Next we have Carlos Buesa from Oryzon Genomics. Hopefully. Can you hear me? Okay. Okay, perfect. Do I stay here then? Okay. I am Carlos Buesa, Founder and Chief Executive Officer of Oryzon Genomics. I would like to thank OTC Markets and Bolsas y Mercados to invite us today. We are a biotech company, as our previous speaker, and we develop innovative therapies in oncology and in CNS. Basically, I am going to talk today to you about our program in AML, acute myeloid leukemia. Okay? Which we are preparing for registrational development. For those of you that does not know the company, we are a listed company in Madrid, with a market cap of around $250 million. Our cash position as of September 1st was $25 million, and we are around 50 people based in Barcelona and in Boston. Okay? This is a very busy slide. I am not going to ask you to read it. I would like to talk about leukemia. Leukemia is one of the more lethal cancers. It is a cancer of the blood, which is caused by a catastrophic arrest of the differentiation of the blood cell progenitors. This is a very deadly disease. Every year there is around 22,000, 23,000 new cases in the U.S. only. For people who gets the disease over 70 years old, the median overall survival for five years is 4%. People who are younger, we can try to treat them if they are in good physical condition, good fit. We can try to treat them by human stem cell transplantation. We cannot do that for seniors. These people, we call them unfit. Why? Because the procedures to prepare a patient towards a bone marrow transplantation are so heavy that if we try to do so, we kill the patients. We do not let the disease to kill the patient, we kill the patient by the treatment. It is absolutely restricted, the bone marrow transplantation to those people who are young and well fit. For those others, which are the immense majority, what we have is a set of drugs which are trying to delay the disease and to increase the quality of life of the patients. What we have today as the main component, the standard therapy approved in the U.S. and in the Western world, is a combination of two drugs, venetoclax and azacitidine. Azacitidine technically is an hypomethylating agent. Not important now. Venetoclax is an agent which is basically helping the cancer cells to die. Okay? One of the components of cancer cells is that they do not recognize that they are odd differently to healthy cells, and they do not enter into apoptosis, which is the programmed cell death. Basically, that is what we are having here in this dense, busy slide. What do we have? What are we doing which is innovative, which is bringing hope to patients? We are having a drug which is iadademstat, which is basically targeting an epigenetic enzyme, which is called LSD1, lysine-specific demethylase 1. No worries about the molecular function right now. Just believe me in that very graphical cartoon that I am going to propose you now. Leukemia is produced by a sort of set of proteins, and they mix together in a sort of very wild party and impair the cancer cells to differentiate. By hitting LSD1, we are basically making this aggregate of proteins collapse, and then cancer cells can differentiate, and they can start entering in programmed cell death. We kind of stop the leukemia process. What we have presented lately is that we have amazing results in a clinical trial that is being done by Dr. Curtis Lachowiez at the Oregon Health & Science University. This is one of the best leukemia centers on the West Coast of the U.S. As you can see on this clinical trial that I am going to refer as ALICE-2, which is a trial that is basically enrolling 24 patients, is having three different goals. The first of all, of course, is to demonstrate safety and tolerability. We are adding an ingredient, our drug, to the basic therapy. Basic therapy is already toxic, so we need to know that if by adding our component, the toxicity, the tolerability remains the same, or it becomes so strong that we cannot continue those in the patient. First goal, tolerability. Second goal, to determine which is the best dosing of our components over the standard therapy. And third goal, to see if we see any sign of clinical efficacy. I will go for goal one and goal two in a moment. As you can see here on the left of this slide, we are having astonishing results. These are patients, 95% of the patients we were seeing that they were responding, which means that the cancer cells were going down. In 84% of the patients, we were having a composite complete remission. And even more, 74% of those patients were having an absolutely pure, complete remission. This is the best thing that you can offer to a cancer patient, is a pure, complete remission. This is how it works. I was explaining you a minute ago how the drug works. Our drug collapses this aggregate of proteins which are impairing the cancer cells to differentiate and to be eliminated. We are also basically promoting the action of the immune system of the patient. And third, and very important, we know that LSD1 inhibition produces the cell death of leukemic stem cells. Cancer stem cells are those cells which are less differentiated than normal cancer cells. They are very hard to kill. They are less numerous, and they are basically, at the end of the day, the ones that produce the relapse on the patient. We basically have these three axes action on the patients. Okay, we are going to present data in ASH in a couple of months from now in New Orleans. ASH is the American Society of Hematology Conference. It is the scientific gathering most important of the year for hematology. We are going to present data. What you are seeing here on the left is only a part of the data that we are presenting. As you can see, we have already tried to administer two doses to the patients to see which is the better. One low dose and one high dose. Why we do that? Because the FDA wants to be sure that when we say this is the recommended phase II dose to move forward in the development of the molecule, we are having the less toxicity and the maximal activity. Okay? Normally, when you get higher doses, you get more toxicity, more activity. When you get lower doses, what you get is lower toxicity and lower activity. What we see here is basically that in total, this—t he patients are basically having 95% of total responses. From this, 74% are complete pure remissions, 11% are complete remissions with partial hematological recovery, and 11% of the patients were morphological leukemia-free status. Okay? Yet when we divided this into two doses, we see that the low dose is already having some non-responses. One non-response is one out of four, 75% of responses, while the 15 patients that we have treated on the high dose are basically having 100% of responses. But guess what? We don't have any difference in tolerability between dose level one and dose level two. We can go to the FDA and say, "Well, okay, we propose to do the dose level two because it's the more efficacious, and still is as tolerable at the dose level one." Okay? We have talked already a bit about efficacy. We have talked a bit about the dose finding, and now about tolerability. The tolerability of our drug in combination with the standard therapy is extraordinarily good. As you can see here, the levels of mortality at 30 days is very low, 0%, and at 60 days is only one patient, by causes alien to the disease or the treatment. It was an unfortunate event. What we know now is that we are not adding on top of the normal toxicity that the standard therapy provides to the patients, produce to the patients, we are not adding anything else. Why? Because one of the reasons why you produce additional toxicity is because your molecule produce toxicity or because the administration of your molecule impairs the elimination of the other molecule. Okay? If you impair the elimination of the other molecule, you get an overdose of the other molecule because you are not able to get rid of it at the normal pace. This is not the case. We don't have drug-drug interaction. The tolerability is excellent. Okay. All in all, we have a very strong rationale to go for a phase III, as I will talk to you in a minute. We have a very profound knowledge of the biology of the LSD1 inhibition and its meaning in the leukemia biology. We know that in some particular groups where the standard therapy is not working at all, we will talk about that in a minute, our molecule is working. We know that we have a rationale to go for these particular subgroups of patients. All this is very nice, but I guess that some of you already are thinking, "Well, this is a crowded market, a crowded space. There are other companies trying to do their best. How are you comparing with them?" The answer is that we are comparing quite well. What you see here is how we compare with emerging triplets that are being tested by the rest of the industry for targeted therapies. Some of you might have heard about the menin inhibitors. These are products which are being developed by Syndax, by Kura Oncology, American companies, by Johnson & Johnson. These are the revumenib, ziftomenib that you see here on the bottom. These patients are basically responding more or less at the same level than us. What you see here is that we have 78% of CRs, and they have 81%, 73%, 68%. Gilteritinib is doing a bit better. What you're seeing in this graph is basically on the vertical, on the Y-axis, is the percentage of patients that you can treat. These other drugs are basically focused on subset of patients that have a specific mutation. Leukemia is one of the cancer which is more heterogeneous genetically. Depending on the mutation that you have, you can have got the black ball or the white ball. We will see that about. The difference between the genetic background makes a lot of difference for leukemia patient. What we see here is that our compound can treat all the patients, 100% of the patients, is what we call mutation- agnostic. It doesn't depend on the mutation that the patient has for being active. That was for the targeted therapies. What happens for other molecules that are being developed by the industry which are for all comers, not specifically leukemia patients having X, Y, or Z mutation? What you see here is the antibodies which are being developed by AbbVie, pivekimab, and by Ipsen, [ICT01], the EVICTION 3. As you can see, we are comparing very well against them. We are having a superior composite CR, 85%, which is compared with pivekimab against AbbVie, is 79%. Which is more important, for pure complete remissions, we are having 10% more, 74% against 63% of the AbbVie's antibody. These are preliminary figures, may vary a bit up, a bit down. What I am trying to tell you here is that we are playing the same league if we are not superior. So we are competitive. Our strategy, instead of going like many inhibitors for a very selected group of patients harboring a certain mutation or the FLT3 inhibitors or going with an antibody against certain antigens and having the problems of tolerability that antibodies have, is to go with LSD1 which covers all the AML patients without having these issues. That's fantastic. What we are going to do moving forward? We are going to go to the FDA to propose in a phase III. How, why, and when? Our registrational plan is simple. We could go and tell the FDA, "We want to do a phase III with all patients." What happens? The all patients is going to cost us a lot of time to determine the delta, the statistical delta that we need to demonstrate to prove that we are better. Instead of that, we can go for the worst patient. Those unlucky patients that are harboring the mutations that are getting them the more aggressive diseases. This is our strategy, and this is how we explain that. What you see there is basically on the right is the deconstruction of all AML patients in three groups. When we talk about all AML patients, what we know. If I go away, you do not hear me, no? That is a pity. I will try. All patients have 14 point months of overall survival. But if we split this population based on three different mutations, we see that the ones that they do not have the aggressive mutations, the lucky ones, are living a median life, an overall median survival of almost 27 months. Those who are very unlucky and have the TP53 mutation, which is the holy grail of the AML, on the contrary, are only living. Where are you? Five months. Here, sorry. Can you hear me now? Good. Five months. And the ones in blue who are having intermediate-risk mutations, they are basically living 12 months. Our strategy here is basically, if we would like to go for wild type, it is working. Our drug is working. But we would need 40 months to demonstrate a delta. This is expensive for a biotech. Instead of that, we go to these specific populations, and we can demonstrate the statistical delta in a much shorter time. Then, what are the data that we have on those populations? In a previous trial, we basically demonstrate that in TP53 patients, which are, as I said, the holy grail of the AML, we got 75% of responses, 63% of complete remissions, and more importantly, we were able already to double the median overall survival. This trial was done only with the addition of azacitidine, not venetoclax. In the previous trial, in ALICE-1, we got 100% for the intermediate risk patients, the blue ones, and we were able to increase 25% the median overall survival. Other intermediate patients, which are myelomonocytic leukemias, M4, M5, we were able to get 86% of composite complete remissions, and the median overall survival was not reached. In fact, there are still three lovely grannies in Spain, in Barcelona, walking their grandsons five years later because we are still having them under compassionate use. Yes, we have preliminary evidence. In the study that we are doing now, we have 100% of TP53 responses and 100% of NRAS, KRAS responses. What we are going to propose to the FDA? We are going to propose the FDA a phase III with two cohorts. One cohort for the intermediate risk, the blue ones. We are going to put 100 patients on our triple combo against 100 patients in the standard therapy. We think that we can do that very quickly. For the TP53 ones, we need to talk with the FDA. We expect that the FDA will agree not to put any control arm because we think it is unethical. Thank you. We think it's unethical to put patients in a control arm to die. We think that they would agree to create a synthetic arm, digital twins, finding those patients with TP53 that in the previous year having exactly the same or almost exactly the same medical profile than the ones that we have incorporated on our study, how they have done with the standard therapy. We can compare in this sort of hypothetical control arm. What we know is that we are not inventing the wheel here. What we are proposing to the FDA is a similar scheme what Syndax, Kura, Johnson & Johnson have proposed to get accelerated approval based on levels of CRs. This study is going to cost us around 24 months, which means that we are going to present the data in December in ASH in New Orleans. We are working to see if we can do an Investor Day in New York one or two days after ASH. With all this data, we are going to submit a briefing to the FDA for a Type C meeting to propose them our ideas for the phase III. We are expecting the minute somewhere here, and then we are expecting to get the go for the phase III by summer. By the end of the year, we are expecting to have the first patients enrolled, which should take us, as I said, 24 months, which means that by 2029, by the end of 2029, we could have the number of CRs sufficient to go to the FDA to request an accelerated approval. Of course, we are not naive. We are not noble. We know how to do it. We have a medical team in Boston. We have done that before. We have also the opportunity, the honor, to have the NCI sponsoring a number of our clinical trials. We have a clinical trial in lung cancer in Yale, another clinical trial in lung cancer as well being led by the Memorial Sloan Kettering Center. This is also opening additional opportunities. We have worked with Clarivate, which is basically a well-recognized consultancy to see what is the market analysis for that We were asking eight U.S. payers, and we said, "Okay, assuming that we are going to double the lifespan of TP53 patients, how would you consider the normal price?" They say around [$ 350,000] per year. Of course, in Europe, it's much lower, but the total commercial opportunity only in the U.S. is superior to [$1 billion] on peak sales per year. So thank you very much. If you have any question, I will be very, very happy to. Any questions, please stick your hand up and wait for the mic. It's all right. I do have a question then, if that helps. What happens to the timeline and the cost if the FDA asks for randomized tests? Well, if the FDA asks for a randomized, I think that the problem is not the cost. The problem is the feasibility because it's difficult to get the collaboration of a doctor to ask him to put a patient of his in a trial knowing that he can go to an arm that is basically to put the patient to die. I think it's unethical. I was talking briefly with the former FDA commissioner in Europe, and he said to me, "Well, these things are always to be discussed, but it seems that you have a case." That's what we got. Fair enough. Any more questions at all? In total, in the different clinical trials in leukemia, around two hemato-oncology, around 260 patients. 260. Well, no. The question is—y eah. The drug is extraordinarily powerful. We are dosing micrograms instead of milligrams, and it's extraordinarily selective, so it goes for the target. You don't get off-target effects. No. These patients are very sick patients, so this patient that died in this trial that was mentioned, it was a catastrophic bad luck because he was a problem on urinary, and he go to a community hospital, he got an infection, and he died. Nothing related with the disease, nothing related with the But it's very well-tolerated. The doctors are very confident with that. All right. Well, I just told you off for not using the mic. We're just going to have lunch now. Be back in about half an hour for the panel discussion. Thank you. Thank you.