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

Good morning, and good afternoon for the participant to our web conference organized by AB Science. About an update of the clinical development of our asset called AB8939. My name is Alain Moussy, I'm the CEO of the company. And with me today, we have the presence of Nicholas Short, who is Professor at the MD Anderson and heading the Department of Leukemia; Olivier -- Professor Olivier Hermine, who has cofounded AB Science and is in-charge of the hematology department at Hospital Necker in [indiscernible] and also Chairman of our Scientific Committee and also a member of the French Academy of Science. And also Christian Auclair who is ex Co-Director of CNRS and IDR and a pharmacologist expert. And with me as well, Laurent Guy, Chief Financial Officer, who will at the end of this presentation, take your questions so that we can answer. So the principle is the same as before. We'll have a presentation which will be rather technical given the content. And at the end, you will be able also to ask the questions, and we'll take some of them and try to respond to them. The questions has to be phrased by writing. So today's objective is to update you on this second platform that we call AB8939 because it's our lead drug and as you know, we are in the middle of a Phase I, and we have some news for you. So what we are trying to do is to develop this drug in acute myeloid leukemia, which is the most lethal leukemia in humans. And their own drugs registered which aren't here on this slide. But 70% of the patients end up anyway dying from this disease. And the 30% who survived, they are the ones who can benefit from a stem cell transplantation which will set them. But most of the patients, they unfortunately cannot benefit from this because it's too toxic or they do it and they relapse. And ultimately, regardless of the treatment that they will take in first line, where most of the drugs are registered, they will relapse and die. And so it remains a huge unmet medical need in this terrible disease. And what we know from the experience is that AML is a heterogeneous disease with outcome that highly depend on genetic factors. And here, we would like to show you a publication which comes from [ Donare ] and which gives the outcome results in terms of survival on one line of treatment. I show you -- a return to the previous slides. You can see here, in first line, when patients cannot take the high dose chemotherapy that we need to do stem cell transplantation, they take a combination treatment of azacitidine and venetoclax which is the standard of care. And the next slide, I'll come back to that, tells you what is the outcome of this treatment depending on the genetics. And you can see here in the red circle, the outcome is completely different, depending on the different mutations that the patients can have. And so it's interesting to see which ones can benefit from the treatment, which ones cannot with some survival, which are very low, like in average or median 5 months or 12 months. And in fact, the high risk, the one with 5 months is essentially made of one mutations called TP53, very well known from the oncologists. And the intermediate encompass two mutations called NRAS and KRAS. So if you want to memorize why I think from this slide, so we know the mutations and it's the problem. So we desperately need drugs that could address in particular this type of mutations because they lead to very poor prognosis. Now one more, I would say, genetic, which is, in fact, the worst prognosis in AML is what the oncologist called MECOM. And the MECOM is a rearrangement, not a mutation. It's a rearrangement of some chromosome, chromosome 3 and you can see here the blue line, that is the survival as compared to other kind of arrangements. And you can see it's the lowest one, which means the lower survival. So the survival is very, very low. And in fact, on this right-hand side, you can see the outcome depending on whether the patient is in first line and treated here or in relapse already. And you can see in the relapse, it's terrible because particularly all patients die within 12 months. And so the median is, in fact, less than 5.5 months. So it's even worse than the TP53 that we have seen in the last slide. So we have already in mind, MECOM, TP53, NRAS, KRAS are all names like that, but it's the mutations that are problematic in AML or the rearrangement that are problematic in AML. Now what can our product do in this disease? So we see a problem, the cell lines, the cancer cell lines are very resistant to the treatments. That's the problem number one. And we propose the product that we have designed offers a new mechanism of actions. It will. This time it will target microtubule, which you can memorize as being the skeleton of the cells. So when the skeleton is destabilized, it does not divide. And that is a very well-known mechanism of action because it was used in products very famous like Taxol, Taxotere, vincristine vinblastine but never in AML for two reasons. Those drugs are eliminated from the cells, the cancer cells by a natural process, I would say, called multidrug-resistance, which consists from the cells to produce a protein called PGP to bind to the chemotherapy and evacuate or wash out literally the treatment from the cells. And so that's how they survive. And the other mechanism of resistance is that those compounds, they are immediately but immediately in 30 seconds, degraded by an enzyme produced by the disease called [indiscernible] So that's why they never been used or if they have been used, it was a failure. And our product has been designed to avoid it. And so it doesn't bind to PGP and it's not metabolized by [indiscernible] So for the First time, we'll be able to use this very effective mechanism of actions, microtubule destabilization in AML. The second problem in this disease is that, despite a very toxic chemotherapy used, there is still some cells, which are the very primitive cells called cancer stem cells that is not killed, destroyed by the treatments because they do not proliferate like the other one. They are more silent. And so those stem cells, even little remains, they will restart the disease immediately and the patients will be -- even if there is a partial response. So the first problem is no response here. There is a response, but then there will be a relapse. And this is really a problem. So we address it through our compound by trying to target the stem cells. And we have found a target, which is ALDH, which actually is very relevant to the stem cells. And if we inhibit IDH, which the product does, then we have a chance to kill the stem cells. So in fact, this product, our product proposed 2 very innovative mechanism of actions that, of course, is of interest for the hematologists. Now I'm going to show you some data that have been already presented just so that you can follow what the product can do in the worst prognosis, so the bad mutations, let's call it. What do we have? This is cell lines, in vitro, as we said. And we have used as a control -- there are 100 cell lines here, and we have used as a control a standard of care called Cytarabine. And when this, I would say, the bar is high, it means it's -- the product is not effective on the cell line. So you can see here all those things. It's the Cytarabine. So it's not very effective in 100 cell lines. And in fact, 8939 was much more effective to kill the cells. So here, we have 66% of the 100 cell lines that we have tested that could be killed by 8939 and was not killed by Cytarabine. And in particular, it included cell lines that bore the TP53 mutations, the one we have described before and even the MECOM. So that gives some hope, right? Then that's another way to look at it. Here, you have a selection of cell lines to illustrate. And you have lots of problems here. Mutations, you can see the TP53, you can see a complex karyotypes, complex rearrangement of chromosome for instance, you can see RAS mutant here, for instance, and you can see MECOM. And when there is one, it means it responds. When there is 0, it doesn't respond. And in fact, you can see here, the standard of care, azacitidine and cytarabine, the concentration needed to kill those line is very high, so it means it's ineffective. And 8939, it's very low. So it means it's effective on all those cell lines that bear -- that had this complex karyotype or TP53. So for instance, here, there is a MECOM and it created that concentration, okay? And here, there was another MECOM. Here, there was a TP53, and it was effective. So it's another way to show that our product is effective in some situations in in vitro. Now we did in vivo in mice, of course. And we used a cell lines to graft the mice coming from patients with MECOM. So the terrible rearrangement. And we so grafted the mice, and we use venetoclax, which is one of the standard of care or venetoclax in combination with our drug. And the first thing here to see is this visual. Here, it's the normal cell lines, not the cancer cell lines. And so you can see venetoclax is not so toxic and our product is not so toxic. It means it will not destroy the hematopoiesis, so the production of the red blood cell, the white blood cells by the bone marrow, which is good news. Now let's go to the cancer cell lines on the right-hand side. And here, you can see that venetoclax, which is high here in the blood, in the spleen, in the bone marrow, cannot kill the cells. It cannot kill the MECOM, right? And our compound, 8939 can, but with some lack of efficacy still. Now when we combine them, it's much better. And so we think we say through that, that, of course, there is an additive effect or even a synergistic effect to combine the drug. And as you know, the purpose of today is to show you the impact in humans, but this is in mice. Now we do the same with the same cell lines grafted in the mice, but with another standard of care, which is Vidaza. And here, you see Vidaza is toxic on the normal cell lines, hematopoietic cell lines. It's very toxic. And in here, our product, single agent is not. So we knew that. So we say our product is not as toxic as some other treatments. And when we combine the treatment, so Vidaza has kind of similar efficacy of 8939, but when we combine with a very, very effective drugs, but one is toxic. So we might not want to use a toxic drug. We might want to use something less toxic like venetoclax in combination in humans or we can do the 3 together, we will show you. Now that visual, we already presented, I want to show it again. It's to illustrate the capacity of the drug to eradicate stem cells, which is far from abuse. So what did we do? We took some mice, and we treated them only for 4 days by cytarabine, that's called RSa, our component or combination, but at very low dose so that at the end, it remains some cancer cell lines in the bone marrow, as you can see here. And in these remaining cell lines -- sorry, cancer cells, we don't know if there are some stem cells. So to know that, we're going to reimplant what's left in new mice, and we're going to see if the study -- sorry, the disease is going to restart. And if it restarts, it means that the stem cells are there. If it does not restart, it means that the stem cells are not there or they have been considerably reduced. And here, as you can see, with cytarabine, there is a restart of the disease as is not the case in 8939 of the combination. So we prove here that our compound really has an impact on the stem cells. Now we, as you know, have -- we are in the middle of the Phase I, and we have finished the monotherapy with 3 days as we have to do and then 14 days, which is more interesting. And this is finished, and we found the maximum tolerated dose. But in AML, all drugs are developed in combination. So -- and one of the key question is what combination since we have the choice. You have seen in the first slide that there are multiple drugs. So it's not so obvious to find the right combinations and also the right population, right? So we are -- we have engaged in the most interesting part of the Phase I, which is the combination part that we do at 14 days of treatment of 8939. And we are going to do the first combination with venetoclax, and we are going to do then what we call a triplet with venetoclax and azacitidine. That's what we're going to do. And in monotherapy, here, it's a data in monotherapy that you have already seen. In monotherapy, we have already some signal of efficacy in MECOM. We knew it from the in vitro test, as you know. So I showed you we had 4 cell lines and 2 were responsive. But in humans, we have treated 4 patients and 2 were responsive, which is very good in MECOM. And the survival are also very good. You remember that all patients died in 12 months' time. And here, we have a survival at 18 months, which is good, very good and 11 months, which is also quite good. So there is some signal in MECOM in monotherapy, although we prefer by far to go in combination. And the combination therapy is what's new today really. And I will leave it to Professor Olivier Hermine, hematologist to describe. Olivier, if you can take over. Are you there? And maybe you should...

Can you hear me? It's okay?

Yes. Okay.

Okay. So welcome to everybody. And so as Alain said, in leukemia, there is chance to have some drugs working in combination. And probably the drugs we have used may synergize with venetoclax, which is an inhibitor of what we call BCL-2, which is a survivor of genes. And we know when we use some combination, we may sensitize the cells to cell death when you add venetoclax. So it was a strong rationale to use the combination of our drug with BCL-2 inhibitors. Can I go to the next slide? So we did try to test 3 patients where previously heavily treated patients in line 3 or 4 of leukemia with what we call high-risk adverse profile with complex karyotypes, mutation in TP53, MECOM rearrangement and NRAS mutation. And we know that this patient have a very, very, very short life expectancy, mostly when they are in second line or third line or eventually in fourth line of treatment, as we can see here. So we -- I will show you the details on the next slide of this patient. So okay. So this first patient was an elderly patient, 74 years old. And with 3 lines of prior treatment, including high-dose chemotherapy, azacitidine and a new compound. And he has a very poor leukemia -- prognosis leukemia because he had a lot of cytogenetic abnormalities. And in addition, he had a mutation in HRAS. And we know that this mutation is associated with a very poor prognosis. And very interestingly, when this patient relapsed with excess of blast in the bone marrow, 8%, we can see after treatment, after 1 set of treatment, you see a decrease of the blood count to disappearance at day 49, meaning that this patient is in complete response. And when you look at the peripheral blood, you see that neutrophil counts increased from 4,000 to 5,000, meaning that the bone marrow start to work again. And the platelet counts remain at the stable level, meaning that we have not too much toxicity in the bone marrow to this patient, which is a great result that we -- it is highly unexpected to see a disappearance of the blast with a normalization almost of the peripheral blood, except that the platelet remains low, but this patient have received a lot of treatment before and probably bone marrow is not very well working. But anyway, with this kind of blood test in the periphery and the reduction and the disappearance of the blast in the bone marrow, it may have a normal life. The second patient with also, old patients, 73 years old. When I said old is old for leukemic patients because we cannot do too much high-dose treatment in this patient and no bone marrow transplantation as well. So this patient received in first line azacitidine and then high-dose chemotherapy plus venetoclax. And it's very important because this patient receive venetoclax, and we know that the chemotherapy may sensitize the cell to venetoclax, but anyway, remain refractory to this treatment. And when you look also the characteristic of this patient, he has a very complex karyotypes with a lot of abnormalities as you can see here. And we know that this complex karyotype are associated to a very poor prognosis. And interestingly, he has an overexpression of EV1 that may come, which is associated also with a very poor prognosis and he has also an undifferentiated acute myeloblastic leukemia. And you can see here in this patient after only 1 cycle of treatment, the number of blasts remained stable and even reduced by 50% from 20% to 8%. And you can see also, which is very interesting, a delay in the reduction of blast probably because, as Alain said before, we target the leukemic stem cells. But interestingly, you see also in the peripheral blood, the disappearance of the blast, the leukemic cells. And associated to that, we have a stability of the neutrophilic count and the platelet count. So despite the reduction of blast, we still have a normal number of white blood cells and the platelets remain always low in this patient heavily pretreated. And what is also very interesting here is that this patient received before venetoclax, and here with our drug, we can resensitize these patients to venetoclax, which is very interesting in terms also of proof of concept and mechanistic understanding of our drug. Next slide. So the last patient was a patient of also 75 years old who received high-dose chemotherapy and he is in progression of 1 line, he received a second line of high-dose chemotherapy and it was primary refractory to both treatment, meaning that he has a very aggressive leukemia. And then we used the standard of care, which is a combination of azacitidine and venetoclax and also refractory to the treatment. So this is a primary refractory to everything when you look at this patient. And here too, he has a complex karyotype and a mutation of TP53, which is also associated to very poor prognosis when you have this mutation in patients with leukemia. As you can see, it was totally resistant to all drugs. And here, when we use the combination of our compound plus venetoclax, you can see also a reduction by 50% of the blast in the bone marrow and same thing in the peripheral blood. And you see the platelets and the neutrophil count remain about the same, which is nice for the patients. So you can see altogether these patients who are very, very aggressive patients with a very poor prognosis leukemia with respect to biological parameters. Also, old patients tolerated quite well the treatment, remaining stable or see a complete response for one patient, which is highly unexpected at this level in combination with venetoclax. So to conclude at this level, we can say that probably this combination with venetoclax may become a potential new standard of care in second line or third line therapy and eventually, hopefully in first-line therapy because we know that almost 90% of these patients died within 1 year after the diagnosis, and we expect if you move in first line, there will be better in the future for these patients. And probably, we do see here at the mechanistic level, a strong synergy between the tubule poisoning and LDH inhibition and venetoclax addition. And probably to explain this result, we may make the hypothesis that EV1 may come and increase the expression of LDH that we do block with our compound, which may explain why you have sometimes a delay in the response when we kill the stem cells.

So what are the next steps? First, we have not finished the Phase I in combination. We are -- we have not even finished the combination with venetoclax. And then we would like to also try the triplet even if there is some potential toxicity with Vidaza, but still it's part of the plan. So we have to finish this Phase I, which is, as you have seen with previous data, encouraging with the combination with venetoclax. Then what? Then instead of engaging directly to a potential registrational study, we think it's better to do an expansion study of a limited number of patients, which could be 15 IML patients. But at the right -- with the right combination, probably the doublet AB8939 plus venetoclax given the encouraging very promising data that you have seen and at the right dose as well. if this is the best combination from the Phase I. So we focus on that. And we also select carefully the patients that we want to treat, and we select them with the same selection factors, I would say, that the ones we would do in a registrational study. And so to speak, we would do a sort of mini trial to see the response rate. And if the response rate is as encouraging as what we have seen in the first 3 patients. And the good news is that in hematology, things are quite repeatable. There is -- it's very objective. There is no questionnaire to be filled in by the patients. It's not a, I would say, subjective opinion. This is a measure of the blast in the bone marrow and in the blood and platelets and neutrophils. So in fact, it doesn't lie. It's extremely objective. And we know the placebo does nothing and it cannot reduce spontaneously blast, right? So that's the advantage. And with 15 patients, we can really have some comfort. And those 15 patients will be very certainly predictive of a registrational study. So if we do that, and we can do it relatively quickly next year, then we have the data that will tell us whether we can -- we have a high chance to register, right? So this is that it's to generate a hypothesis, a strong robust hypothesis that makes us comfortable at a reasonable price. So we think this expansion phase study could be strategic, I would say, in the development plan. Now if we move to a further next step, that's what could we do to register the drug in a registrational study. And we have started to discuss that with FDA, EMA, although it's very preliminary at that stage, but still -- and we have several opportunities there. So the first one is to go in line 1. And to go in line 1 in the patients who are aged and who cannot take the high-dose chemotherapy that will lead them hopefully to a graft. And okay? And here, we will not do all patients but we would do only the adverse genetic, which we have seen includes TP53 mutations, NRAS, KRAS mutations, complex karyotype, what we call Monosomy 5 if I would say, it is abnormal rearrangement on 5 and 7, on chromosome 5 and 7 and the [ famous entire bone makeup ]. So that group of adverse genetics, we know defeats the standard of care, which is the combination venetoclax plus Vidaza. So the combination to beat is or the standard of care is venetoclax plus Vidaza. And you have seen the data, the previous data, venetoclax plus AB8939. So the difference is Vidaza will replace it by 8939. And what is interesting is that we have 2 patients who took venetoclax and even one who took venetoclax plus Vidaza and failed. So we know that because they responded to the treatment and they had MECOM and they have TP53 and complex karyotype, so it means that where the doublet, the standard of care, venetoclax plus Vidaza is not so good or very poor, our combination could be much better and so can become the standard of care. So that's the strategy we would like to pursue with an expansion phase to limit the risk in 15 patients and then registration study. So I hope I have been clear to explain to you the strategy going forward. But clearly, this optional one makes sense and will be -- so previously, we will have this expansion phase before. Now the second option is also to combine 8939 plus venetoclax, but not in line 1, later in line 2 or 3. That is possible. And we can take again only the adverse genetics, so those ones you will see after how much of the market it represents or old patients that we can do also because there is a high unmet medical need in what we call like-to-like pre-refractory relapse because if they relapse, then they die, right? So we could do that as well, but those patients are more fragile, et cetera, more complex. So maybe in line 1, in fact, it's better if we focus on those negative or adverse genetics. And then we have another strategy, and they are not mutually exclusive those 3. We can do all of them if we have the money. But we can focus on the small makeup. It's a small group of patients, however, with terrible prognosis. And you have seen that our compound has even activity in monotherapy. Can we combine with venetoclax as well? Not so obvious, we have to discuss with the agencies, but still we could at least do monotherapy. So -- this is what we are discussing with the authority and progressively with the data that we're going to generate, it's going to be clearer and clearer. And then we'll engage in one registrational study, which doesn't mean we're not going to do another one because you see we can position the product in different line of treatments. Okay. So then I would like to leave the opportunity to our experts to comment what we have -- the science and the clinical data. And we'll ask Christian Auclair to give whatever opinion he wants to give on the data that we have generated so far. Christian, are you there?

Okay. Hello, everyone. I am very pleased to participate to the webinar. So I would like to share the feeling of a veteran pharmacologist. In fact, we have been involved in the first historical experiment that led to the selection of the molecules for the treatment of refractory acute leukemia. In fact, some experiments we have conducted in collaboration with Institut Gustave Roussy, which is the largest antitumor hospital in Europe. And we have also been every time in collaboration with a specialist, including those of Institut Gustave Roussy for the tubulin experiment. And in fact, what struck us were the following 3 points. First of all, it's exceptional ability to disrupt tubulin. In fact, the people of [indiscernible] we are very familiar with such molecules are very surprised to the very efficiency in the disruption of the tubulin, which result, of course, is apoptosis and the killing of tumor cells. The second point is a strong antiproliferative actions on blast coming from patients having AML. Usually, this blast, which is characterized by the many mutations and also complex karyotype are resistant to many antitumor agents. And we have observed very surprising that this molecule was very efficient, including in the blast having, as example, some critical mutations of monosomy 7, which disappears with chromosome 7 and it was also very surprising. The third point is a complex and sensibility to the multidrug resistant phenotype. Alain previously mentioned this point. The phenotype resistant is very common in leukemia and especially in this kind of leukemia and in leukemia stem cells and in fact, this multidrug resistance is very efficacious to reflux to release the drug inside the cells and it's the result of a strong resistance either at the beginning of the treatment or maybe for the acquired resistance. That is to say the increase of the phenotype increase with -- during the time course of the treatment. And so honestly, in fact, we have never seen such properties combined within single molecules. Even in pharmacology, you have molecules which have a very strong activity, and such mechanism of actions of other point. But the characteristic of these molecules is that they combine a lot of characteristics, which is very efficient in terms of antileukemic activity. And the last point and strongly important point is that the effect on leukemic stem cells. The point is for the treatment on so-called residual disease, residual disease. It's the fact that when after maybe a complete remission or partial remission, the people in maybe 1 month or 6 months start new development of the disease. And this point has come from the fact that it remains in the bone marrow some leukemic stem cells and unexpectedly also the molecules that target one enzyme, which are involved in the metabolism of the stem cells. The stem cells have a special metabolism and designed to survive in difficult conditions. And ILDH in this situation provides some components which allow the stem cell to survive. And the molecules, our molecule is able to selectively inhibit this enzyme and kill the stem cells. So it's a very critical point. And when we can summarize the situations, we have a molecule, which is a very efficient inhibition of the blast and the cells which are proliferative cells and also very efficient in the inhibition of leukemia stem cells. So of course, it's a very, very, very important point. All this points has led us to propose to develop this molecule for the treatment of refractory leukemia. And clearly, the first clinical result for us right. Thank you.

Thank you, Christian, for this detailed opinion. And Christian has been at the origin of this discovery of this drug in his lab, and so we're pleased to see the progress. And now we are going to leave Nicholas Short. Short, are you there?

Yes, I am. Yes.

It's a pleasure to welcome you here. I know it's very early because you're in Houston and very early for you, but thank you very much to be there. Nicholas has been -- he followed the development of the drug for -- since the beginning. He has been advising us, and it's an honor to have you on board. Please, Nicholas, tell whatever you want about our program.

Thank you very much. Thank you. Thank you for the invitation. So as mentioned, yes, I'm a clinical investigator at MD Anderson in our leukemia department. I focus mostly on acute leukemias, and I also run our Phase I group within our department. So again, as mentioned, I've been working with AB Science for quite a while advising on this drug. So just as a background, I know this is already stated, but just from a clinical perspective, I would just really, really reinforce that what Alain said was earlier, which is that the TP53 mutated and the MECOM rearranged AML really are absolutely the worst subtypes of AML. So this is like the lowest hanging fruit to find a drug. If you can just find some clinical activity, the standard of care is so poor in these that you can -- that I think this is really ripe for development of a drug if it is active in either of these subsets or both. So the median survival of these patients newly diagnosed is 6 months. I would argue there's no standard of care because even though aza-ven is the "standard" for like older patients with these diseases, if you look at the subgroup -- if you look at like the trial that led to aza-venetoclax being approved, aza versus aza-ven, there's no benefit adding to the combination compared to the standard in these subtypes. So we really don't have any good outcomes. And even young patients who are treated with intensive chemotherapy. Their median survival, if they have a MECOM or high burden TP53 can still be 6 to 9 months. So it's extremely poor outcomes. And we have no good salvage -- there at no good salvage therapies, no frontline therapies. And then as far as the KRAS and NRAS, this is not as bad as the TP53 and MECOM, but this is particularly a poor prognostic molecular profile for patients treated with aza-venetoclax, for example. So older patients, these patients do not do as well and the median survival is only about a year. So we definitely need -- and separately, these are mutations that we also see emerge with some of our therapies like venetoclax-based therapies, FLT3-based therapies. So there's a lot of NRAS, KRAS driving resistance across AML. So that's just kind of some background on why I think these subtypes are so important that we have targeted therapy for them. So as been shown, the single-agent activity, I think -- obviously, it's only 4 patients, but in MECOM rearranged AML to have 2 out of 4 responses is very significant. Again, I would -- we've shown and we've published that the response to maybe salvage therapy in these patients is like at best 10% -- 10%, 15% at most. And so 2 out of 4 is impressive in this particular group. And I think when we think about what would lead to an approval of a drug in this space. So this is -- yes, it's a very rare subtype of AML but it is such a poor risk subtype that if we look for reference from other recent approvals in AML. So for example, menin inhibitors for KMT2A rearranged leukemias, those got an FDA approval with a response rate of 20%. Now CR/CRh, right, so a very specific type of response, but a response rate of only 20% was what was basically submitted to the FDA in a single-arm study and led to approval in those diseases. And now these drugs, even though they're only approved in that specific subtype are being used all the time off-label because they're in NCCN guidelines for NPM1 because there's also activity there. They're being used in the frontline setting. Obviously, there's a lot of clinical trials developing that. But once you get a drug approved even in a very narrow space, there's a lot of use of it, at least in the U.S., right, where we can use drugs off-label. So I think that like if this was recapitulated, like you could get anywhere near a 50% response rate in a larger study of MECOM, even really 25%, 30%. Based on the historical expectations, this could be adequate for kind of an FDA approval based on a single-arm study. And then I think ultimately, our goal with any of these drugs that are showing activity as single agents is to do combinations to do either the AB8939 plus venetoclax, which has already been studied or do the triplet combination in the aza-ven, AB8939. So I think what we've seen with -- at least with the doublet, right, with this AB8939 plus venetoclax is significant blast reductions in what I would call ultra-high-risk AML. Like if you look at stratification, there's adverse risk. But within adverse risk AML, the really, really high risk are the TP53 and the MECOM. So these -- I think these -- the activity that's been seen so far is very encouraging. But obviously, we want to see this with larger studies. So I mean, what I would say is that the early data that we've seen so far really suggests significant activity in the highest risk subtypes of AML. These are the subtypes that actually other companies don't want to -- their drugs are not working in these subtypes. So they're trying to develop their drugs and kind of like the subtypes that are not as high risk. So this is like -- these are the types of trials that would enroll extremely well and very quickly in these high-risk patients because these are what comprise the vast majority of our relapsed population. And the bar is so low, I think, to show a benefit in these particular subtypes. So I would just say that if these response rates, again, are shown in a larger trial expansion, I think that there's really well positioned to have this drug developed in both the salvage setting, which is where most of these adverse risk patients are, but also in the frontline where our standard of care is so poor with what we currently have.

Nicholas, thank you very much for this very clear, I would say, a summary of the key points. We are following your direction, in fact, to develop this drug. And so now no more science, just some business consideration. We, of course, are interested to understand what's the market. So given the incidence, given the estimation of the percentage of patients which would be in the high-risk profile, this high risk is defined as this group of patients who are at ultra risk or high risk given the data. And we don't here differentiate between line 1, line 2, line 3. It's all the ones who are high risk, I would say. And then we see that the market could be 1 billion in U.S. and a little bit less in Europe, but with the rest of the world, we thought 2 billion. So it's an extremely large market for a small company like us despite the fact that they are treated only by hematologists, so the number of hospitals is limited to visit. So it's a sort of indication which we can actually deliver throughout the value chain. Now let's have a look at the IP, we have 2 patents there. We have a first patent, which is -- we have different lines of protection, with orphan drug status, which we have received both from FDA and EMA. And we have the composition of matter. So the composition of matter has an extension of 5 years. So we need to add it at the end, but our patent would protect the compound until 2036, but with the 5 years 2031. And we have another patent for the adverse genetics, and you have seen that our drug is essentially -- could make a strong difference on this adverse genetics. That's another patent that would protect until 2044. So you should probably memorize 41-44, which gives us plenty of time to do the development and try to register. That is the end of this presentation. And thank you for listening. It's not completely finished because we're going to take a few questions, not a lot because we would like to limit the call to 1 hour.

Laurent?

So we have a first question regarding the next steps. Do you plan in the coming 12 months to initiate new clinical studies with AB8939?

Okay. So new studies as compared in AML or outside of AML according to question?

In AML and outside AML.

Okay. So outside of AML, no. Although I'm sure Nicholas and Olivier would say why not high-risk myelodysplasia, which is another indication close to the AML. But no, so far, maybe later. And then for the AML, yes, we plan to finish the Phase I. So it's not a new study and start the extension phase. So in the next 12 months, the strategy would be, one, to finish the Phase I and two, to implement the expansion study that would secure the whole development and tend to engage in the Phase II. Okay. And other questions?

No more questions at this time.

Okay. So I don't know if any of you, Olivier, Nicholas, Christian, you want to add anything?

Olivier is on the phone?

Olivier?

Yes. I think it's a very important trial because as Nicholas short said before, it is a real unmet medical need. And we have a lot of patients in which we cannot -- we don't know what to do to this patient and mostly the elderly one because we cannot perform bone marrow transplantation. But even in younger patients, bone marrow transplant usually is associated to the failure because the patient relapse even after bone marrow transplantation. So we do need something here. And as we have been saying before, nobody wants to engage in this unmet medical need population of patients, which are highly resistant to chemotherapy and standard of care with Vidaza and venetoclax. So here, maybe because we have this unique mechanism of action, which is a tubule poisoning and IDH inhibition and sensitization to venetoclax, we expect to see something here very interesting for this population. And although I hope that we do see will last very long. But as we said before, the life expectancy today is only 6 months, which is very short. And to reach like 9 months of survival, even 1 year will be a great advance in this disease. And hopefully, we may cure some patients also. And in addition, I would like to say also because we do not see too much toxicity and we see quite a stabilization of the peripheral blood and particularly the neutrophils, which allows the patient even if they are not in complete response to have almost a normal life outside the hospital because they are not at high risk of infection because of the neutrophil count and the platelets remain at around 30,000 or 40,000. It's also good for this patient. And also with chemotherapy, usually, we see some toxicity, and we can prolong the treatment. But here, it seems that the treatment is quite well tolerated, which is quite a good news also for this patient.

Program, whether we have enough money to carry out the next phase?

Okay. So for Phase I, yes, of course. For the registration study that would Intel 200 patients, except MECOM, probably 80 patients, no. We would need to raise the money. And for the expansion phase, it would be probably nice to -- we'll see what we do on that. I would say it's a question that is on our table at this time. Another question? Okay. So as a conclusion, I think the conclusion could be the Slide 21. And for the slide -- so the -- first of all, the combination with venetoclax, which has been highly recommended by our R&D team and the discussions we had with the different hematologists seems to be really the right one. And again, there was -- it's the combination of 3 mechanism of actions. Venetoclax inhibits BCL-2 pathway that blocks the apoptosis of the chemotherapy. We bring with AB8939 destabilization of the skeleton, so microtubule plus the targeting of the stem cells that we hope to be able to remove. So the 3 together -- the 2 together give 3 mechanism of actions, which adds up and at the end are probably synergic. So that looks the right one, plus, as Olivier said, safe because you have seen venetoclax is relatively safe as compared to others. And our product also -- so the 2 together is relatively safe. And there is no such high toxicity in any of those 2 compounds. So the choice of the chemo was very smart, okay? And when we have the 3 first patients, which is the important readout, okay? It's very, very preliminary, but so important for us. That's why we have what we call today. It's 3 out of 3 with a response, not complete response in all the case, but still a response in what Nicholas called ultra-high-risk situation in Line 3 in Line 4. So we wanted to share that with you. It's highly preliminary, but it gives a lot of credit to the mechanism of actions to the choice of the duplet and of course, encourage us to continue because we see something like the light into darkness, and we want now to follow it up to the end, and we're going to go step by step. And of course, we'll be very pleased to organize more [indiscernible] for you to give you the outcome. Thank you for your listening, and I hope it has been clear enough. Otherwise, you can still write us. We'll try to respond to your questions. Thank you to all of you and in particular, to Nicholas in Houston. Thank you. Goodbye now.