MaaT Pharma SA (MAAT) Earnings Call Transcript & Summary

Welcome. I'm Herve Affagard, CEO and Co-Founder of the company. Welcome to this session. Good evening, depending if you are in Europe, or good morning if you are in the U.S. I'll be introducing this session today. And I'd like to remind that this is our first edition of the MaaT Pharma R&D Day, and we will be presenting today our data. And also, importantly, we will be presenting to you our road map towards the construction of a new pillar of treatments against cancer leveraging on the microbiome potential. As a looking forward statement, I'd like to remind that today's presentation discussion contains looking-forward statements that are subject to various risks and uncertainties. Today, I'm glad that the presentation is going to be made -- the presentations will be made by several key opinion leaders that are very important in the field, as you will notice. The event will run from 4:00 to 6:00 p.m. CET. And that's going to be at the end of the presentation, a Q&A session of 15, 20 minutes. We will be answering the questions on the language where you have asked the question. Just after this presentation, the webcast of this presentation will be made available on the website. And the presentation is going to be taking place both in English and with subtitle in French for those who are more easy with reading French. So our first speaker will be Dr. Joel Dore from INRAE. He is one of the most prolific contributor to the field regarding the concept of ecology, microbiome ecology. And then I'll be introducing the way we see the potential of the field, of the microbiome space. After that, Professor Holler will be driving us through the different applications that we can see, especially in the field of oncology. With that, we will initiate the presentation of an initial set of data with Dr. Florent Malard together with Emilie Plantamura. They're going to be discussing some of our clinical trials. After that, we will be continuing the presentation with Professor Mohamad Mohty, and he will be presenting our road map regarding MaaT033, our second product. Then Professor Zarour from the University of Pittsburgh will also taking us through the potential of the modulation of the microbiome in the field of immuno-oncology. And then we will also present our strategy in terms of entering the field of immuno-oncology with Dr. Emilie Plantamura. The -- all of that, the clinical data, the clinical programs that we are presenting before, that's supported also by a very strong product development road map and that will be presented by Marianne Robin as well as Dr. Carole Schwintner. And to finish, I'll come back with the closing session, and we're going to have the Q&A. As a wrap-up before we go through the presentation, I just want to set the tone in terms of the key message for today's session. MaaT Pharma has a unique strategic positioning in growing -- on the growing microbiome market. We do believe that there is a terrific expansion since the last 15 years on the field. And MaaT Pharma is pioneering what we call the microbiome ecosystem therapies, which will be presented later. We had a very strong focus in oncology, which is where we see the -- there is the most potential but also the most need for the patients. We have created a leading position in the field of oncology with already 2 candidates that are in the clinic, MaaT013 and MaaT033, which will be presented today. And also, we are generating a new generation of product using our M-A-A-T platform, MaaT platform. We also have a clear company strategy in terms of growing, developing and developing the company and a secure cash runway position. Indeed, everything we have announced during the IPO has been achieved, so we are working as per plan today. And we are anticipating also the future and building a new cGMP manufacturing facility that will open in mid-'23. And the way forward is very clear to us, with the aim to build a global reference in the microbiome. With that, I will leave it to Joel Dore so that he can introduce us to the general concept from a scientific point of view in terms of what it is we are doing.

Well, thank you very much, Herve, for this introduction. I'm Joel Dore, Director of Research with INRAE and University of Paris [indiscernible], and it's a pleasure to be able to introduce MaaT Pharma R&D days with this presentation on the microbiome revolution, introducing microbiome and its potential in oncology. I will start saying that we humans are microbial. We are ecosystems and symbiosis, each of us interacting with around 50 trillion bacteria, which is numbers as many as we have human cells in our body. And as we are able today to count genes, we know that they represent, on average per individual, 600,000 microbial genes which is 25x the number of genes of the human genome. They are present on the skin and at every mucosal interface of the human body with a high density of population in the intestines. Microbiome science today is really changing a lot. This is one component of the revolution, essentially as we address the microbiota at the level of genes and strains and species. Now what we can say in terms of contribution of the microbiota is that it essentially provides key protective functions under normal conditions. There are functions that are provided by human genes and functions provided by the microbiota. And it's essentially the interaction between these functionalities that allow us to conceptualize the host microbes' symbiosis. Now the microbiota acts at various levels. It's an endocrino-metabolic regulator, essentially driving the potential risk of onset of chronic conditions in the realm of metabolic disease. It's an immuno-inflammatory regulator, interacting with the immune system and maintaining immune homeostasis, it's acting as an antimicrobial barrier protecting us from colonization by environmental microbes. And it's also acting as a neuro-vegetative regulator, essentially maintaining crosstalk between all -- with all the organs of the human body, including the heart and the brain. Now we become microbial from the very moment of birth, where the newborn meets the microbiota environment. And in the early days of life, we will mature our immune system, our natural defenses at the same time as we will develop our microbiota in terms of diversity and complexity. And this leads to this unique symbiotic condition where the microbiota is, as every cell, every tissue, every organ recognized as a component of self by our immune system. The maintenance of this recognition is really essential to the maintenance of health and well-being. Now it's a complex system, so there will be risks of alteration. When disruption comes at the level of ecology, it's associated with loss of the barrier function and risk of infection, for example, by Clostridioides difficile, a well-known intestinal pathogen. And when disruption comes at the level of immune tolerance is associated with loss of immune homeostasis and risk of immune, autoimmune or immune-related conditions and also nonresponse to treatments that are directed towards immunity. 25% of the world population is expected according to the World Health Organization to be affected by one of several chronic conditions by 2025, which is essentially the very near future. We were able to describe alteration of the microbiota in a number of conditions. Looking specifically for microbiota alteration, we have come to realize that what we deal with in conditions that concern the central nervous system, the gastrointestinal or hepatic arena, metabolism, infections and immunity, what we deal with is an alteration of host microbe symbiosis, with parameters of the microbiota being altered, but also a leaky gut syndrome, those 2 combining their effects to induce inflammation that will lead to oxidative stress that, in turn, will further alter the microbiota. And so we can have vicious circle, we can have circle causalities that will maintain the disease condition essentially. So this is a complete revision of our initial perception of what could have been just a microbiota-related condition. Now this has many impacts, one of them is that we have at least 4 actionable levers to support innovations in diagnostic, in monitoring, in prediction, but also to support innovation in prevention and therapy. And when the concept we had was that of a continuum between the states of health and state of disease, essentially if we can have circular causalities, what we have to deal with is conditions where we can have what is called critical transitions, between alternative stable states of health and pre-disease or disease. So this may make the restructuring of health quite complicated. Now in this context, what we are dealing with is the potential for an urgent shift in paradigm. We're adopting holistic approaches to health will allow to make enormous progress in the treatment or in the prevention. Now the normal healthy or health-associated microbiota is essentially a number of features that we are still addressing and for which we are still building knowledge today. But they are depicted in the cartoon on the left here. They are, of course, host genetics, but also environmental factors such as geographical location, exercise and stress, diet, very important component as well as treatments, antibiotics, obviously, a very important component as well. And so we'll justify and go quickly. Key features of the health-associated microbiota involved high richness. I already mentioned that, which is also a driver of robustness of the microbiota, its resistance to change and its ability to reconstruct itself after a stress, which is called resilience. We also have a shared core microbiome, a small set of species that we do tend to share between individuals quite commonly. And there's also a number of symbionts of health-associated microbes that are actually driving immune homeostasis and are very important in that matter. One important feature is that they may be influenced by those numerous factors, but also amenable to modulation. So we cannot do very much with the human genome, but we cannot actually modulate the microbiome with nutrition and with microbiome therapy. That will be useful for the maintenance or the restoration of microbial symbiosis when it has been altered or when there is risk of alteration. Now when we look specifically in terms of zoom on microbiota richness, what we were able to do is to describe it as a major health stratifier. And it came as a surprise, but there is not a usual bell-shaped distribution. When we look at the distribution in a number of individuals as a function of number of genes in a metagenome, what we see is this separation between a low microbiota richness set of individuals and a high microbiota richness set of individuals. We were also able to show that low microbiota richness is associated with ultra-metabolic and inflammatory traits in overweight and obesity. It's associated with nonresponse to calorie restriction in overweight and obesity. In this context, low richness microbiota is predictive. This is associated with high severity and faster progression in severe liver conditions such as cirrhosis. Here again, it's predictive of the fate of the patient. And it's associated with nonresponse to cancer therapy. We will zoom into this specific aspect just after. But what we know is that the normal population, nonobese, around 15% of the population is having a low richness microbiota. But when we turn to overweight, moderate obesity, then it's 40%. And when we deal with morbid obesity with IMCs over -- or BMI over 40, then it's 75% of the population. So this feature is really following the severity of the disease condition. And specifically zooming into cancer therapy, what we have been able to observe is that the low gene count is associated with a lesser overall survival in patients receiving allogeneic stem cell transplants. This is in blood cancer when the patient responds to chemotherapy, then it's subjected to a bone marrow transplantation. And in this context, survival is strongly impacted by the richness and diversity of the microbiota. Low gene count is associated with a higher mortality by acute graft versus host disease, which is a complication following stem cell transplantation. And the level of improvement when there is a high diversity microbiota is up to 30%. And low gene count is associated with lesser progression-free survival in immunotherapy, in 2 context, in melanoma, but also in lung cancer and other solid cancers. So in this case, the interaction is with the treatment itself. And well, in this context, the possibility to restructure completely the microbiota by fecal microbiota transfer will be really a key aspect of the intervention. So to conclude, modulating the microbiome opens new horizons towards personalized holistic approaches. Human tissues, human organs interact on a constant basis with our microbiota with mutual benefits typical of a symbiosis. Alteration of host microbe symbiosis comes with loss of protective functions. The gut microbiota is a really relevant target for the maintenance and restoration of host microbe symbiosis and a complete reconditioning and modulating host microbe symbiosis should be a major line of innovation of microbiome medicine of the future. From prevention of onset of mild chronic diseases to the treatment of severe iatrogenic conditions for which medicine sometimes has no solution, and it's the case in -- as illustrated in oncology. Key features of the healthy host microbe symbiosis can be restored by MaaT Pharma's strategy using microbiota as a therapy. Thank you very much for your attention, and I wish you a wonderful MaaT Pharma R&D days.

So thank you very much, Joel. It was a very, very clear presentation as usual. And I'm taking it from here, and I'll tell you how we will be driving value from the microbiome space, leveraging on what has been presented before. And especially, I want to insist in the fact that MaaT Pharma has a unique positioning beyond leveraging the potential of the full complexity, the full ecosystem. We are not here developing products that are 1 strains, 2 strains or x strains. Here, we are developing a network of bacteria, which is the full ecosystem. The objective for us is really to restore the symbiosis between the microbiota -- which is the link, the dialogue between the microbiome and the immune system, so that we can improve the condition of the patient. So this full ecosystem approach is very important and makes us unique. Also, second, our focus is oncology. That's where we do believe there is a high unmet medical need and also a very strong rationale in terms of the modulation of the microbiome so that either you can act directly into the disease like it is for GvHD or pair with other treatments, such as immune checkpoint inhibitors. And we know that the microbiome has a very strong role in terms of providing patients with disruptive solutions. Third, we have established a proof of concept already in a Phase II in a very severe disease. We are talking here about steroid-refractory GvHD patients, where we have demonstrated that the modulation of the microbiome is improving the situation for the patients. And those patients, they are very severe. They are usually one-way ticket patients, so it's very important for us. We are very happy that we have been able to prove that there is an improvement on that severe population. And now we are entering the Phase III in Europe and the clinical trial is ongoing. And fourth, as for any biological product, it's very important that you can master your bio processes. And here, we have set a cGMP facility, which is scalable and which will support the entire pipeline beyond all the ranges of product, and that will support the clinical pipeline for the next few years. So the 2 projects that we have today in the clinic are MaaT013 and MaaT033, so there are 2 different products. However, they share some commonalities and the key commonalities are the fact that they are a high-diversity product, meaning we will be providing the full menu of the microorganisms to the patient. That's a full ecosystem and also this product is acting as an immuno restoration, thanks to the [indiscernible] that will be presented later, which is present in all our products in a standardized manner. We have also another generation of product -- range of products, which is MaaT03X. It's a co-fermented product. The first one, we call it the native because we start from donations from donors. Here with the co-fermented product, we are with a donor-independent product. And not only we are donor independent, but also we are able on that range of products to set a specific signature that we define using machine-learning algorithm. So here, we will be setting a specific microbiome in the gut of the patient so that they can better respond to the treatment against cancer. All of that is possible thanks to the use of our MaaT platform. Just to finish on that section, 2 slides before we finish that section. So the 2 products, that's a kind of a wrap-up, MaaT013 has entered Phase III in Europe. So that makes us the most advanced company in the world regarding microbiome and oncology. MaaT033 has achieved the Phase Ib study in acute myeloid leukemia patients. So that's data we will be sharing today, and we hope that we're going to have a nice publication later in the year. MaaT013 is also used as a proof of concept in advanced melanoma. And here, as I said a little bit earlier, MaaT013 will be used to pair with immune checkpoint inhibitors. So this clinical trial is sponsored by AP-HP, the Hospital of Paris, and that's ongoing as well. The MaaT03X product, the new generation, we plan to enter into the clinics in 2023 in an indication, which is not yet disclosed. And finally, the support of the development of the product will be also going to the next stage because we are setting a new facility. That's going to be 1,500 square meters that we will expand to 3,500 square meters, if needed, through the partnership with a CDMO named Skyepharma. So that will open mid-'23. In terms of the market penetration, so we start with a niche market and free strategy in GvHD, MaaT013, that's 2,000 patients per year, then we multiply by 10 going to all patients receiving stem cell transplantation with the second product, MaaT033, then we multiply again by 10 with the 3X products where we will be targeting solid tumors. And of course, that's only the beginning of the story and the potential of our AMT platform and the products we will generate from MET platform are very large because it could be potentially all the immune inflammatory related disease. So the potential is huge. But for the next 10 years, we have already a comprehensive, I would say, market expansion and penetration. Thank you very much. So as you have understood, we are here talking about a new pillar in oncology. We have surgery, we have immunotherapy, radiotherapy. Now we have the microbiome. And Professor Holler will be talking to us on his vision on how the microbiome will just shift the medicine paradigm in terms of taking care of our cancer patients. Thank you, Professor Holler.

So thank you, Herve for this kind of introduction, and it's my pleasure and my honor to give you an overview about the microbiome as a new frontier in hematological cancer treatment. I'm Ernst Holler, I was a former Director of the Clinical Transplant Program at the University of Regensburg, and I'm now senior professor and involved in clinical and experimental allogeneic transplantation. Now I want to convince you that we have strong interactions. I call it a ménage à trois between the microbiome and the immune cells in many diseases, and in oncology and in stem cell transplantation with immune cells and tumor cells, and all 3 are important for optimal immuno regulation, and this will be the topic of my introduction in stem cell transplantation. So if we talk about stem cell transplantation, I want to briefly introduce the principles. You have a donor and a recipient. The recipient has leukemia, which cannot be treated otherwise, and therefore, he needs the transplant after conditioning, which reduces tumor cells, which prevents rejection. Stem cells are received from the HLA identical donor, and this stem cell transplant does not only contain stem cells, but also all mature cells from the blood, including the lymphocytes from the donor. After a period of aplasia, the hematopoietic system is reconstituted by the recipient cells, and also the immune system is reconstituted. And the reconstituted immune system makes some problems, but it's also important to cure patients. We can cure about 50% to 70% of leukemia patients. However, if the cells are too much activated, we have immune reactions called graft-versus-host disease. They can lead to lesser complications overall in 20% to 30% of our patients. And a very specific problem is if this graft-versus-host disease is refractory to treatment, then mortality goes up to 80%. On the other hand, if we have no immune reaction, we have no immune reaction against the leukemia, the so-called leukemia effect, then the patient has relapsed. On the right side, you see the leukemic cells in the upper slide, and you see graft-versus-host disease of the skin and of the inflamed gut. Now the gut microbiome is an old player in allogeneic stem cell transplantation. It was not called the microbiome, it was called the intestinal flora. But already in the '70s, van Bekkum observed that mice grown under completely germ-free conditions do not develop graft versus host disease. They survive 200%, whereas on the right side of the slide, mice grown under conventional conditionings -- conditions died from graft versus host disease. After seeing comparable results in some other animal models, Also, the first reports came up that complete decontamination in children reduces graft versus host disease. And so microbial decontamination and antibiotic prophylaxis for standard practice until 2015. However, we saw a new era in stem cell transplantation. With the human microbiome project, we were able to do a performer molecular microbiota analysis by 16S RNA sequencing. And with this, we could detect a lot of never-cultivated species, and we saw that decontamination is rarely achieved. On the left side, you see the distribution of bacteria prior to transplantation in the green and blue bands and the white bands are the conventional protective good bacteria. The red one, the pathogenic. And you see in leukemia patients, there are already some from the previous treatments. If you compare this with the right side, you see patients early after transplantation. And in those patients who have GvHD and on antibiotics, you see that now the red microbiota, the pathogenic one, now have taken over the whole microbiome. With antibiotics, it's quite similar and without GvHD -- without GvHD and without antibiotics, you have a mixture between the normal distribution and the post-transplant distribution. Now these findings were first reported in several single-center studies. But in the late '20s, we could -- we were able to confirm also in multicenter studies, the relevance of these findings. The first study, we addressed the enterococcal expansion in 4 centers across different continents. And you can see the results in the Sloan Kettering Cancer Center and in the other centers. And in both centers, the predominance of this red bacteria, the bad ones, the enterococcus was associated with a much poorer survival in patients due to treatment-related mortality and graft-versus-host disease. And this was also seen in a more general analysis. You see the time course of diversity, microbial diversity after transplantation. At day 0, the day of transplant, has already gone down, and it goes down further in the first 20 days, and this is again occurring in all centers across the world. And those patients have a low diversity early after transplantation. They have a much poorer outcome. They have higher treatment-related mortality. So microbiota -- dysbiosis, loss of diversity affects the outcome after transplantation. Now we asked for the causes, why do patients have dysbiosis? On one side, GvH destroys the gastrointestinal cells and very important cells in the gastrointestinal tract are the paneth cells, and cells producing antibacterial peptides, which are important for homeostasis of the microbiota. You can see histology of the gastrointestinal tract without GvHD and with GvHD, and you see this brown sales on the bottom of the epithelial cells. This is the production of antibacterial peptides. And this is almost completely gone in patients with graft-versus-host-disease and this can be also observed on the level of PCR analysis on the right side. Now the second major reason for dysbiosis and for a loss of protective, good commensal bacteria is the use and the early use of broad spectrum antibiotics. Our patients are severely immunosuppressed and therefore, develop infections. But you have to treat them with broad spectrum antibiotics. If patients need them very early even before the day of transplant, and this is the red curve, these patients have a very high treatment-related mortality due to GvHD and associated complications. If starting of antibiotics is delayed after transplant, called late antibiotics, the mortality is in between 21%. And if patients are lucky not to need antibiotics -- and unfortunately, these are only less than 10% of patients, the mortality goes down to 7%. This was a large retrospective analysis in 2 centers in Regensburg and in New York. And we saw, in addition, that mainly the commensal clostridia and other protective bacteria are gone if we use early antibiotics. This was an independent risk factor, even if a good risk patient needed early antibiotics, he had a higher chance of developing graft-versus-host-disease. Now in the next years, we tried to understand what happens if we apply antibiotics. We know that commensal bacteria produce protective metabolites, so-called short-chain fatty acids like butyrate and tryptophan metabolites like indoles. This protective metabolites are important for stabilization of the host and the patient. If these metabolites are lost by antibiotic treatment, the immuno regulation, which is needed in GvH tissues, is also lost. Here, you see on the left side a correlation of the receptors for these multiple lights in biopsies, with the most important GvH preventing cells the regulatory T cells. And on the right side, you see that patients try to protect themselves with these regulatory T cells. They have the marker FoxP3. But if patients are on antibiotics, on the right side, the red ones, then this protective reaction is almost missing. Now these associations don't stop in the setting of stem cell transplantation. You will hear about immune checkpoint inhibitors. And we recently also get more and more aware that microbiota-derived products, metabolite, protective metabolites, are also important for antigen-specific T cell and for CAR T cell treatment. The left side, you see the cartoon, the tryptophan metabolites into the short chain fatty acids stabilize the CAR T cells. And on the right side, you see antigen-specific T cells suppressing tumor growth, and those who are grown in metabolites -- in protective metabolites, are the most efficacious one. So we can expect that the role of microbiota is much broader than in stem cell transplantation. So what we need is restoration of microbiota. This microbiota produce protective metabolites. I mentioned the short-chain fatty acids. I mentioned the [indiscernible], they also produce cytokines, stabilizing the epithelial cells like IL, Interlukin-22. And these metabolites and these cytokines are important to restore immune tolerance. I showed you the regulatory T cells, but also epithelial tolerance as it is done the Interleukin-22. Microbiota restoration, therefore, should help to restore the right balance. And with this, I thank you for your attention and give back to the organizers. Thank you.

So hello, everybody. This is our pleasure to be here today to discuss the results of the Phase II clinical trial early access program using MaaT013. So after the great presentation by Professor Holler, regarding the importance of microbiota in the setting of stem cell transportation and more particularly graft-versus-host-disease, I'm going to discuss the clinical risk. So I am a Professor of Hematology at Saint Antoine Hospital in Sorbonne University, Paris, France. So what we are going to deal with in the sense that receive allergenic stem cell transportation, this is the treatment of acute graft-versus-host-disease. This is a very important complication in these patients. That has been associated, as you have seen with Professor Holler presentations with intestinal dysbiosis. And in fact, in patients that are going to receive allogeneic stem cell transportation for leukemia, lymphoma, myeloma, they're going to receive chemotherapy and all patients are going to receive antibiotics that will have a very detrimental effect on the gut microbiota induced dysbiosis an important loss of diversity that lead to complications, infectious complications, of course, but also this acute graft-versus-host-disease. And in fact, around the world, we are going to perform 2 -- 22,000 allogenic stem cell transplantation per year graft-versus-host-disease, in fact since it's 10,000 patients per year and half of the patients are not going to respond to the first line treatment with steroids. More than half of the patients will have a GI involvement, so this is very frequent, and it will lead to a very, very high mortality, up to 90%. So we need to develop some new strategy on what of this very promising and exciting strategy, the use of MaaT013 as I'm going to show you in the next slides. So how does it work? So MaaT013 aims to restore the interactions between the microbiome and the immune system to treat graft-versus-host-disease, and there is a broad range of effect. It will induce some immune homeostasis restoration, will induce Butyrate and it will lead to an increase in regulatory T cell that will control graft-versus-host-disease. It also increased the diversity of the microbiota that will lead to an inhibition of the pathogens on productions of metabolite. So this is a so-called Butyrate that we use the T regs with some immunoregulatory effect. And finally, it will restore the barrier integrity and it will decrease the risk of infectious complications, sepsis, and it will contribute to the decreased risk of acute graft-versus-host-disease in those patients. So MaaT013 restarts the microbiome to cure gastrointestinal graft-versus-host-disease. So what are the characteristics of the product. This is a full microbiota with high richness, high diversity a full ecosystem with all the bacteria and that contains the so-called Butycore that is a set of several Butyrate producing bacteria with this immunoregulatory effect. We give this with 3 doses, so every 5 to 7 days with 150 millimeter per enema bags. And we are so fast while available clinical data and going to develop it further HERACLES Phase II clinical trial that including 24 patients the early access program when we have the data for the first 52 patients, but now more than 100 patients have been treated with evaluations of the overall response rate at day 28. That is a classical endpoint to acute graft-versus-host-disease. So this is, and this is a current indication this is to create the acute graft-versus-host-disease. So there is 2 strategy. Now as I told you, this is always a clinical data from the Phase II clinical trial HERACLES with 24 patients treated in Europe, so 4 countries involved, all patients with very severe GI acute graft-versus-host-disease, grade 3 to 4, steroid refractory. So this is a most severe disease. On all patients, we see 3 doses of MaaT013. This is monotherapy. They did not receive any additional treatments, any other immunosuppressive treatment were added to the MaaT013, and it was a second-line trademark. In the early access programs, only patients were treated in France, 52 patients treated with GI acute graft-versus-host-disease grade 3-4. It was steroid-refractory but also there is some patients with steroid dependence acute graft-versus-host-disease, similarly to the data in our case patients received 3 doses of MaaT013 on single treatments over 2 weeks. And patients were more easily [ treated ] for acute graft-versus-host-disease because they receive 1 to 6 previous lines of treatments different MaaT013. So regarding the results, here as a result for the Phase II clinical trial in our case of 24 patients, so there are some very promising result. When we look at the response rate, at day 28, it was 38%, but in fact, more patients respond. And if we look at the best GI overall response rate is 12, 52%, including 38% of complete response. In those patients, it was, so as I told you, the receiver patients, all of them with grade 3 or grade 4 involvement, all of them with steroid-resistant acute graft-versus-host-disease. And we have a very good safety profile with only 39 adverse events reported within the first 24 hours of the administrations and the safety signals was consistent with adverse events profile expected in this very fragile patient population because we know that these patients after allogeneic stem cell transplantation develop acute graft-versus-host-disease this developed very frequently this kind of events that were reported in the clinical trials. Very importantly, the complete response rate and very good partial response rate strongly correlate with survival. And I think that the recent translates into a long-term effect with an improved overall survival in those patients. So here are the patient, overall survival. So this is why I just told you in patients that achieved a response. The overall responder rate was 34% at 6 months and 12 months, versus only 20% at 6 months and 30% at 12 months in nonresponder patients, highlighting that patients that respond have a long-term response and patients that survive at 6 months, at least -- they are cured for than -- vs graft-versus-host-disease with no disease recurrence and with the sustained oral survival for those patients. So some very impressive results for these very high-risk populations. How does it track? So we look at the microbiota composition. And as you can see here, at baseline, when we look at the microbiota diversity based on the Shannon Index. So Shannon Index, this is an index we use to assess the diversity of the bacteria. And diversity and at baseline before any MaaT013 treatments, the diversity was very low, both in responder patients that are in black and nonresponder patients in white. And in fact as soon as the second visit. So 1 week after the first and question of MaaT013 we saw an increase in the responder patients on the bacterial diversity that were sustained at visit 3, on visit 4 at day 28. While the diversity in nonresponder patients remain very low. There is no increase on -- at day 28, the diversity wasn't completely higher in responding in patients compared to the nonresponding patients highlighting that the response we see in the patients was really linked to a restoration of the gut, microbiota diversity with the use of MaaT013. Regarding the data of the early access program. So we confirm as the promising results in a more diverse population, it was also we used 3 doses, second to 7, 9 of treatments, so a medium of 4 product line of treatments also some patients very easily pretreated. A majority of them are steroid-resistant, so the most severe involvement, 70% steroid dependence, 94% at grade 3, so severe disease, and 77% receive ruxolitinib. So ruxolitinib, this is a drug that is now going to be approved as second line treatment in steroid resistance in acute graft-versus-host-disease but still associated with a high risk of treatment failure, over 50%, despite this there are some good reasons. So we really need to have also some third-line treatment for patients that are going to fail ruxolitinib on the fact most of the patients treated in the early access program received ruxolitinib, and we have a very high response rate of 58% at day 28. And if we look at the best GI overall response rate within the first 28 days, it reached 67%, including 30% of complete response. Similarly, for the [indiscernible], we have a good tolerability and safety profile on the response correlate with the survival of the patients. So here is a survival result. This is for the all patients responding and not responding, 29% at 6 months, 38% at 12 months based on previously published data as OS, the overall survival is expected to be 20% ruxolitinib-resistant patients at 2 months. So it's a real improvement. And when we compare responders in blue compared to nonresponders in black, it reached 70% at 6 months and 59% at 12 months in responders compared to 21% at 6 months from 7% at 1 year in the nonresponders. So this is a very impressive result that highlights. That is the achievement of responses really associated with the acute graft-versus-host-disease in those patients. So there is some very promising clinical results that decided to start pivotal Phase III clinical trial. So MaaT013 increases the responders' microbiome diversity. As a clinical response to MaaT013 translate into an increase of overall survival. The safety was good. Several adverse event were consistent with adverse events profile expected in this patient population, and the data strongly supports the hypothesis that referring the gut microbiome diversity can impact the survival outcome in acute graft-versus-host-disease patients. So I would like to thank all my colleagues, including patients in Phase II and also that treated some patients within the compassionate programs. And thank you to all. So now I will let my call, Mrs. Emilie Plantamura, that is Head of the Clinical Development in MaaT013 that will give you the perspective of the pivotal Phase III clinical trial by MaaT Pharma.

Thank you, Dr. Malard for this excellent presentation. Hi, everyone. I'm Emilie Plantamura, Head of Clinical Development at MaaT Pharma. Today, I'm going to present the ARES study that follows the results from the Phase II ARES study. The ARES study is investigating MaaT013 in acute GvHD. This trial is an international study, including 6 to 8 countries with first-time countries working with MaaT013, and we plan to include up to 50 reference centers. This is a pivotal single-arm trial with MaaT013 used as third-line treatment after steroid and ruxolitinib failure in acute GvHD. The study in consideration is planned to be around 29 months because we include 1 year follow-up for all patients. We plan to recruit 75 patients, and the first patient was treated in March 2022 in Spain. So let's talk about the timelines of the ARES trial. In Europe, the clinical trial was approved in 3 European countries: France, Germany and Spain, and we expect to expand to additional European countries. Regarding the time line, as I said, the ARES trial started in March 2022. We expect to have a first safety and efficacy data review with the Data Safety Monitoring Board by the end of 2022 -- beginning of 2023, when we have recruited 30 to 35 patients. Then we plan to have the primary endpoint analysis at end of 2023. And the end of the trial with the overall survival analysis by the end of 2024. Regarding the U.S., we are currently under discussion with the FDA. And as soon as we have the feedback from the FDA, we plan to expand and initiate the U.S. sites as soon as possible. In terms of results, once we have the results, we plan to -- we target to have MAA submission and BLA submission by beginning of 2025. Regarding the design of the ARES pivotal trial. As I said, the patient population is patients with acute GvHD, so patients have been receiving allogeneic hematopoietic stem cell transportation. We include [ 80 ] patients with acute GvHD with GI symptoms that are refractory to corticosteroids and also refractory or intolerant to ruxolitinib. Once the screening phase is achieved where the investigator ensure that the patients fulfill all the inclusion criteria, the patient is included and treated, and the treatment sequence comprises free administration of MaaT013 within 10 days. At day 28, we evaluate the overall response rate, which is a primary endpoint, and we evaluate the GI response with the complete response, the very good partial response and partial response. And this is a classical endpoint used in acute GvHD. The patients are then followed until 12 months to evaluate the overall survival as well as safety. So the ARES objectives, as I said, the primary endpoint, the efficacy. So the overall response rate based on the GI response at day 28 through complete response, very good partial response and partial response. The other secondary objectives are, of course, the safety with the overall safety assessment and also adverse events, there is adverse events and laboratory abnormalities. The secondary efficacy endpoints, overall response rate for all organs, not only GI, the duration of response and other classical endpoints using clinics to commercial viable progress, increased label as well as quality of life. Importantly, we plan to have some exploratory end points to evaluate the activity of MaaT013 on immune markers and the impact on resource utilization. In conclusion, MaaT013 is used secure acute GvHD, and it's a first-in-class high richness, high diversity, full ecosystem microbiome therapy, including and containing rich core. With MaaT013, we plan to cure acute GvHD, GI acute GvHD through the restoration of the microbiome. And you know all that acute GvHD is a severe complication of allogeneic stem cell transplantation, and it impacts around 10,000 new patients in Europe, in the U.S. and Europe. Today, we have treated more than 100 patients in the Phase II trial and the early access program. And in this setting, MaaT013 showed a very, very good safety profile in this high immunocompromised population. And we show also very promising efficacy results as presented by Dr. Malard with the GI ORR, but more importantly, the impact on the overall survival at 6 and 12 months. So to conclude, MaaT013 is the first microbiome therapy in the world to enter a Phase III trial in hemato-oncology, and the next step will be to have the first data review of ARES by beginning of 2023 by the assembly. Thank you very much, and I leave the floor to Professor Mohty.

Thank you very much, Emilie, for lovely talk. And it is now my great pleasure to jump into this event. I'm Mohamad Mohty from the Sorbonne University Saint-Antoine Hospital in Paris, in France. And for the next few minutes or so, I'll discuss with you the role of MaaT033, which is an oral microbiome ecosystem therapy aiming to improve outcomes for patients with liquid tumors. So what is MaaT033? This is an optimized oral capsule, which was developed by MaaT Pharma to restore and maintain a healthy gut microbiome in patients with severe dysbiosis. This is a high richness and a high diversity, full ecosystem intestinal microbiota therapy. It's an oral drug, which makes it very attractive. And it has been developed so far in the so-called CIMON Phase Ib study, which is a dose-finding study already completed. And our goal is to develop it in a randomized large multicenter trial, the so-called OR-ALLO trial, which I'll discuss later, with the indication of prevention of allotransplant complications. So looking into the capacity of MaaT033 to restore and protect the gut microbiota, I would like to emphasize the strong available research evidence, showing here on the left-hand side from this publication in the New England Journal of Medicine, that those patients with a higher diversity microbiota are going to enjoy an improved survival. And here, we're talking about an allogeneic stem cell transplant procedure where patients will receive a chemotherapy plus or minus radiation for conditioning. But these patients are coming to transplant while having received a lot of chemotherapy and antibiotics. There is a clear status of dysbiosis and lots of diversity, they will receive their allogeneic stem cell transplant, and they may develop a large, wide spectrum of different complications, including infections, acute graft-versus-host-disease, but many other complications. And of course, our goal is to use MaaT033 to prevent and therefore, improve the outcome of these patients. And in order to achieve this, we have already -- we believe we have a strong mechanism of action because this MaaT033 product allows to reset the microbial network. Because of its high richness and diversity, but also the Butycore actually, it can allow to restore the gut barrier integrity, and this is about a prevention of infections. The higher diversity would allow to inhibit the pathogen growth and the production of the metabolites. And this is about the Butyrate, the short chain fatty assets and all of this is about immune regulation and most importantly, the restoration of the immune homeostasis and we know that restoration of the immune homeostasis is crucial I think to improve the outcome of these patients. So the development of MaaT033 relied so far on the CIMON Phase 1b trial. This is the first clinical trial, which has evaluated the drug in humans. These were patients with acute myeloid leukemia or high-risk myelodysplastic syndrome who received intensive chemotherapy, which means these are patients who are going to be in a severe status of dysbiosis. And that was a study -- a dose finding study, Phase Ib, which was a multicenter study in France, 6 center, including the 21 patients. And the primary endpoint, as you may guess, was about safety. However, we had a key secondary end point about the engraftment of the product. So you can see here the design of the study. Day 0 is the day of inclusion. And as I mentioned, these were mainly acute myeloid leukemia patients who received an intensive induction therapy. And as it is the case in a Phase I trial, we had different cohorts, which are shown here. So after inclusion, the patient will receive the treatment according to the schedule of each cohort. Cohort 1 included 3 patients, cohort 6 -- cohort 2 included another 6 patients cohort 3, 6 patient cohort 4, 6 patients. And actually, we didn't need to perform cohort 5 because already when looking into the first 4 cohorts, we were able to have sufficient data in order to guide further development of the product. And when you look to the overall results. The news are really very good, because the MaaT033 agents displayed a good safety profile in the CIMON study. We have 21 patients who were exposed when he completed the treatment 100% drug compliance but this is really a very important. And when you look to the DSMB evaluations and there were 4 meetings, which were held and actually 4 out of 4 recommended the cohort escalations. So 4 SAEs were considered not related to the study drug by the investigator. We had 1 SAE, which was possibly related, but this was about an infectious diarrhea event. But interestingly, we didn't detect in this case any pathogen, which was contained in the MaaT033 product. And actually, this patient recovered within 4 days. The most frequent usual adverse events were GI disorders, but they were mild, moderate, and this is really consistent with the AE profile expected in this patient population. Interestingly, because that was during the COVID-19 pandemic, no SARS-CoV-2 infection occurred or was detected during the study period. And when you look to the engraftment of the product, you can see here the shape of the curves according to the different cohorts. Actually, we had a strong rapid but also persistent engraftment, which, of course, allowed to select the optimal dosage that will be used in our future pivotal randomized trial called OR-ALLO. So as you can see, the results from the CIMON study with this MaaT033 product are really very exciting. And there is a huge and very attractive market opportunity, because it's about prevention of complications of inpatient receiving allotransplant. But in all hematological malignancies in general, and you can see the figures of the U.S. market, the big 5, but also Japan. So approximately, we're talking more -- about more than 22,500 procedures per year. So the next step, as I mentioned, is about a randomized clinical trial, which will evaluate this MaaT033 product to prevent complications of allotransplant and hopefully improve survival. So we aim to include more than 300 patients, 324 for the time being in a randomized, double-blind, placebo-controlled study. Very, very high-level study. And the goal is to evaluate safety, tolerability before and after allogeneic stem cell transplantation. And of course, it's about also evaluating the engraftment and the efficacy in order to improve the overall survival through improvement and prevention of these complications. And we hope to start this exciting study by early 2023. You can see the design of the study relatively straightforward because we would include the allo transplant patient candidate, and they will start actually their treatment with the MaaT033 around 3 weeks before actually the conditioning. This is the pre-transplant phase. Then we have the conditioning regimen. This is the chemotherapy. They usually use the preparative regimen. We usually use before graft infusion, but also we will use the drug after infusion of the stem cell transplant product. And, of course, we'll have the follow-up and look into the different outcomes. So clearly, we do have a very strong rationale that suggests that this is going to be a very promising new treatment for allotransplant. It's oral, easy to use, high richness, high-diversity microbiota therapy. It allows to restore and maintain a healthy microbiome in patients who have already a severe dysbiosis. And the mechanism of action is more and more well established, especially this issue of short-chain fatty acid, including the butyrate and other metabolite production, which we know are crucial in regulation of the immune system and restoring homeostasis. And ultimately, as I mentioned, this is really a strong endpoint. We aim to improve the survival of those patients receiving an allo transplant. And I would kindly remind you that allo transplant is the only curative treatment for many hematological malignancies, but also nonmalignant diseases. And based on the development through the Phase I trial, a CIMON trial, we know already that it's going to be feasible because the safety profile is great. And in terms of activity, displaying high rapid and persistent engraftment. So we're really looking forward towards starting this trial very soon. So with this, I'd like to thank you all for your attention, and I hope you will enjoy the Q&A session. Thank you very much.

My name is Hassane Zarour. I am a professor of medicine, immunology at University of Pittsburgh. I am cancer immunologist, interesting in new immunotherapy of cancer, in particular melanoma and also interesting in microbiome-based therapy of cancer. So we know that immune checkpoint inhibitors has become one of the most potent therapy of solid tumors melanoma and many others. This is a very good news of the past 15 years in the field of oncology and cancer immunotherapy. So however, most part of the patients still do not respond to a single or dual immune checkpoint, so there is a major room for improvement in this. And this has fostered a lot of research to better understand the mechanism of response and resistance to immune checkpoint inhibitor and that's what my lab has been doing also over the past years. We know that there are many mechanisms within the tumor microenvironment that participates and contribute to resistance to treatment and to immune response to cancer. And we know that's, I think, one of the big news of the past 5 to 7 years that outside the tumor micro environment, there are also some mechanism that also modulate response to immune checkpoint inhibitor, in particular, the gut microbiome. So what we know about the gut microbiome in cancer immuno therapy stems from, I think, to study publish first in 2015 in science, mouse model of mouse melanoma. We did not respond to immune checkpoint inhibitors but mouse model were responsive to immune checkpoint inhibitor when they were given some common cells on specific, I think our microbial transplant from responsive mice [indiscernible] reader brought by Dr. [indiscernible] and Dr. [indiscernible] So following this seminal work, additional work on this slide in-human corrected for the first time, gut microbiome composition pretreatment, so preimmune checkpoint broker inhibitor with a favorable or unfavorable outcome and they were as shown in the Slide 3, series of cohort of patients the 2 melanoma cohorts, 1 from [indiscernible], one from [indiscernible] Group, the other by the Chicago group and [indiscernible] GSK identified a certain a certain number of common cells with a high abundance in the [indiscernible] responder retreatment, mostly [indiscernible] and [indiscernible] for the MD Anderson cohort, Bifidobacterium and [indiscernible] the Chicago cohort. The third cohort of patients really either with anti-PD-1 or CTLA-4, were patients with renal cancer or lung cancer, non-small cell lung cancer, in this case, this group in increase or one at a command safety the responders. So this was really the first demonstration that get microbiome pretreatment could correlate with the outcomes, suggesting that possibly manipulating the gut microbiome could impact respond to immune checkpoint blockade. So this was, I think, the good news from this similar study. However, one to also acknowledge that there were some significant discrepancy between the tox identified in this study and not a lot of commonality, which I think raised also, at the same time, a certain degree of skepticism in the field. So we, in Pittsburgh, in collaboration with [indiscernible] tried to revisit the question to evaluate all of the good microbiome in cancer immunotherapy and really 2 type of study. The first was the same type of curative study, correcting the good microbiome with outcome, cohort of patients treated using in initial program in Pittsburgh. So one important finding is we managed to show that good microbiome pretreatment predict response at 9, 10 months, almost a year of treatment. I would to say this is an important finding because most part of the study prior to us use different outcome, [indiscernible] response 3 months or pre-launch, a stable disease. So we here demonstrate that this is the most relevant time at endpoint when we are of the microbiome. So we can displace them any question. And what does it mean? Does it mean that tumor interesting mechanism in the tumor microbe environment, pre-demand early on treatment and that role of the gut microbiome comes after that. So I think that's the number of questions that needs to be answered. And we used the opportunity of this study to evaluate using metagenomics of good microbiome composition pretreatment. And you can see on the right summary of findings, find increased relevance of [indiscernible] in the [indiscernible] of nonresponders. So similarly to what has been found in the previous [indiscernible] study, and increased abundance in [indiscernible] and also in bacteria [indiscernible] of the patient who did good. So this was somewhat confirmatory of the previous published study and really support that possibly microbiome intervention may help bringing these good [indiscernible] may help improve outcome in patient and ongoing immunotherapy. What we also did in this study is to collect this microbiome composition with the occurrence of immune adverse event. This is really a problem, mainly during [indiscernible] we had to stop treatment because of this immune adverse event. And as shown in the left using metagenomic data really can show that the people who experience adverse event or who do not have really 2 distinct microbiome profile in the gut. We went further, ensure that among the good microbiome composition created with adverse event, there was in fact different composition: One that created with adverse in and good microbiome; another one, which increased abundance of [indiscernible] species which correlate with cells adverse events, specific type of adverse events dominated with our trial and bad outcome. And so this finding also support that there may be room for a microbiome transfer transferring out the good microbiome, that accurate with [indiscernible] and may overcome this adverse event. In fact, I think there's a few public study in a small case number, particular CTLA-4 treated patients with colitis, where fecal microbiome transplant was beneficial in this patient. So this may be another application of gut microbiome intervention. So mechanistically, we still don't know how this work and what are the mechanism used by the gut microbiome to regulate response in immune checkpoint blocker. There are many studies out there using the single specious single [indiscernible]. It's difficult to really know if really this makes sense in human so what we have done so far in our study is to look at the cells in the gut microbiome, the non-bat are the whole cells and look at the transcriptome and found out that there was increased activation of LPS pathway, of ILA pathway, supporting that this immunosuppressive pathway and chronic inflammation may be implicated in the resistance to immune checkpoint blockade and this through the action of certain [indiscernible]. These are the data here. So besides this correlative study, we were also interested by proof of principle, really demonstrating, it has never been done before that using a microbiome intervention we could provide benefits to patients would in response to immune checkpoint blockade and [indiscernible]. A year ago, in this trial, a single arm trial, of patients who are treated with pembrolizumab. And when they were nonresponder and confirmed nonresponder, they were treated with 1 single administration of [indiscernible] transplant from a long-term responder in addition to [indiscernible] a round of pembrolizumab. It was a small trial, and we were really pleased to see that among the 15 patients that didn't respond to PD-1 alone, 6 of them had a favorable outcome, either objective response or a prolonged stable disease. So this is more core. We don't have to interpret the data, but I would like to underline that similar study was done in Israel in a small quarter of 10 patients with similar type of finding and really support that -- really there is a hope that future microbiome therapy, may -- by mimicking the responder profile of the gut microbiome may improve response to immune checkpoint inhibitor. So overall, and in conclusion, I think that I would like to underline that is now mounting evidence against microbiome composition moderate both clinical response upon ICI and [ integrated ] events and support that microbiome intervention capable of breaking what may be a good microbiome composition may overcome resistance, at least in a certain fraction of the patient to immune checkpoint inhibitors. It may be another response to all case of resistance to immune checkpoint inhibitor but to a number of them, and also may contribute to limit toxicity to the immune checkpoint inhibitor, which may be very important when the trend now is to combine them, increasing the likelihood of toxicity occurrence. The second point is that there is multiple signature that may be correlated with outcomes or that may explain why there is some level of discrepancy between the study. One has to consider that gene [indiscernible] across species. So many species may mechanistically act through the same pathway. We also have shown that there is a different community called enterotype, which are linked to beneficial or detrimental clinical outcome, which explains some of the discrepancy with the study. So -- and this suggests that the success of future microbiome intervention will be to identify this enterotype and to enrich the microbiome therapy with these enterotypes. Finally, I would just underline, and having -- and being involved in this classical, as they call it, [ microbiome ] transplant, obtained from long-term responders, this is a very difficult process having to face many hurdles. And I would say the future in clinical practice is very difficult to see, as opposed to novel FMT-like products, which may be easily feasible and implemented in clinical practice. So I'm going to end up my talk here, and we'll be happy to take any questions.

Thank you, Professor Zarour. Hi again. I'm Emilie Plantamura, Head of Clinical Development at MaaT Pharma. I will share with you a few details on the very interesting investigatory trial of MaaT013 in the immuno-oncology setting. This trial is sponsored by AP-HP and in collaboration with the Institut Gustave Roussy, INRAE and, of course, MaaT Pharma. As Professor Zarour explained a minute ago, both the richness and the profile of microbiome have been shown to impact response to ICI in melanoma patients. Interestingly, MaaT013 is by design an extra-rich microbiome, which we tried as many different species as a standard human gut microbiome. And using our metagenomic analysis tool, gutPrint, we also confirm that many of the ICI favorable species identified in the literature are indeed present in MaaT013. This led us to develop a collaboration with AP-HP, Institut Gustave Roussy and INRAE to develop a proof-of-concept trial exploring the potential impact of MaaT013 in patients with metastatic melanoma receiving ICI. So this is the biggest trial. And this trial is a multicenter, randomized, placebo-controlled study in 60 patients with metastatic melanoma receiving 2 ICIs, the anti-PD-L1 ipilimumab, and the anti-CTLA4 nivolumab, which are the standard of care therapies in France. Its principal investigator is Professor Franck Carbonnel at AP-HP together with Dr. Caroline Robert of the Institut Gustave Roussy. The key endpoints will be evaluated after 23 weeks, and we will evaluate the safety, of course, of MaaT013 as well as the overall response rate versus placebo in this population. As you can see on this slide, the overall design for the standard of care therapeutic regimen of ICIs with MaaT013 being administered together with each ICI cycle for the duration of the trial. During all the trial, blood and stool samples will be collected to better understand the impact of treatment of MaaT013 on the gut microbiome and the host parameters. At the end of the treatment, of course, we will evaluate the efficacy, the overall response rate according to the standard resist evaluation. So to conclude, as you have understood, PICASSO, even in the investigate proof-of-concept trial, which give our partners and ourselves the opportunity to better understand the impact of MaaT013 richness and diversity on response to ICI. Importantly, this is a randomized trial, building upon, but also potentially supporting a better understanding than first MaaT013 trials presented by Professor Zarour with us earlier. In parallel, MaaT Pharma is developing new innovative assets to fill its pipeline and address the unmet medical need in immuno-oncology. These products will be targeted, designed, new generation microbiome ecosystem therapies based on the extensive analysis of patients responding to ICIs. By leveraging both the gut microbiome diversity and some key targeted functions, we hope to improve response rates to immune checkpoint inhibitors and potentially might mitigate their toxicity. Thank you very much.

Thank you, Emilie. Hi, everybody. I am Carole Schwintner, Chief Technology Officer at MaaT Pharma, and I will present you, together with Marianne Robin, our Head of R&D, the MaaT Pharma's pharmaceutical strategy to leverage the microbiome potential to improve cancer therapies. And our platform microbiome ecosystem therapy has generated a diverse line of product candidates based on 2 different approaches: The native donor-derived approach has led to the development of MaaT013 and NMR presentation; and MaaT033, an oral form presentation for a high diversity full ecosystem donor-derived products. The second approach consists in the complementation range of products, which are indication-specific design ecosystems. This displayed on an innovative ecosystem customization technology to target immuno-oncology markets. All our developments were based on technology called bricks, which are the foundations for our platform. Those bricks include: First, collection procedure, which allows to safely collect donor-derived materials; where the second one is the pool and freezing procedures to maintain the overall key attributes of the microbiota, and together with the collection, it allows us to produce MaaT013 products; third, development versus the approach of a delivery -- oral delivery process, meaning being able to first freeze dry the microbiota while maintaining its attribute, and second of all, develop the capsule, enabling us to deliver this microbiota at the right place in the intestine. This third brick together with the collection and potent freezing part allows us to develop and produce MaaT033 capsules today; the fourth development or most recent one is the fermentation technology. This co-fermentation technology allows us to multiply the overall microbiota and to develop a wide range of products, MaaT03X, in the future. All those processes are also complementary to our characterization and design tools displayed in the print. To go a little bit deeper in each brick, we -- first, I have developed the collection process, which is the key procedure for MaaT -- for the donor-derived range of products. From thousands of candidates down to a few qualified donor, we use comprehensive procedure, including questionnaires, physician consults and a range of biological testings, more than 45 parameters are tested in defined frequencies to maximize the safety on our regular monitoring of the donors and the products. This procedure today has been validated by multiple regulatory agencies, allowing us to start clinical study in various countries. And it has been validated while MaaT013 has displayed an excellent safety profile in more than 100 fragile immunocompromised patients in -- especially in acute GvHD in the ATLAS study, but also in HSCT patients seen in the CIMON study. Third part -- second breakthrough, sorry, of the processes was how to use this safely collected material and transforming in a drug with -- while maintaining all the key attributes of the microbiota. The core material is then collected and transformed into a drug by using proprietary collection device and also attentive diluent, which allows us to use a fully cGMP closed process, maintaining all the attributes of the microbiota. In the key attributes, what we have in our product, in our full product is that we see a superior richness. As you can see on the graph, this richness is on average about 500 OTUs, with a very consistent results from batch to batch, whereas in single donors, you observe a level of richness, which is about 320 OTUs. This formulation allows us also to maximize the Butycore and to perfectly standardize all the parameters we have tested, including the richness, but also all other parameters like butyrate levels, for example. Other characteristic and the biological activity of the initial microbiota is therefore preserved in the frozen product, allowing us its best activity as it has been demonstrated with an excellent engraftment of the product in the patients in GvHD in the ATLAS study, for example. The third part of the process, the third brick we have developed is the oral formulation. Again, the pool material collected with our qualified donors is then freeze dried with a patented process, and this freeze drying process also allows to maintain the key attributes. Here, what I show you is the similarity between the frozen product and the capsule. And as you see, the capsule displays a similarity to the frozen product of more than 85%, which is the level, the threshold we have identified as signing the identity of product. Meaning that when 2 products are of more than 85% similarity with the [indiscernible] Index, they are absolutely identical. So here, as we see, is that this identity is perfectly maintained by the process. On the second hand, we have developed with our partner bioproducts a proprietary capsule with a target to deliver at the ileocolonic part of the intestine, which we believe allows the product to maximize its activity and therefore, the engraftment in the patient intestine and the interaction with the immune system. This capsule, this formulation, has been tested in the clinical study Ib, which is we already presented, CIMON, and where we have observed excellent safety and activity of the product validated, therefore, the process. We also used gutPrint at the heart of our med discovery platform, gutPrint is our tools, allowing us to first collect data, characterize them and also going a step further in prediction and design for future generation products. First element of gutPrint is the collection of data. Data collected from various backgrounds, clinical and preclinical studies, pharmaceutical development and also product manufacturing. Those are our own data. We complement them inside this database with literature-based data and also collaboration. Altogether, those data are stored and formated in a state-of-the-art support validated for by all -- well, inside all the European regulatory and the [indiscernible] approach for good regulatory levels. The data we are storing are various. We collect [indiscernible] like clinical status, demographics or immune data. We also obviously have a look at the gut microbiome parameters with omics analysis, indexes and several deeper analysis of this gut microbiota. And also, of course, we compare with product parameters, including, obviously, omics, but also all product characteristic like bioactivity or several process parameters, which are key to ensure the quality of the product inside. In the end, all those data from those various background in this database allows us to go a step further with AI learning or characterization. Indeed, gutPrint includes a set of tools for microbiota analysis. They are proprietary data, proprietary pipelines developed by MaaT Pharma to allow the characterization of all living microorganisms in our product and of course, in the clinical samples we get. It includes bacteria, archaea and fungi, for example. It allows us to go to taxonomy, but also -- diversity, but also metabolism specific to first strain detection or biomarker identification. Some of the tools are also reduced for our cGMP processes, of course, to allow us to analyze that as a product or monitor them, but also they are part of our QC release to allow the delivery to the patient. Third pillar of gutPrint is the artificial intelligence-based algorithm. From clinical and donor data collected and stored inside our database and also the literature, we combine them and analyze them with artificial intelligence tools, machine learning tools, which allows us to define the best target profile for a specific indication we have previously identified. This allows us to start drug design, which Marianne will explain to you a little bit more just in a few minutes. And when we have several candidates, we can go to the validation step with in vitro or in vivo trials, preclinical trials, prior to the clinical approach. Now I think Marianne, can you please explain to us a little bit more about the drug design.

Thank you, Carole. Hello to all. I'm Marianne Robin, I'm the Head of R&D here at MaaT Pharma. And as was shown earlier, our new exciting artificial intelligence-based algorithms help us to efficiently translate clinical data into therapeutic insights, but also allows us to have a fully integrated platform that can streamline development from discovery to first-in-man clinical trial. This platform is on live in the development of our next generation of products which are called MaaT03X. MaaT03X are designed as combo therapy to improve the response rates to immune checkpoint inhibitor treatment in solid tumor, and doing so by modulating the gut microbiome. MaaT03X composed of a highly rich fully supportive ecosystem with indication-specific key functionalities. It is manufactured using our co-fermentation technology and delivered orally. To say a bit more about our co-fermentation technology, this technology allows us to manufacture targeted profile, which contain, as I was saying earlier, a full supportive ecosystem and indication-specific key functions. And the result of the fermentation is pluggable on all of our technological bricks, for example, using patented cryo protectants or freeze drying capabilities as well as our capture, we can have an oral formulation. This process is donor independent, meaning that it's highly scalable and has lower costs. And as you will see in the next slide, the process is also highly reproducible. We have tested it in over 15 microbiota profiles, so far, with the maintenance of the core microbiota, Butycore, as well as high richness. And the reproducibility batch-to-batch is also excellent with [indiscernible] index superior to 80%. And now I will let Carole present to you the next step for the platform.

Thank you, Marianne. In the next step for us is to build the European largest specialized cGMP manufacturing facility for our MaaT platform. We are currently in the project of building a dedicated 1,500 square meter size, which could also in the future be double, if needed. This plant is designed to support the commercial manufacturing for both MaaT013 and MaaT033 in the next 15 years or so, but also the clinical manufacturing for the MaaT03X products we are currently developing. This facility will be hosted by our partner, Skyepharma. Skyepharma today manufactures approved drugs for United States and Europe and is regularly inspected by regular -- regulatory authorities, sorry, from, of course, U.S.A. and Europe, but also KFDA and ANVISA, allowing us to have a wide view of potential future. This new building has also been designed to be able to host R&D activities giving a fluid communication between R&D, industrialization and manufacturing activities. We are really very excited at the moment to build the next step, the next chapter of our manufacturing activities by implementing this project. Now I leave this down to Herve, who will give you his vision for the coming years for MaaT Pharma. Thank you very much for your attention.

Okay. Thank you very much for your attention. That has been a terrific session. So thank you very much to all the presenters. So it's time to go to the ending remarks and then we will finish with the Q&A. So be prepared for your questions, please. The -- just as a wrap-up, I think it's very important we share with you how we see the next milestones. So the one important is the interment review of MaaT013 Phase III clinical program. We see that we're going to have on hold half of the patients by H1 '23, as it has been announced to the market. And then we will be evaluating the primary end points by H2 2023, at the end of the recruitment of all the patients. So that will be the readout by the end of '23, the readout of the primary end point. We are also expecting with the next product, MaaT033, to launch another Phase II/III clinical trial. The name of the product is [ orallo ]. That has the potential to be pivotal in case the results are good enough, and we are expecting to start this clinical trial by the end of the year in '22. Also MaaT013 is under evaluation for combination with immune checkpoint inhibitors. We also are going to be having access to some biological markets once we have recruited half of the patient, and that's going to be H1 '23. And this readout will be very important for MaaT Pharma in terms of securing the product development road map, so that will be a key milestone for us as well. And MaaT3X, the fermented product, we are expecting it will enter late H1 '23 into the clinics. That's going to be a Phase I/II study in an indication which is not yet disclosed, but that will be in combination with immune checkpoint inhibitors. And then we have been talking already a lot about our new manufacturing location, and that would be okay for '23, mid of '23. And of course, meanwhile, we have secured our existing manufacturing facilities so that we do not have a disruption in terms of the production. And we will then transition to the next, I would say, stage in terms of the size of the manufacturing site by mid-'23. So with that, we are good, and I'd like to welcome your questions. And we'd be happy to answer each of your questions. So once again, questions in English, we will be answering in English; questions in French, we'll be answering in French. Thank you very much, and happy to answer all your questions.

Welcome back. We are now starting the Q&A session together with the MaaT Pharma speakers with me in this room and also our key opinion leaders such as Dr. Joel Dore, Professor Zarour, Professor Holler, Professor Malard, all experts in the oncology and in microbiome. We will start with our first question. So Savita with us will be moderating the Q&A. So Savita, if you want to start with the first question?

My first question is to Carole from Clement [ Pierre ]. The question is, what is the difference between MaaT013 and MaaT033?

MaaT013 is our first lead product, is a microbiota-based product built from a pool of donations and is a high richness, high diversity product delivered by enema for any immediate engraftment to the colon. Our second product, MaaT033, is an oral presentation, allowing to deliver a little dose of bacteria at the targeting delivery in ileocolonic region, which allows the microbiota to seed, to rebuild a new microbiota inside the patient. So that is the main difference between the 2 references.

The second question is to Professor Malard from Mr. [indiscernible], which compliments you on your great talk, professor. And the question was, how are responders versus nonresponses defined in the clinical trials?

So thank you for that question. That is very important. And in fact, for the response, we consider a very good partial response or complete response as the responders for the primary end point, while all patients were considered as nonresponders. And for the complete response, it was the kind of growth as the disappearance of all symptoms of GI acute graft versus host disease, while for very good partial response, it was defined as an [ informal ] for at least 2 stage of GI severity for GI acute graft versus host disease.

Thank you, professor. The third question is to Dr. Plantamura. And the question -- the first question was, what is the preparation of acute GvHD patients who become resistant or cannot tolerate ruxolitinib?

Yes, of course. Thanks for good questions. So among acute GvHD patients, approximately 50% of patients do not respond to the first-line therapy based on corticosteroids, and another 20% cannot tolerate corticosteroids tapering. But regarding the second line, this is based on rich studies and KOL feedback. And we saw that around 50% to 60% of patients with GI symptoms remain refractory or intolerant to ruxolitinib.

Emilie, another question for you, I'm afraid, from Thomas [ Branken ]. In the HERACLES trial, the GI ORR data seems to suggest efficacy is decreasing by day 28. Can you clarify why and around which time does ORR peak?

Usually, the GI response is observed after the second dose of MaaT013, and this is where we saw the best GI response. And sometimes, unfortunately, in these very severe patients, they have infectious event requiring antibiotics use. And in that case, we see a decrease of efficacy of MaaT013 due to the antibiotics. And sometimes, unfortunately, a patient die in the meantime. So that's why we saw a decrease in the response between the second dose and the day 28 evaluation.

Our next question is to Professor Dore. From [ Stefan Gwinev ], this was asked both in French and in English, actually. Is there a required diet to keep this new microbiome on the long term? [Foreign Language]?

I will answer just in English, I think. Thank you very much for the question. It's highly relevant, what you are suggesting, to maintain the microbiome. And what we know from a nutritional study so far, I stress the impact of nutrition actually, and it's highly relevant. What we know is that a diet highly diversified in fiber, rich and diversified in fiber in general will promote a microbiome that is highly diverse and also rich in butyrate-producing bacteria. So this is the first element I will make. And then if we want to go beyond simple nutrition, but think of complementing the diet with other elements, then we can go just beyond targeting the microbiome but also helping the maintenance of the right microbiome by targeting gut tolerability, inflammation, oxidative stress. And this can come with glutamine, for example, or certain probiotics that are highly effective in protecting the barrier as well as acting as anti-inflammatory components, as well as polyphenols that can be quite effective on the toxicity of rux.

Thank you. Going back to Emilie on the CIMON trial. The question was, were the engraftment seen with MaaT033 in the CIMON study? And actually, we can ask that to Dr. Mohty because he's back online. Welcome. So the question was, were the engraftment seen with MaaT033 in the CIMON study consistent across patients or was there variability?

Yes. Sorry. Go on Professor Mohty.

No. Please do, Emilie. Ladies first.

Okay. Thank you. Yes, indeed, we saw variability in the magnitude of engraftment among patients, because we observed the importance of the baseline status of the patient, the microbiota richness but also the immune status of the patient. But we saw that there was homogeneity between the levels of richness reached between the patients.

And also, I would like to add, because maybe the question is alluding to whether there are characteristics of the acute leukemia by itself, or some other disease or patient characteristics that have influenced engraftment. And the short answer, as far as we know today, no. So the engraftment is consistent across all, I would say, tested patients. But obviously, this is a Phase I trial.

My next question is for Herve from [ Mr. Buchner ]. Seres Therapeutics compounds SER-155 currently in Phase Ib is being targeted for graft-versus-host disease and allogeneic transplants. Could you shed some light on the competition with MaaT013? And a similar question from [ Eric Banpu ]. Can you compare your approach to your U.S. competitors?

Okay. Thank you very much. So for the benefit of the audience, SER-155 is a design -- product that has been designed for use on several factors, which has started a clinical trial with a first patient announced by the end of '21. So I don't think it compares with MaaT013 at all because MaaT013 is really positioned on third line with patients that have been resistant to steroids and ruxolitinib. So it's really positioning, which is specific. I think the question has more to do with the comparison with MaaT033. So to make it very short, I think we have 2 differences with Seres. First, regarding the product, our product is a full ecosystem. We are not focusing on specific taxa because we are targeting a very strong functional redundancy on those patients where the dysbiosis is very different from one patient to the other. So we really believe that our approach in restoring the full ecosystem is appropriate on those patients. And also the second element, which differentiates us a lot, is that we leverage on the data from MaaT033. So we have the first-in-human approach. We have probably less preclinical assessment. Our view of the preclinical data is that it's not always translating to humans. So the way we have designed MaaT033 is really to leverage on the patients that we have treated with MaaT013, which is close to 130 today.

And maybe if you allow me to add something to what Herve said, and this is like a role in the philosophy of some... [Technical Difficulty]

Mohamad, it's breaking.

I think all the [indiscernible] that were very specific or...

Sorry, professor, we can't hear you. So unfortunately, I think we're going to move to the next question, if you don't mind. I apologize for that. The next question is to Professor Zarour. And so the question is from Mr. [ Venar ]. Can you elaborate on the role of the [indiscernible], which is credited for a major role in many benefits of microbiome treatment with ICI, please.

Yes. So I would say that the data of [indiscernible] still needs to be further investigated, right? It's clearly come out with a French study as highly present in the stool of responder, mostly non-small cell lung cancer. But beside the study in non-small cell lung cancer in French, in multicenter also, because we propose as a biomarker response in [indiscernible], this doesn't come out if you compare to other study or the tumor type, this readout doesn't come out as a predominant comments are present in the microbiota responder we did in particular large study. So in Pittsburgh, we reanalyzed many, many cohorts of the patients [indiscernible] so far. And this doesn't come out as one of the comments are linked to response, right? So it may be something specific to non-small cell lung cancer. I think we need more data to have a final opinion. And again, I think this underlines the number of questions that needs to be answered, what we call gut microbiome, is it relevant across different cancer or is it too specific? We still don't have the answer to that. Is it also treatment specific? And we still don't have the answer to this question. So that's important things that we need to answer in the future.

Thank you very much, professor. Next question to Herve. We're going back to MaaT013 and the ARES trial. We have 2 questions, 1 from [ Thomas Franken ] and 1 from [ Mr. Haden ], about the status -- the regulatory status with the FDA. And knowing that ARES is a single arm trial, what percent of response rate on the primary end point do you need? And have you had some feedback from regulatory agencies on the design?

So first on the FDA. So just as an update, we are recruiting in Europe as we speak today with MaaT013 as part of the ARES clinical trial. When we submitted the clinical trial authorization in Europe, we did the same in the U.S. However, we have been put on hold by the FDA in '21. We have submitted the Type A meeting request by the end of the year as it was announced during the IPO. And since then, we have ongoing conversation with the FDA, with the support of well-respected regulatory consultant support in the process on our side, aiming to resolve the clinical hold. The actions are still ongoing, and I don't -- I can't today provide you with a more detailed answer. That's ongoing. Regarding the single arm, it has been discussed with the European agency as well as part of a protocol, scientific advice. They have endorsed the design of a single arm clinical trial, yes. So for Europe, that was agreed with the EMA before we submitted, and then authorized in several countries by national agencies as a single arm.

A question for Professor Holler from [ Jakob Mako ]. What are other examples of future indications that microbiome therapies could be applied or expanded towards, please?

So I mentioned at the end of my talk, the CAR T cell therapy, which is the new approach in oncology, more specific cell therapy when graft versus leukemia induction in the course of allogeneic transplantation. I think we are in the beginning of understanding how microbiota shape the CAR T cell therapy. But I would say this is the next step. And I also would like to make the point that we have a lot of problems in our hematological patients with resistant -- vaccine-resistant infections. And I think modulation of resistance could be another aspect, which is important for hematologic patients.

Thank you, professor. Another question for Herve, from the same person actually. What are the advantages of the co-fermented product versus MaaT033?

So the co-fermented product shares similarities with the native product were what you want to do in patients, whatever the kind of patient it is, you want to restore a functional microbiome. So that's true for hematological malignances and it's true also for patients undergoing immune checkpoint inhibitors. Moreover, the way we designed the co-fermented product allows us to bring specificities in the mode of action to trigger certain immune pathways. So that comes in addition to what we have done so far in hematological malignancies. So this product on that aspect is more designed. And of course, as you would imagine, it's a donor-independent product. So it's also more easy in terms of the supply chain upstream.

Next question for Carole, which is a related question, which are the challenges to scale up the microbiome production? And I guess this was more about MaaT03X, but maybe also MaaT013 and MaaT033.

Thank you, Savita. Yes, of course, so this new range of products, it's a key issue to try to anticipate what the scaling up difficulties could be. In the donor-derived products, the challenge is mainly to manage the future number of centers and donor management, which is more an organizational difficulty point. Whereas for MaaT03X and the fermentation, we have identified pretty early in the development and worked on the critical parameters so that we try to anticipate which difficulties we could have. And we have already mimicked the process -- the future process so that we could parameter our work on -- fine-tune the parameters so that we would be able to work in the future with a larger scale. We have already made several scale-ups, which were satisfactory.

Thank you, Carole. Next question for Herve. So it was actually asked in France -- in French, sorry. [Foreign Language] In English, do you envisage to partner in other indications, larger indications, such as depression and maybe partner that?

[Foreign Language] Do I need to say the same in English or? So we are -- we always welcome collaborations. MaaT Pharma is today focusing on oncology mainly. The question was on depression, so we know there is a strong link between dysbiosis and depression as it is for other psychiatry or neurological diseases. So we would welcome discussion with partners on that field, but there is no plan to do it by ourselves today.

Thank you, Herve. Another question for Emilie, and we're going back to more technical questions. And I think there will be 2 more questions, and then we'll have to conclude our session. From Anthony Williamson, how does the human engraftment observed with MaaT033 compared to that observed with MaaT013, Emilie?

So we cannot compare directly the engraftment of MaaT033 versus MaaT013 because we did not test the product in the same population. For example, MaaT013 was tested in GvHD patients, which are quite different compared to AML patients in MaaT033. So we cannot compare directly. I mean the engraftment is the magnitude -- the magnitude of species colonizing the patient, and since the baseline patients of -- characteristics of patients are not the same, we cannot compare directly, unfortunately.

Okay. And thank you, Emilie. And one last question, a very general one, but one that can open perspectives. Excluding money, what are the current limits to the approach explaining that it took so long to add a new pillar to oncology? And is AI changing the rules? And I think this one is for you, Herve.

Yes. Thank you. So the potential is huge. And indeed, I think there was some very important milestones in oncology treatment since surgery, chemotherapy and everything. So the most recent one being immunotherapy is probably. So I think today, we are at a stage where we can observe a lot of data, not only the microbiome data, but first, we can absorb several microbiomes, not only the gut microbiome, but all the microbiomes. We have also the data from the host. And as it has been explained by Professor Zarour, it's not an easy science because there is many parameters that comes into play. A normal microbiome, just to remind you, it's 250 species. So once you are playing with data, it's immediately huge. So that's where the artificial intelligence and everything comes into play, together with the ability to produce those products. Because it's not like producing 1 bacteria or the other, it's really to grow in all those bacteria together so that you can maintain the functionalities and all of that. So it's very important. So I think today, we are at a stage where IA and also the bioproduction, it comes to a level of maturity where we believe it's possible together with our friends from the academic world generating more and more data. I think we are at a stage where, within the next few years, we're going to have a lot of projects on that field. And I mean, it was not so long. If you think about the first gene of catalogs -- the first catalog of genes, I think it was in 2010, something like that, if I'm correct, Joel.

Yes.

If you compare to other industries like the car industry, the IT industry, which is also growing very fast, it's not that long, I would say. So we need to be a little bit more patient, but that's coming. Thanks to a company like us and also the others from the field, I think we are going in the right direction. Just want to remind that there's a potential BLA that will be submitted or data being submitted in the U.S. with potentially the first product approved within a year from now. So I think we are getting close to the level of maturity that everybody is expecting.

I think that's a very good conclusion. Thank you, Herve. Just to remind everyone who's connected that the slides will be made available on the website, it's the question that has been asked. And thanking everyone, all our professors gathered here and all the people inside of MaaT013 Pharma who have contributed to this R&D day.

So yes. So thank you very much. It's our first ever R&D Day, and I would like to thank the presenters for their contribution on sharing the potential of microbiome in oncology and further. I would like also to thank the more than 250 registered participants for their attention. We are very excited, as you have understood, with what lies ahead with -- for MaaT Pharma. And our path is clear, we are aiming to build a global reference in the microbiome for the benefit of million of patients. That's really what drives us. We remain committed to delivering what was announced during the IPO. We remain committed to change the medical paradigm together with our partners, and to anticipate the future with new indications, leveraging on our editing microbiome ecosystem therapy platform and building our new GMP facility next year. So thank you all and have a lovely evening or day, whether you are in Europe or in Asia or in the U.S. Thank you very much and talk to you very soon.