. And we are going to move to the step 3, which logically on the basis of the mice data that we have observed is a combination strategy where we're going to combine our compound with venetoclax or azacitidine, preferably venetoclax, [indiscernible]. And then we're going to do what we call the triplet, okay? Here, it's a doublet, 89 plus something, so venetoclax. And here's the triplet. We're going to add an azacitidine and venetoclax. And you remember, back to those slides, okay? That's azacitidine. It kills nicely the cancers, and that's venetoclax. And the triplet will be the sum of the 3, and that might be a killer, as we like to say. So -- but we have to be careful because we have to find the right dose of 8939 to be combined by those 2 approved drugs. So we're going to do that as a next step. Let's continue. We would like to share with you some, I would say, a case report, as we like to say. So the first one, we already presented to you, but let's remind it because it was an interesting one. It was the first in-human dose, extremely low dose and only 3 days on these patients who was aged and refractory to the 3 gold standards that we have just described, azacitidine, venetoclax and assay, just to give the challenge for the drug to do something at that low dose. And we saw a beginning of a response because the blast in the bone marrow have gone down from 15% to 9%. The threshold that we like to pass is 5% just for you to appreciate the quality of the response. But still, it's a partial response. And you can see also -- you're not hematologist, but the neutrophil in the platelet count are fine, which means that the bone marrow can produce the hematological cells. And you can see that by looking at the number of neutrophils and platelets. It means that the bone marrow is regenerated, so to speak.

Can I say something from this patient? What we observed here. First, it is a highly refractory patient, elderly patient, which usually have no treatment possibilities. And also because they are old, usually they die very rapidly because any treatment we use are quite toxic. Here, what is very interesting is that, first, we do see a reduction of the blast count probably due to the effect on the microtubule. Second thing which is very important and what keep patients with leukemia, we had no toxicity on neutrophils and platelet because they did increase, whereas we didn't cure and remove all blasts from this patient, which is very rare in treatment of leukemic patients. It's very important because even if we don't cure the patient, we have a normal value in the blood with respect to neutrophils and platelets, no bleeding and no infection for this patient. And more interestingly, only with 1 dose, you see the patient died almost more than 1 year after the first injection, meaning that we are probably preventing the relapse. And then even if the patient was not in complete response, we have probably killed part of the leukemic stem cell, preventing the massive proliferation and relapse of this patient because after 1 dose, you see almost 1 year of overall survival with a normal blood cell count, which usually do not cure in patients with leukemia because when they are in relapse, they died very rapidly in 3 months period of time, mostly for elderly patients. So these results were very, very, very surprising and also very convincing about the mechanism of action of what we do see here.

And so that one we communicated to you, but not in details. Here, you have more details and you have the medical explanation from Olivier. So the next cases that we like to present is this one. Here, we are in 14 days in the step 2 at the dose which is considered as normal, I would say. That patient is young, but has an adverse cytogenetic risk. So it's much more difficult to treat those kind of patients, and it was in relapse. And after one cycle of 14 days, his blast count, which was 55%. So you imagine in the bone marrow, is bone marrow was populated by 55% of blast. So almost more than 50%, so leaving little room for normal generation of cells. And in one cycle of 14 days, it went down from 55% to 8%. So the cut of 5% is not passed, but it's a deep response, right? It's a deep response. In the blood, it has also decreased. And the neutrophil met the criteria known by the hematologists, which is above 1 giga per liter. And so it was a very satisfactory response. I don't know, Olivier, if you want to comment on that slide.

I think it's similar to the previous question because here, in addition, we show that the patient has a very aggressive disease. Also he received before high-dose chemotherapy, what we call flag and Idarubicin. He has also quite of adverse cytogenetic risk. And this patient responds very well in terms of, I should say, inhibition of the proliferation going from 55% to 8% without toxicity because he can increase his neutrophil count, which is very good. And so this one show -- and we have not yet the follow-up to this patient to see if indeed it will relapse later on and what is the time after this injection, is still free of blast in the circulation, which are proliferating.

Thank you. Then we move to this section on MECOM. You remember, MECOM, I told that it's a subpart of the patients who unfortunately have the worst prognosis and where we think that our product might help, and I will explain you why under the control of Olivier. So what is a MECOM? MECOM is a first -- let's start before explaining what it is with the prognosis. The left graph is interesting. You can see in AML, the survival depending on the genetic. And so you can see at the bottom, that's a survival depending on the time. So they are almost all dead at 2 years and more than 50% are dead at 1 year. And the worst of the worst is the blue -- light blue line or curve. And what is it that's what we call and the [indiscernible] MECOM. So in fact, the MECOM patients, they are those ones here that represents in this sample, 3%, I said 5%, it's 5%, 3%, 4%, depends on the studies. But you can see they are the ones with the worst, most pejorative prognosis, okay? So it's a challenge for the hematologists to treat those patients because they are refractory relapsing to everything. There is no treatment for those patients. And when you take those patients here, so the abnormal chromosome 3 abnormalities, as we like to say, you have 2 populations, first line and then when they relapse. So untreated is first line. So you can see they almost die 24 months, is this curve here. But if you take them in relapse, which means second line or later, you can see that they are almost all dead at 12 months. So in less than 1 year, all dead. And in 6 months' time in relapse, 50% of them will already have died. So it's frightening, in fact. And this is the super high, high unmet need in AML. By the way, AML is an orphan disease, orphan by the number of patients, but often also by the lack of solution that we have. And here, we are on a subset of those patients, the so-called MECOM that is important for AB Science and for this drug. Now let's move to the next slide. Alex I try to -- Olivier, I talk under your control, but that's the extract of a publication that I would like to make it understandable so that the audience understands why we think that there is a case of 8939 in MECOM, whereas no treatment the MECOM respond to no treatment. It starts with ALDH. ALDH is the target of our products. So how can we link ALDH with MECOM? That's the question. So ALDH is a marker of the survival prognosis in AML. That is known. So in AML, the higher the expression, the worse the prognosis that we know, that's published, okay? All right? And we know MECOM as the worst prognosis for. So maybe there is a link between ALDH expression and MECOM. It's not obvious, but maybe okay, that would explain the poor prognosis of AML. Now what do we know that MECOM is a rearrangement or mutation of this part of chromosome 3 of the locus Q26 that encodes for what for a gene, which is a transcription factor called EV1. That is the important gene, EV1. And what EV1 is doing, that's the key of the story. EV1 is a regulator of the expression of ALDH. That's the link. EV1 is a regulator of the expression of ALDH. And it has an outstanding role in the formation and transformation of hematopoietic cells, the one in the bone marrow and in particular, stem cells. So what we do believe, and we hope it's more than a hypothesis, but at that time, let's be cautious, we call it a hypothesis, is that in MECOM, this rearrangement of this part of the chromosome 3 will lead what we can call so EV1 to over-express ALDH, which will induce a high resistance of leukemia stem cells, which will lead to poor survival, okay? And because we act on the ALDH, we might overcome this resistance in particular, not only in MECOM, but in particular in MECOMs. If that is true, maybe we can provide a solution to the MECOM. And you have seen that we have that AB8939 has an impact on the leukemia stem cells, as Olivier said, 1 out of 100,000, 1 out of 1 million, they are all invisible. So it's difficult to detect. But if that is true and it seems it is, then maybe we have a solution to offer to the makeup. Olivier, I don't know if you want to say anything on that?

Something which is very interesting is that MECOM, leukemia usually are not very proliferating. So because most of the population is made of cells, what we may call stem cells because they do express ALDH1. So in most of the cases, these cells do not proliferate that much, but they remain in the bone marrow, preventing the normal cells to proliferate and to differentiate. So the patients are neutropenic and no platelets and anemic and they died of that, but not of the proliferation. And they are quite resistant to any treatment because they are the phenotype of stem cells. So here, if we target the stem cells with our product by targeting ALDH1, we will kill these cells or at least we will prevent that they proliferate and also we prevent that they prevent the normal cells to proliferate. So this patient will have normal neutrophils, normal platelets, normal hemoglobin. They will not proliferate that much because we target ALDH1. Eventually, we may kill these cells by the effect of the microtubule disorganization. So it's a perfect type of leukemia, which usually is, as I said, with a poor prognosis, but in the case where you try to target ALDH1 might be a good prognosis in this case.

So let's see if the hypothesis stands in humans -- in nonhumans, in nonclinical and in clinical. So what do we have in MECOM and that is new for tonight. So we have -- you remember -- sorry to make some backward, but you remember that slide, 100 cell lines. Well, since we had 100 cell lines, we looked at how many MECOM we had. And in fact, we had 4 MECOM, which is kind of okay, we said 5%, 4%. So we had 4 cell lines, which are MECOM and what we can see here, that's the concentration of 8939 to kill the cells. We see low concentration here. So 2 out of 4 cell lines our product could kill the MECOM cell lines, which are refractory, 2 out of 4, 50%, but not 100%, 2 out of 4. Then I showed you, you remember, the combination with Vidaza, which was perfect in terms of curing the mice from cancer. We looked at the genetic of this cell line transplanted in the mice, and it was a MECOM. That is very interesting because in vivo, in mice, but in vivo, we could cure mice, right? So -- and then we went -- we look at our data in Phase I. And you remember, we have treated 28 patients in step 1 and now 10 patients in step 2, 38. And we have 4 MECOM, 10% and it's normal that we have more than 5% because we are in refractory relapse. So in fact, the refractory relapse will select the resistance and so select the MECOM. So even if in first line, you have 4%, 5%, you end up having twice more in relapsed/refractory. So it's normal that we have roughly 4 MECOM. Now out of the 4 MECOM, we have 2 response and huge response, 55% to 5% and 13% to 3% that I will show you. That is very good. Why? Okay? It's not 100%, but we have roughly 50% in nonclinical, 50% in clinical, and it works in mice. So 9 data, and we have 5 positive data out of 9 data. So I don't know if you want -- before we present the case, if you want to say something about that, Olivier, this data in MECOM?

No, I think this data confirm that we have seen in patients and which is quite interesting. And because usually, we don't see such a response in this type of leukemia in PDX model. So I think it's very encouraging that it might be a good population to target, although it is a worse population, but if we can improve even a little bit, it will be very nice.

I show you the 2 responding case. So that one was at 3 days of treatment, very low dose. The patient was between old and not old, and it was refractory to azacitidine. And here, we have a complete response with a decrease of the bone marrow from 55% to 5%, which is quite spectacular. And you have a nice level of neutrophil and platelets. And so the patient is responding really. And you can see he died, but he died, we treated it 3 days, but he died close to 1 year. And you remember he was there. You see, you remember that curve. It was on that part there. And you can see the number of patients surviving close to 1 year in MECOM in relapsed/refractory, almost nobody. So if you make a MECOM survive 1 year, it's almost impossible, given that curve. And that patient was there after 3 days of treatment with our compound. So noticeable. Then we have that case. So that case, the patient's MECOM was treated 14 days, and it was refractory. And again, he has a complete response because his bone marrow responded from 13% to below 5%, 3%. The blood also circulating cells went down and the level of its eosinophils, platelet was completely acceptable. And so it's a clear response -- complete response for this MECOM patients. So it's part of the 2 patients that you see there. So well, we have 50% response. Now in the next slide, I try to make you understand what we can do. First of all, we're in Phase I and the Phase I is not finished because as you have seen here, we will do the combination, still Phase I, right? And the combination might be useful when you see the data in mice. And so the next step would be to do a Phase II in MECOM. We really are thinking of doing a Phase II in MECOM, although the market is very small, but it represents EUR 100 million. But still, it's okay for us, right? And the interesting thing is that we could and we will -- we will discuss with the authority soon, authorities being FDA EMA. We will discuss a registration Phase II -- that's what we want to share with you tonight, a registration Phase II. What could it be? It could be a single-arm study, noncontrol with less than 60 patients, not a lot, but it's very rare. So -- and we know that there are some response still because patients participate to clinical studies. And the response rate is 14% to beat. And you have seen that we are doing rather 50%. Of course, 2 out of 4 is 50%, 2 out of 4 nonclinical is also 50%, 5 out of 9 data that we have positive is more than 50%. So the 50% is based on very limited data. But anyway, there is very limited number of cases. So the question is, what we have seen so far, does it give a good hypothesis for the Phase II that will recruit a very limited number of patients, less than 60. Maybe yes. And if yes, and if we do -- we don't need to do 50%, we need just to be 14%, right, to win. Let's show you some examples of other development in AML. The main inhibitor are new class of drugs. And one of this drug has been registered recently with a Phase I/II that is there which is 95 adults, but it was a Phase I/II with in the Phase II only 57 patients. And it's a targeted drug for those mutations here, the arrangement of dead gene, which is complex or mutation on dead gene here. So it's totally new. They have just been registered by FDA in November this year, okay? And the company, the biotech is called Syndax that you can see here at the bottom, Syndax. So in this targeted therapy, we also have a targeted therapy on ALDH, so to speak, and stem cells. Here, Syndax has run a 95 Phase I/II study, but only 57 in the Phase II. And so they've registered on the 57. And they have showed in relapsing remitting for their category of patients, a response rate of 23% complete response rate or near complete, close to complete of 23%. That's it. And they have been registered, right? And as you can see here, the second drug called Ziftomenib belonging to Kuva is another biotech, they are doing like us, 30 patients in relapsing remitting, right, and very limited number of patients, and they will compete not with us, but with the other Menin inhibitor that targets this mutation and this region. So you can see that the way that we are proceeding is that we try to understand what's the target of the product, and we try to focus on the patients who can benefit the most from the target. So here in the Menin inhibitor is those mutations. In our case, it is maybe the MECOM and you can see here, in fact, the MECOM is more rare than the mutations developed by the -- sorry, that the mutations developed by the Menin inhibitor. So if they could do it with 57 patients, maybe FDA would accept an even smaller Phase II with MECOM, like less than 50. Who knows, maybe 40. We don't know. We're going to discuss with them, and it's an open label. So it's something we can do that is not that expensive. And although the recruitment is a challenge because it's rare, it's not impossible, right? So it's something that is in the range of feasibility. That's what I would like to share with you. It's done by Syndax for Menin. We could do it for MECOM and there is no competitor for MECOM. So...

Just to add something here is that now we are changing the paradigm of treating patients with leukemia because when they are refractory to either high-dose chemotherapy or the combination of like aza plus venetoclax, any kind of chemotherapy we will not work in this patient. So now what we try to find is to find targeted therapy, which may work in this patient. And now because of the progress of molecular biology and cytogenetics, now we have cut the leukemia in different subtypes. And Menin is an intermediate group of prognosis. And now we know that a very poor prognosis. But if we can target this population, even in a nonrandomized study, if we do show response rate and also increase of the overall survival, we may register with a very low number of patients.

Yes. Then the second objective is to capture the full market potential in broader forms of AML, so not limited to MECOM because it's not because our product could be a good solution in MECOM that we should drop all the other ones. So for the other one, it would be maybe another Phase II, second Phase II, which we have mixed here 2 ideas. But the first idea is to stay in relapsed/refractory and to try to do a study, but that would be a more number of patients like probably we don't know, we have to discuss with the authority. And we'll see if we can combine or do it in monotherapy, we have to discuss. But we could try to do a Phase II in relapse. But there is another idea. You have seen that we have nice data in combination with venetoclax and azacitidine in mice. And you have seen also that in the Phase I, we're going to go for the triplet. So we're going to test the triplet. And the duplet, venetoclax, azacitidine is the gold standard in line 1. So I show you the slide again. Okay. So azacitidine, venetoclax, which is here, azacitidine, venetoclax, that's what we are doing. We are combining those 2. It's what we will do. We're going to combine those 2 agents with our company, the triplet. And it's the doublet, which is a gold standard. So once we have done that in the Phase I, we have the choice to position the triplet somewhere here in the pink box or we can go first line. First line is much more difficult in terms of development. We can stay in the pink boxes and try to develop a triplet or a doublet or even a monotherapy in non-MECOM. That's one possibility that we have here or we go first line, which is more challenging. In fact, we can do the 2. So there are 3 types of pathway. The first one is MECOM. It's a sort of short study, which would be probably desired by everybody because the patients die. The second is to try to treat the relapsing remitting where there is no approved drugs really and then to move to first line, okay? So that's the 3 ideas that we will try to do in the future when we start Phase II. And we are going to discuss this strategy with the authority in the first semester of 2025. And in parallel, we'll finish the Phase I with the combo. And then we will be ready to start the Phase II. So we will do the 2 in parallel, finish Phase I and I would say, aligned with the FDA and EMA on the strategy of the Phase II with 3 options in mind, MECOM refractory relapsing and even first line that we should not abandon. The intellectual property is good. We are protected by orphan drug in the U.S.A. the compassion of matter protects until 2036. We can have a 5-year extension if we want after that. And there is even the second medical use patent. I don't know if you remember, but when we saw the first MECOM, we actually have filed for a new patent. And so that would protect the MECOM until 2044. That's what we can say on this second platform. It's a little long and technical, but we hope that you have learned the potential of 8939. And I would say that I go back to the very first slide, you remember, we have 2 compounds, in fact, because this first one is in injectable. That's why we're developing in hematology. But there is a second one, which is oral. It's still in nonclinical and that could be developed in solid tumors, and we would do sarcoma. So that second compound has the same characteristic and could also remove the stem cells, which is also a challenge, but not in hematology, in sarcoma or some solid tumors. So what the message we would like to pass there is that AB Science has invented a new platform, which is very innovative in the sense that it has 2 mechanism of action in one and in particular, the stem cells and removing the stem cells or addressing the stem cells issue in oncology in leukemia, but outside of leukemia is very innovative. It's something which is not touched today. And we try to -- we will try through that platform to pioneer it and use maybe MECOM as the first difficulties on the road that we could solve. If we can bring something to the MECOM, it will be a good, I would say, a good entry for the rest, and we could then continue the development of that strategy in AML and beyond. Now I know that you have questions for the second platform masitinib platform. So I'll be short, but I know that you want to know where are the discussions on the partnerships and the discussions are ongoing. That's what we can say and no more. And AB Science will provide an update on masitinib in the different indications in the next communications, but not in this one. And we will do that probably beginning of January. But certainly, the question you have in mind is where is the discussion of the partnership, they are ongoing. Now let's do a few words on the financing. So we have raised EUR 5 million in Q4, which provides a financial runway for more than 12 months. So we are secured until at least the end of next year. And we would like to share with you the financing strategy of those 2 platforms. So for masitinib, it's clear, it's the partnerships. And everybody knows that, right? And we're working very actively on that. But there is a project which is already financed, which is the sickle cell because the sickle cell and Olivier is there, he is the one who has been instrumental for that. He has succeeded to convince the jury to finance the Phase II. It's a public program, but we keep the rights in case it works. And there is a significant grant of EUR 9.2 million. So it will take 2 years, and Olivier is on it. Olivier, you want to give maybe short -- just a word because we're going to develop in January, just a word.

We show that sickle cell disease, which is an hemoglobin disease activate abnormally the mast cells, which cause all of the symptoms that the patient experience, including neurological symptoms and skin symptoms and so on as we do see in mastocytosis. So we made the hypothesis that if we do block mast cells, we may improve the general status of this patient. And we have evidences in mice models and now we are ready to start the Phase I study in patients with sickle cell disease to prevent this complication.

Thank you. So Olivier is going to be the one leading in this. This is -- we'll go back to that in January because we have a lot to say about that, that will explain you where we stand as compared to the landscape. What we're going to do is the landscaping of different projects as we try to do today for AB8939. So AB8939, the Phase I is financed through our equity raise and the money we had at the bank. The Phase II, we will do it on our -- I would say, on our money, but the data that we are generating, although preliminary, are capturing the interest of potential partners that we will -- and we'll continue also we have started some discussions and the strategy is to collaborate on our different platforms, I would not say as soon as possible, but to collaborate because it's a more secure way to develop the drugs. And we are doing that on masitinib very actively, but we will also do it on 8939. The data are preliminary, but they are very interesting. And it's for sure, there are potential partners in this world, which are in AML today, which will be interested. So that's what we would like to share with you. It's already 1 hour. So we don't -- the way we'll do -- take your question is that I don't know if Alex is there and want to share the e-mail or give the e-mail where you can send questions. Otherwise, what we will do is that we'll do a writing summary of that, and we will send you an e-mail address where you can send the questions, and we will try to respond to your questions. And also for the ones who are -- have difficulties to follow in English because we had to do it in English since there were -- some of the audience were English speakers. We will try to do a translation in French because we recognize very technical, difficult to follow. But if needed and if you want, we will try to do a translation in French of this presentation. Olivier, do you want to have the last word? Maybe no last word. So probably he has gone already back to the hospital.

My microphone was mute. Okay. No, no. I said, it is a very promising new development, AB8939. And maybe we change the life of some patients in leukemia significantly with really an unmet medical need.

Thank you. That's what we will try to prove. There are companies like, for instance, Blueprint, who started very small by taking a fraction of the GIST patients refractory, address that and then build up. So we think we should do the same and target something maybe small, but not done by nobody with a targeted therapy strategy, try to prove something 14% to beat if we do -- if there is one thing to keep in mind, Syndax registered with 23% near complete response rate, 23%. It's not a lot, okay? In these patients who do not die as rapidly as the MECOM. So in fact, people think, I don't know, Olivier, if you would share. But if we show with 8939 in MECOM something like around 20% plus, a little bit sustainable with survival, a little bit of survival, it might do it, right?

Yes. Although I think later on, the drug will be even better in first-line therapy. But first...

Absolutely. So MECOM, relapse remitting, but don't forget first line. So we will try to show that. And thank you for listening, and we will come back to you early January for more information. Thanks.

Thank you.

Thank you.