Welcome. I'm Hervé 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. Also importantly, we will be presenting to you our roadmap toward 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 distribution contains looking forward statements that are subject to various risks and uncertainties. I'm glad that the presentation is gonna 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 to 6 P.M. CET, and that's gonna 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. The presentation gonna be taking place both in English and with subtitle in French for those who are more at ease with reading French. Our first speaker will be Dr. Joël Doré from INRAE.
He's one of the most prolific contributor to the field regarding the concept of ecology, microbiome, ecology. 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 initial set of data with Dr. Florent Malard together with Emilie Plantamura. They're gonna be discussing some of our clinical trials. After that, we will be continuing the presentation with Professor Mohamad Mohty. He will be presenting our roadmap regarding MaaT033, our second product.
The Professor Hassane 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. Then we will also present our strategy in terms of entering the field of immuno-oncology with Dr. Emilie Plantamura. All that, the clinical data, the clinical programs that we are presenting before, that's supported also by a very strong project development roadmap, and that will be presented by Marianne Robin, as well as Dr. Carole Schwintner. To finish, I'll come back with the closing session, and we can have the Q&A. As a wrapper, 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 a growing microbiome market. We do believe that there's a terrific expansion since the last 15 years on the field. MaaT Pharma is pioneering what we call the microbiome ecosystem therapies, which will be presented later with a very strong focus in oncology, which is where we see the most potential, but also the most need for the patients. We have created a leading position in the field of oncology with already two candidates that are in the clinic, MaaT013 and MaaT033, which will be presented today. We are generating a new generation of products using our AI platform, MaaT platform.
We also have a clear company strategy in terms of growing and developing the company in a secure cash runway position. Indeed, everything we have announced during the IPO has been achieved, so we are working as per plan today. We are anticipating also the future and building a new cGMP manufacturing facility that will open in mid-2023. The way forward is very clear to us, with an aim to build a global reference in the microbiome. With that, I will leave it to Joël Doré 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, Hervé, for this introduction. I'm Joël Doré, Director of Research with INRAE and Université Paris-Saclay, 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 a 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. It's essentially the interaction between these functionalities that allow us to conceptualize the host microbes symbiosis. 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 immunoinflammatory regulator, interacting with the immune system and maintaining immune homeostasis. It's acting as an antimicrobial barrier, protecting us from colonization by environmental microbes. 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. 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.
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. 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 non-response 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. Now, 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 two combining their effects to induce inflammation that will lead to oxidative stress that in turn will further alter the microbiota. We can have a vicious circle.
We can have circular causalities that will maintain the disease condition, essentially. 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 four actionable levers to support innovations in diagnostic, in monitoring, in prediction, but also to support innovation in prevention and therapy. 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. 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. There 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. Just if I go quickly.
Key features of the health-associated microbiota involve 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. 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. We cannot do very much with the human genome, but we can actually modulate the microbiome with nutrition and with microbiotherapy.
That will be useful for the maintenance or the restoration of microbe-host 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. It came as a surprise, but there is not a usual bell-shaped distribution. When we look at the distribution in number of individuals as a function of number of genes in the 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 altered metabolic and inflammatory traits in overweight and obesity. It's associated with non-response to calorie restriction in overweight and obesity.
In this context, low richness microbiota is predictive. It 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 non-response to cancer therapy. We will zoom into this specific aspect just after. What we know is that the normal population, non-obese, around 15% of the population is having a low richness microbiota. When we turn to overweight, moderate obesity, then it's 40%, and when we deal with morbid obesity, with BMI over 40, then it's 75% of the population. This feature is really following the severity of the disease condition.
Specifically zooming into cancer therapy, what we have been able to observe is that a 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. In this context, survival is strongly impacted by the richness and diversity of the microbiota. A low gene count is associated with a higher mortality by acute graft-versus-host disease, which is a complication following stem cell transplantation. The level of improvement when there is a high diversity microbiota is up to 30%. Low gene count is associated with lesser progression-free survival in immunotherapy in two contexts, in melanoma, but also in lung cancer and other solid cancers.
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. 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.
It's the case as illustrated in oncology. Key features of a 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.
Thank you very much, Joël. It was a very, very clear presentation as usual. 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. Especially I want to insist in the fact that MaaT Pharma has a unique positioning. We are leveraging the potential of the full complexity, the full ecosystem. We are not here developing products that are one strength, two strengths, or X strengths. 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 microbiome, which is the link, the dialogue between the microbiome and the immune system, so that we can improve the condition of the patient.
This full ecosystem approach is very important and makes us unique. Also, second, our focus is oncology. That's where we do believe there's a high unmet medical needs and also 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. 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 two, 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. 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's an improvement on that severe population. Now we are entering the phase III in Europe, and the clinical trial is ongoing. Fourth, as for any biological product, it's very important that you can master your bioprocesses. Here we have set a cGMP facility, which is scalable and which will support the entire pipeline beyond all the ranges of products. That will support the clinical pipeline for the next few years. The two products that we have today in the clinics are MaaT013 and MaaT033. They are two different products.
However, they share some commonalities, and the key commonalities are the fact that they are high diversity products, meaning we will be providing the full menu of the microorganisms to the patients. That's a full ecosystem. Also this product is acting as an immune restoration, thanks to the ButyCore 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 product, 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. Not only we are donor independent, but also we are able on that range of product to set a specific signature that we define using machine learning algorithm.
Here we will be setting a specific microbiome in the gut of the patients, 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, two slides before we finish that section. The two 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 a phase Ib study in acute myeloid leukemia patients. That's data we will be sharing today, and we hope that we're gonna have a nice publication later in the year. MaaT013 is also used as a proof of concept in advanced melanoma.
Here, as I've said a little bit earlier, MaaT013 will be used to pair with the immune checkpoint inhibitors. 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. 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 gonna be 1,500 sq m that we will expand to 3,000 sq m if needed, through the partnership with a CDMO named Skyepharma. That will open mid-2023. In terms of the market penetration, we start with a niche market entry strategy in GVHD, MaaT013.
That's 2,000 patients per year. We multiply by 10 going to all patients receiving stem cell transplantation with the second product, MaaT033. We multiply again by 10 with the MaaT03X product, where we will be targeting solid tumors. Of course, that's only the beginning of the story and the potential of our MaaT platform and the products we will generate from the MaaT platform. Are very large because it could be potentially all immune inflammatory related disease. The potential is huge, but for the next 10 years, we have already a very comprehensive, I would say, market expansion and penetration. Thank you very much. As you have understood, we are really here talking about a new pillar in oncology. We have surgery, we have immunotherapy, radiotherapy, now we have the microbiome.
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.
Thank you, Hervé, for this kind introduction. It's my pleasure and my honor to give you an overview about the microbiome as a new frontier in hematological cancer treatment. I am Ernst Holler. I was a former director of the clinical transplant program at the University of Regensburg, and I'm now a senior professor 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 between immune cells and tumor cells, and all three are important for optimal immunoregulation, and this will be the topic of my introduction in stem cell transplantation. 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. The reconstituted immune system makes some problems, but is also important to cure patients. We can cure about 50%-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 lethal complications overall in 20%-30% of our patients.
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 a relapse. On the right side, you see the leukemic cells on 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 1970s, van Bekkum observed that mice grown under completely germ-free conditions do not develop graft-versus-host disease.
They survive to 100%, whereas on the right side of the slide, mice grown under conventional conditions died from graft-versus-host disease. After seeing comparable results in some other animal models, the first reports came up that complete decontamination in children reduces graft-versus-host disease. Microbial decontamination and antibiotic prophylaxis was standard practice until 2015. However, we saw a new era in stem cell transplantation. With the Human Microbiome Project, we were able to perform a molecular microbiota analysis by 16S rRNA sequencing. 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, and the green and blue ones and the white ones are the conventional protective good bacteria.
The red one are the pathogenic. 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. In those patients who have GvHD and are 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. These findings were first reported in several single center studies, but in the late twenties, we were able to confirm, as in multicenter studies, the relevance of these findings.
The first study, we addressed the enterococcal expansion in four centers across different continents, and you can see the results in the Sloan Kettering Cancer Center and in the other centers. 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. This was also seen in a more general analysis. You see the time course of diversity, microbial diversity, after transplantation. At day zero, the day of transplant, it 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. Those patients have a low diversity early after transplantation. They have a much poorer outcome. They have higher treatment-related mortality.
Microbiota dysbiosis, loss of diversity, affects the outcome after transplantation. Now, we asked for the causes. Why do patients have dysbiosis? On one side, GvHD 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 these brown cells 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. This can be also observed on the level of PCR analysis on the right side. Now, the second major reason for dysbiosis and for 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%. 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 two centers in Regensburg and in New York. 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. These protective metabolites are important for stabilization of the host and then the patient. If these metabolites are lost by antibiotic treatment, the immunoregulation, which is needed in GvHD tissues, is also lost. Here you see on the left side a correlation of the receptors for these metabolites in biopsies with the most important GvHD-preventing cells, the regulatory T cells. On the right side, you see that patients try to protect themselves with these regulatory T cells. They have the marker FoxP3.
If patients are on antibiotics, on the right side, the red ones, then this protective reaction is almost missing. 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, where the tryptophan metabolites into the short-chain fatty acids stabilize the CAR-T cells. On the right side, you see antigen-specific T-cells suppressing tumor growth. Those who are grown in metabolites and protective metabolites are the most efficacious one. We can expect that the role of microbiota is much broader than in stem cell transplantation. What we need is restoration of microbiota. This microbiota produce protective metabolites.
I mentioned the short-chain fatty acids, I mentioned the indoles. They also produce cytokines stabilizing the epithelial cells like interleukin 22. 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 by the interleukin 22. Microbiota restoration, therefore, should help to restore the right balance. With this, I thank you for your attention and give back to the organizers. Thank you.
Hello, everybody. This is our pleasure to be here today to discuss the result of the phase II clinical trial on early access program using MaaT013. After the great presentation by Professor Holler regarding the importance of microbiota in the setting of stem cell transplantation and more particularly graft-versus-host disease, I'm going to discuss the clinical results. I am a professor of hematology at the Hôpital Saint-Antoine on Sorbonne University in Paris, France. What we are going to deal with in patients that receive allogeneic stem cell transplantation, this is a 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 the intestinal dysbiosis.
In fact, in patients that are going to receive allogeneic stem cell transplantation for leukemia, lymphoma, myeloma, they are going to receive chemotherapy and all patients are going to receive antibiotics that will have a very detrimental effect on the gut microbiota, induce dysbiosis with an important loss of diversity that lead to complications, infectious complications of course, but also this acute graft-versus-host disease. In fact, around the world we are going to perform 22,000 allogeneic stem cell transplantation per year. Graft-versus-host disease is very frequent 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%.
We need to develop some new strategy on one of these very promising and exciting strategy, the use of MaaT013, as I'm going to show you in the next slides. How does it work? MaaT013 aims to restore the interactions between the microbiome and the immune system to treat acute graft-versus-host disease, and there is a broad range of effect. It will induce some immune homeostasis restorations. It induce the butyrate, and it will lead to an increase in regulatory T cell that will control acute graft-versus-host disease. It also increase the diversity of the microbiota that will lead to an inhibition of the pathogens and productions of metabolite. This is the so-called butyrate that induce the Tregs with some immunoregulatory effect.
Finally, it will restore the barrier integrity, and it will decrease the risk of infectious complications of sepsis, and it will contribute to the decreased risk of acute graft-versus-host disease in those patients. MaaT013 restores the microbiome to cure gastrointestinal acute graft-versus-host disease. What are the characteristic of the product? This is a pooled microbiota with high richness, a high diversity, a full ecosystem with all the bacteria. And that contains a so-called ButyCore, that is a set of several butyrate-producing bacteria with this immunoregulatory effect. We give this with three doses, every five to seven days with 150 mm per enema bags. We have first of all available clinical data I'm going to develop. First, the HERACLES phase II clinical trial that's 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 20. That is a classical endpoint to evaluate acute graft-versus-host disease. This is the current indication with the GI acute graft-versus-host disease. There are two strategies now, as I told you, clinical data from the phase II clinical trial, HERACLES, with 24 patients treated in Europe, so four countries involved. All patients with very severe GI aGVHD, grade three to four, steroid refractory, so this is the most severe disease. All patients received three 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 treatment. In the early access programs, only patients were treated in France, 52 patients treated with GI acute GvHD grade two to four. It was steroid refractory, but also there is some patients with steroid dependence acute GvHD. Similarly to the data in HERACLES, patients received three doses of MaaT013 on single treatments over two weeks. Patients were more heavily treated for GvHD because they received one to six previous line of treatments before MaaT013. Regarding the results here, the result for the phase II clinical trial, HERACLES, on 24 patients. There are some very promising results. When we look at the response rate at day 28 was 38%, that in fact more patients response.
If we look at the best GI overall response rate, it was 52%, including 38% of complete response. In those patients, it was so as I told you, very severe patients, all of them with grade three or grade four involvement, all of them with steroid-resistant aGVHD. We have a very good safety profile, with only 39 adverse events reported within the first 24 hours of the administration. The safety signals were consistent with adverse events expected in this very fragile patient population, because we know that these patients, after allogeneic stem cell transplantation, they develop aGVHD, develop very frequently this kind of adverse events that were reported in the clinical trials.
Very importantly, the complete response rate on very good partial response rate strongly correlate with survival, highlighting that the response translate into a long-term effect with an improved overall survival in those patients. Here are the patients of the overall survival. This is why I just told you, in patients that achieve a response, the overall response rate was 44% at six months and 12 months versus only 20% at six months and 30% at 12 months in non-responder patients, highlighting that patients that response have a long-term response. Patients that survive at six months at least, they are cured for the aGVHD, with no disease recurrence and with the sustained overall survival for those patients. Some very impressive results for these very high-risk populations. How does it work?
We look at the microbiota composition. As you can see here, at baseline, when we look at the microbiota diversity based on the Shannon index. Shannon index, this is an index we use to assess the diversity of the bacteria, so alpha diversity. At baseline, visit one, before any pimasertib treatment, the diversity was very low, both in responder patients that are in black and in non-responder patients in white. In fact, as soon as the second visit, one week after the first administration of madsertib, we saw an increase in the responder patients of the bacterial diversity that was sustained at visit three and visit four at day 28. While the diversity in non-responder patients remained very low, there was no increase at day 28.
The diversity was significantly higher in responding patients compared to the non-responding patients, highlighting that the response we see in the patients was really linked to restorations of the gut microbiota diversity with the use of MaaT013. Regarding the data of the early access program, we confirm the promising results in a more diverse populations. It was also we use three doses, second to seventh line of treatment, median of four previous line of treatment. Some patients very heavily pre-treated. A majority of them are steroid-resistant, the most severe involvement. 70% are steroid dependent, 94% are grade three, severe disease, and 77% receive ruxolitinib.
Ruxolitinib, this is a drug that is now going to be approved as second-line treatment in steroid-refractory acute GvHD, but that is still associated with the high risk of treatment failure, over 50%. Despite this, there are some good results. We really need to have also some third-line treatment for patients that are going to fail ruxolitinib. In fact, most of the patients treated in the early access program received the ruxolitinib, and we have a very high response rate of 58% at day 28. If we look at the best GI overall response rate within the first 28 days, it reached 67%, including 40% of complete response. Similarly to the result in HERACLES, we have a good tolerability and safety profile and the response correlate with the survival of the patients.
Here are the survival result. This is for all the patients responding and not responding, 49% at six months and 38% at twelve months, based on previously published data. OS, the overall survival, is expected to be 20% in ruxolitinib-resistant patients at two months. It's a real improvement. When we compare responders in blue compared to non-responder in blacks, it reached 70% at six months and 59% at twelve months in responders compared to 29, 21% at six months, and 7% at one year in the non-responders. This is some very impressive result that highlight that the achievement of response was rarely associated with the cure of acute graft-versus-host disease in those patients.
There is some very promising clinical results that led us to decide to start a pivotal phase III clinical trial. MaaT013 increases the responders' microbiome diversity as a clinical response to MaaT013 translates into an increase of survival. The safety was good. Severe adverse events were consistent with the adverse events profile expected in these patient populations. The data strongly supports the hypothesis that restoring the gut microbiome diversity can significantly impact the survival outcome in acute graft-versus-host disease patients. I would like to thank all my colleagues who included patients into the phase II HERACLES study and also who treated some patients within the compassionate use programs. Thank you to all. Now I will let my colleague, Dr. Emilie Plantamura.
Emilie Plantamura, that is Head of the Clinical Development with MaaT Pharma, 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, which follows the results from the phase II HERACLES study. The ARES study is investigating MaaT013 in acute GvHD. This trial is an international study, including six to eight 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 a third-line treatment after steroid and ruxolitinib failure in acute GvHD. Study duration is planned to be around 29 months, because we include one year follow-up for all patients. We plan to recruit 75 patients, and the first patient was treated in March 2022 in Spain. Let's talk about the timelines of the ARES trial.
In Europe, the clinical trial was approved in three European countries, France, Germany and Spain, and we expect to expand to additional European countries. Regarding the timeline, 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 30-35 patients. We plan to have a 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 target to have a 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 having received allogeneic hematopoietic stem cell transplantation. We include adult 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 exclusion, inclusion criteria, the patient is included and treated, and the treatment sequence comprises three 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. 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 the safety.
The ARES objectives, as I said, the primary endpoint, the efficacy, 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 are overall response rate for all organs, not only GI, the duration of response, and other classical endpoints used in clinics, overall survival, progression-free survival, as well as quality of life. Importantly, we plan to have some exploratory endpoints, and to evaluate the activity of MaaT013 on immune markers and, the impact on resource utilization.
In conclusion, MaaT013 is used to cure acute GVHD, and it's a first-in-class, high richness, high diversity, full ecosystem microbiome therapy, including and containing ButyCore. The MaaT013, we plan to cure acute GVHD, GI acute GVHD through the restoration of the microbiome. You know, all that acute GVHD is a severe complication of allogeneic stem cell transplantation, and it impacts around 10,000 new patients in the U.S. and Europe. To date, we have treated more than 100 patients in the phase II trial and the early access program. In this setting, MaaT013 showed a very, very good safety profile in this highly immunocompromised population. We showed also very promising efficacy results as presented by Dr. Malard with the GI ORR, but more importantly, the impact on the overall survival at six and 12 months.
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 the beginning of 2023 by the DSMB. Thank you very much, and I leave the floor to Professor Mohamad Mohty.
Thank you very much, Emilie, for a lovely talk. It is now my great pleasure to jump into this event. I'm Mohamed Mohty from the Sorbonne University and Saint-Antoine Hospital in Paris in France. 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. 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 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 the study already completed. Our goal is to develop it in a randomized large multi-center trial, the so-called ORALLO trial, which I'll discuss later, with the indication of prevention of allo transplant complications. 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.
Here we're talking about an allogeneic stem cell transplant procedure where patients will receive a chemotherapy plus or minus radiation for conditioning. These patients are coming to transplant while having received a lot of chemotherapy and antibiotics. There is a clear status of dysbiosis and loss of diversity. They will receive their allogeneic stem cell transplant, and they may develop a wide spectrum of different complications, including infections, acute graft-versus-host disease, but many other complications. Of course, our goal is to use MaaT033 to prevent and therefore improve the outcome of these patients. In order to achieve this, we believe we have a strong mechanism of action because this MaaT033 product allows to reset the microbiome 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 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 acids. All of this is about immune regulation and most importantly, the restoration of the immune homeostasis. 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 Ib 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. That was a study, a dose-finding study, phase Ib, which was a multicenter study in France, six-center, including 21 patients, and the primary endpoint, as you may guess, was about safety. However, we had a key secondary endpoint about the engraftment of the product. You can see here the design of the study. Day zero is the day of inclusion, and as I mentioned, these were mainly acute myeloid leukemia patients who received an intensive induction therapy. As it is the case in a phase I trial, we had different cohorts, which are shown here.
After inclusion, the patient will receive the treatment according to the schedule of each cohort. Cohort one included three patients. Cohort two included another six patients. Cohort three, six patients. Cohort four, six patients. Actually, we didn't need to perform cohort five because already, when looking into the first four cohorts, we were able to have sufficient data in order to guide further development of the product. When you look to the overall results, the news are really very good because the MaaT033 agent displayed a good safety profile in the CIMON study. We had 21 patients who were exposed, 20 completed the treatment. 100% drug compliance, so this is really very important.
When you look to the DSMB evaluations, there were four meetings which were held, and actually four out of four recommended the cohort escalations. Four SAEs were considered not related to the study drug by the investigator. We had one 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. Actually, this patient recovered within four days. The most frequent usual adverse event 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.
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 ORALLO. As you can see, the results from the CIMON study with this MaaT033 product are really very exciting. There is a huge and very attractive market opportunity because it's about prevention of complications of in patients receiving allotransplant, but in all hematological malignancies in general, and you can see the figures of the U.S. market, the Big Five, but also Japan.
Approximately, we're talking more than 22,500 procedures per year. 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. We aim to include more than 300 patients, 224 for the time being, in a randomized, double-blind, placebo-controlled study. Very high level study, and the goal is to evaluate safety tolerability before and after allogeneic stem cell transplantation. 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 three weeks before actually the conditioning. This is the pre-transplant phase. 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. Of course, we'll have the follow-up and look into the different outcomes. Clearly, we do have a very strong rationale that suggests that this is going to be a very promising new treatment for allo transplant. 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.
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. Ultimately, as I mentioned, this is really a strong endpoint. We aim to improve the survival of those patients receiving an allo transplant. I would kindly remind you that allo transplant is the only curative treatment for many hematological malignancies, but also non-malignant diseases. Based on the developments through the phase one trial, the CIMON trial, we know already that it's gonna be feasible because the safety profile is great, and in terms of activity, it displayed high, rapid, and persistent engraftment. We're really looking forward towards starting this trial very soon.
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.
Okay, very good. My name is Hassane Zarour. I'm a professor of medicine and immunology at the University of Pittsburgh. I'm a cancer immunologist interested in immunotherapy of cancer, in particular melanoma, and also interested in microbiome-based therapy of cancer. We know that immune checkpoint inhibitor have become one of the most potent therapy of many solid tumor, melanoma, and many other. This is very good news of the past 15 years in the field of oncology and cancer immunotherapy. However, most part of the patients still do not respond to a single or dual immune checkpoint blockade. There is a major room for improvement.
This has fostered a lot of research to better understand the mechanism of response and resistance to immune checkpoint inhibitor. 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 participate and contribute to resistance to treatment and to immune response to cancer. We know that is, I think one of the big news of the past five to seven years, that outside the tumor microenvironment, there are also some mechanisms that also modulate response to immune checkpoint inhibitor, in particular the gut microbiome.
What we know about the gut microbiome in cancer immunotherapy stems from a study published first in 2015 in Science mouse model of a mouse with melanoma who did not respond to immune checkpoint blockade. Mice responded to immune checkpoint inhibitors when they were given specific commensals or FMT, fecal microbiota transplant from responsive mice. I think this was really the proof of principle brought by Dr. Zitvogel and Dr. Gajewski lab. Following this, similar additional work shown on this slide in humans correlated for the first time gut microbiome composition, pre-treatment, so pre-immune checkpoint inhibitor with a favorable or unfavorable outcome.
There were, as shown in this slide, three series of three cohorts of patients. Two melanoma cohorts, one from MD Anderson, Wargo group, the other by the Chicago group and Tom Gajewski, identified a certain number of commensal with a high abundance in the stool of responder pre-treatment, mostly Eubacterium and Faecalibacterium prausnitzii for the MD Anderson cohort, Bifidobacterium and Collinsella for the Chicago cohort. The third cohort of patients with either anti-PD-1 or CTLA-4 were patients with renal cancer or lung cancer, non-small cell lung cancer in this case. Zitvogel group find increased abundance of Akkermansia and Eubacterium in the responder.
This was really the first demonstration that gut microbiome pre-treatment could correlate with outcome, suggesting that possibly manipulating the gut microbiome could impact response to immune checkpoint blockade. This was, I think, the good news from this seminal study. However, one has to also acknowledge that there was some significant discrepancy between the taxa identified in each study, and not a lot of commonality, which I think raised also, at the same time, a certain degree of skepticism in the field. We in Pittsburgh, in collaboration with Hassane Zarour, tried to revisit the question to evaluate all the gut microbiome in cancer immunotherapy, and we did two type of study.
The first was the same type of correlative study, correlating the gut microbiome with outcome in a cohort of patients, treated with immune checkpoint blockade in Pittsburgh. One important finding is we managed to show that the gut microbiome pretreatment predict response at nine, 10 months, almost a year of treatment. I have to say this is an important finding because most part of the study prior to us used different outcome, you know, clinical response at three months or prolonged stable disease. We here demonstrate that this is the most relevant time point when we evaluate the gut microbiome, so we can dismiss the many question and what does it mean.
Does it mean that interesting mechanisms in the tumor microenvironment play a predominant role early on treatment, and that the role of the gut microbiome comes after that. I think that's a number of questions needs to be answered. We use the opportunity of this study to evaluate using metagenomics gut microbiome composition pretreatment. You can see on the right a summary of findings, the increased abundance of Bacteroides in the stool of non-responders. Similarly to what has been found in all the previous published studies. An increased abundance in Firmicutes and also Actinobacteria in the stool of the patient we did good.
This was somewhat confirmatory of the previous published study and really support that possibly microbiome intervention may help bringing this good commensal and good taxa may help improve clinical outcome in patients undergoing immunotherapy. What we also did in this study is to correlate gut microbiome composition with the occurrence of immune adverse event. This is really a problem, mainly upon dual immune checkpoint blockade. People have to stop treatment because of this immune adverse event. As shown in the left, using metagenomic data really can show that the people who experience adverse event or who do not has really two distinct microbiome profile in the gut. We went further and show that among the gut microbiome composition correlated with adverse event, there was in fact two different composition.
One that correlated with adverse event and good outcome. Another one, which increased abundance of Streptococcus species, which correlate with serious adverse events, specific type of adverse events dominated with arthralgia and bad outcome. This finding also support that there may be a room for a microbiome transfer, transferring the gut microbiome that you know correlate with good outcome and may overcome this adverse event. In fact, I think there's a few published study in a small case number, in particular CTLA-4 treated patient with colitis, where a fecal microbiome transplant was beneficial in this patient. This may be another application of gut microbiome intervention.
Mechanistically, we still don't know how this works, and what are the mechanisms used by the gut microbiome to regulate response to immune checkpoint blocker. There are many studies out there using, you know, single species, single taxa. It is difficult to really know if really this makes sense in humans.
What we have done so far in our study is to look at the cells in the gut microbiome, the non-bacterials or the host cells, and look at their transcriptome, and found out that there was increased activation of LPS pathway, of IL-8 pathway, you know, 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 commensal. These are the data here. Besides this correlative study, we were also interested by proof of principle, really demonstrating, as it has never been done before, that you know, using a microbiome intervention, we could provide benefits to patients who didn't respond to immune checkpoint blockade.
That's what we did in this Science paper published a year ago. You know, in this trial, a single-arm trial, patients were treated with pembrolizumab, and when they were non-responder and confirmed non-responder, they were treated with one single administration of fecal transplant from a long-term responder in addition to additional round of pembrolizumab. This was a small trial, and we were really pleased to see that among the 15 patient that didn't respond to PD-1 alone, six of them had a favorable outcome, either objective response or prolonged stable disease. This is more cohort. We don't have to interpret the data, but I would like to underline that similar study was done in Israel in a small cohort of 10 patients with similar type of finding.
It really supports that there is a hope that future microbiome therapy may, by mimicking, the responder profile now of the gut microbiome may, improve response to, immune checkpoint, inhibitor. Overall and in conclusion, I think I would like to underline that there is now mounting evidence that gut microbiome composition modulate both clinical response upon ICI and immunogenic 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 very actually not be the response to all case of resistance immune checkpoint inhibitor, but to a number of them.
Will also may contribute to limit toxicity to this immune checkpoint inhibitor, which may be very important when the trends now is to combine them, increasing the likelihood of toxicity occurrence. The second point is that there is multiple signature that may be correlate with the outcomes. That may explain why there is some level of discrepancy between the study. One has to consider that gene are relevant across the species. 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, you know, explain some of the discrepancy with the study.
This suggests that, you know, the success of a future microbiome intervention will be to identify this enterotype and to enrich the microbiome therapy with these enterotypes. Finally, I would just underline having and being involved in this classical fecal microbiota transplant obtained from long-term responders, this is a very difficult process you face, you know, many hurdles. I would say the future in clinical practice is very difficult to see as opposed to a novel FMT-like products which may be easily feasible and implemented in clinical practice. I'm going to wrap up my talk here, and I will be happy to take any question.
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 investigator led 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 with thrice as many different species, as a standard human gut microbiome. Using our metagenomic analysis tool, gutPrint®, we also confirmed 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. This is a PICASSO trial, and this trial is a multicenter randomized placebo-controlled study in 60 patients with metastatic melanoma receiving two ICIs, the anti-CTLA-4 ipilimumab and the anti-PD-1 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 follows 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, MaaT013, on the gut microbiome and bios parameters. At the end of the treatment, of course, we will evaluate the efficacy, the overall response rate according to the standard RECIST evaluation. To conclude, as you have understood, PICASSO is an investigator-led, 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 FMT 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 pharmaceutical strategy to leverage the microbiome potential to improve cancer therapies. Our platform microbiome ecosystem therapy has generated a diverse line of product candidates based on two different approaches. The native donor-derived approach has led to the development of MaaT013, an enema presentation, and MaaT033, an oral form presentation for a high diversity, full ecosystem donor-derived products. The second approach consists in the co-fermentation range of products, which are indication-specific design ecosystems, designed on an innovative ecosystem co-fermentation 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 was the approach of delivery, oral delivery process, meaning being able to first freeze-dry the microbiota while maintaining its attributes, and second of all, develop a capsule enabling us to deliver this microbiota at the right place in the intestine. This third brick, together with the collection and pool and freezing part, allows us to develop to and produce MaaT033 capsules today. The fourth development, the 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, MaaT 38, MaaT in the future. All those processes are also complementary to our characterization and design tools displayed in gutPrint. To go a little bit deeper in each area, we first 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 donors, we use comprehensive procedure including questionnaires, physician consults, and a range of biological tests. 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 studies in various countries.
It has been validated while MaaT013 has displayed an excellent safety profile in more than 100 fragile immunocompromised patients, especially in aGVHD in the HERACLES study, but also in HSCT patients in the CIMON study. The second part of the processes was how to use this safely collected material and transforming into a drug while maintaining all the key attributes of the microbiota. The pooled material is then collected and transformed into a drug by using proprietary collection device and also patented 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 pool 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. All the characteristics and the biological activity of the initial bacterial 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 aGVHD, in the HERACLES 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. 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. 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 two products are more than 85% similarity with the Bray-Curtis index, they are absolutely identical. Here, as we see, this identity is perfectly maintained by the process.
On the other hand, we have developed with our partner, Biocodex, a proprietary capsule with a target to deliver ideally to the colonic part of the intestine, which we believe allows the product to maximize its activity and therefore the engraftment in the patient's intestine and the interaction with the immune system. This capsule, this formulation, has been tested in the clinical study Ib, which has been already presented, CIMON, and where we have observed excellent safety and activity of the product, validating therefore the process. We also use GutPrint at the heart of our MET discovery platform. GutPrint is our tools allowing us to first collect data, characterize them, and also going a step further in the prediction and design for future generation products. First element of GutPrint is the collection of data.
Data collected from various background: 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. All together, those data are stored and formatted in a state-of-the-art support validated for by all the. Well, inside all the European regulatory and the GAMP five approach for a good regulatory levels. The data we are storing are various. We collect host parameters 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.
Of course, we compare with product parameters, including obviously omics, but also all product characteristics 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 tool for strain detection or biomarker identification. Some of the tools are also used for our cGMP processes.
Of course, to allow us to analyze data 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 the gutPrint is the artificial intelligence-based algorithm. From clinical and donors data collected and stored inside our database, and also the literature, we combine them and analyze them with an artificial intelligence tool, the 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, she'll say in a few minutes. 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. 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 now live in the developments 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 treatments in solid tumor, and doing so by modulating the gut microbiome. MaaT03X is 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. The result of the fermentation is pluggable on all of our technological bricks. For example, using our patented cryoprotectants, our freeze drying capabilities, as well as our capsule, we can have an oral formulation. This process is donor-independent, meaning that it's highly scalable and has lower costs. As you will see in the next slide, the process is also highly reproducible. We have tested it over 15 microbiota profiles so far, with the maintenance of the core microbiota ButyCore, as well as the high richness. The reproducibility batch to batch is also excellent with a Bray-Curtis index superior to 80%.
Now I will let Carole present to you the next step for the platform.
Thank you, Marion. Indeed, 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 sq m size, which could also in the future be doubled, 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 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 exciting at the moment to build the next step, the next chapter of our manufacturing activities by implementing this project. Now I leave the stand to Hervé, 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. Thank you very much to all the presenters. Now it's time to go to the ending remarks, and then we will finish with the Q&A. Be prepared for your questions, please. Just as a wrap-up, I think it's very important we share with you how we see the next milestones. The one important is the interim review of MaaT013 GvHD phase III clinical program. We see that we're gonna have enrolled half of the patients by H1 2023, as it has been announced to the market. Then we will be evaluating the primary endpoint by H2 2023 at the end of the recruitment of all the patients.
That will be the readout by the end of 2023, the readout of the primary endpoint. 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. We are expecting to start this clinical trial by the end of the year in 2022. Also, MaaT013 is under evaluation for combination with immune checkpoint inhibitors. We also are gonna be having access to some biological markers once we have recruited half of the patients, and that's gonna be H1 2023. This readout will be very important for MaaT Pharma in terms of securing the product development roadmap. That will be a key milestone for us as well.
MaaT03X, the fermented product, we are expecting it to enter late H1 2023 into the clinics. That's gonna be a phase Ib-I-II study in an indication which is not yet disclosed, but that will be in combination with immune checkpoint inhibitors. We have been talking already a lot about our new manufacturing location, and that will be okay for 2023, I mean, 2023. Of course, meanwhile, we have secured our existing manufacturing facilities so that we do not have a disruption in terms of the production. We will then transition to the next stage in terms of the size of the manufacturing site by mid-2023. With that, we are good.
I'd like to welcome your questions, and we'll be happy to answer to each of your questions. 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 three opinion leaders, such as Dr. Joël Doré, Professor Zarour, Professor Holler, Professor Malard, all experts in the oncology and in microbiome. We will start with our first question. Savita with us will be moderating the Q&A. Savita, if you want to start with the first question.
Sure. Good evening, everyone. My first question is to Carole from Clémence 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. It's a high richness, high diversity product delivered by enema for an immediate engraftment into 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 allow the microbiota to seed, to rebuild a new microbiota inside the patients. That is the main difference between the two references.
The second question is to Professor Malard from Mr. Bernstein, which compliments you on your great talk, Professor. The question was: How are responders versus non-responders defined in the clinical trials?
Thank you for that question. That is very important. On impact for the response, we consider very good partial response or complete response as the responders for the primary endpoint, while all patients were considered as non-responders. For the complete response, it was defined, of course, as the disappearance of all symptoms of GI acute GvHD, while for very good partial response it was defined as an improvement for at least two stage of GI severity for GI acute GvHD.
Nice. Thank you, Professor. The third question is to Dr. Plantamura. The first question was: What is the proportion of acute GVHD patients who become resistant or cannot tolerate ruxolitinib?
Yes, of course. Thanks for this great question. Among acute GvHD patients, approximately 50% of patients do not respond to the first-line therapy based on corticosteroids, and another 20% cannot tolerate corticosteroid tapering. Regarding the second line, this is based on REACH studies and KOL feedback. We saw that around 50%-60% of patients with GI symptoms remain refractory or intolerant to ruxolitinib.
Thank you, Emilie. Another question for you, I'm afraid, from Thomas Rankin. In the HERACLES trial, the GI ORR data seems to suggest efficacy is decreasing by day 28. Could you clarify why, and around which time does ORR peak?
Usually the GI response is observed after the second dose of MaaT013. This is where we saw the best GI response. Sometimes, unfortunately, in this very severe patient, 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. That's why we saw a decrease in the response between the second dose and the day 28 evaluation.
My next question is to Professor Doré, from Stéphane Renard. This was asked both in French and in English, actually. Is there a required diet to keep this new microbiome on the long term?
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. What we know from nutritional studies 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. This is the first element I will make. If we want to go beyond simple nutrition but think of complementing the diet with other elements, we can go just beyond targeting the microbiome, but also helping the maintenance of the right microbiome by targeting gut permeability, inflammation, oxidative stress. 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. Polyphenols that can be quite effective on the, toxicity of, ROS.
Thank you. Going back to Emilie on the CIMON trial. The question was: Were the engraftments seen with MaaT033 in the CIMON study? Actually, we can ask that to Dr. Mohamad Mohty because he's back online. Welcome. So the question was: Were the engraftments seen with MaaT033 in the CIMON study consistent across patients, or was there variability?
Yes.
No, this is.
Oh, sorry. Go on, Professor Mohty.
Yeah. 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. We saw that there was homogeneity between the levels of richness reached between the patients.
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. The short answer, as far as we know today, no. The engraftment is consistent across all, I would say, tested patients, but obviously, this is a phase one trial.
Thank you, both. My next question is for Hervé from Mr. Bechner. Seres Therapeutics compounds SER-155, currently in phase 1b, 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 Van Puck: Can you compare your approach to your U.S. competitors?
Okay. Thank you very much. For the benefit of the audience, SER-155 is a product that has been designed to focus on several taxa, which has started a clinical trial with the first patient announced by the end of 2021. 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. It's really a positioning which is specific. I think the question has more to do with the comparison with MaaT033. To make it very short, I think we have two 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 disease is very different from one patient to the other. We really believe that our approach in restoring the full ecosystem is appropriate on those patients. The second element which differentiates us a lot is that we leverage on the data from MaaT013. We are the first in human approach. We have probably less preclinical assessment. Our view of the preclinical data is that it not always translate into human. The way we have designed MaaT033 is really to leverage on the patient that we have treated with MaaT013, which is close to 130 today.
Thank you.
Maybe if you allow me to add something to what Hervé said, and this is like role in the philosophy of.
Mohamad, it's breaking.
I think all the assets were.
Sorry.
-very specific for ta-
Sorry, Professor, we can't hear you. Unfortunately, I think we're gonna move to the next question, if you don't mind. I apologize for that. The next question is to Professor Zarour. The question is from Mr. Renard: Can you elaborate on the role of Akkermansia muciniphila, which is credited for a major role in many benefits of microbiome treatment with ICI, please?
Yes. I would say that, you know, the data of Akkermansia still needs to be further investigated, right? It's clearly come out, you know, with a French study, as, you know, highly present in the stool of responder, mostly non-small cell lung cancer. But besides the study in non-small cell lung cancer in France, in multicenter also, it has been proposed as a biomarker of response in melanoma. This doesn't come out if you compare to other study, other tumor type. This really doesn't come out as a, you know, predominant commensal present in the microbiome of responder within particular large study. In Pittsburgh, we reanalyze many cohorts of immunotherapy, but so far, this doesn't come out as one of the components or link to a response, right?
It may be something specific to non-small cell lung cancer.
I think we need more data to have a final opinion. Again, I think this underlines you know the number of questions that is to be answered. What we call a gut microbiome, is this relevant across different cancer or is it history specific? We sort of don't have the answer to that. Is it also treatment specific? 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 Hervé. We're going back to MaaT013 and the ARES trial. We have two questions, one from Thomas Franklin and one from Mr. Hedden, about the status, the regulatory status, with the FDA and, knowing that ARES is a single arm trial, what overall response rate on the primary endpoint do you need? And have you had some feedback from regulatory agencies on the design?
First on the FDA, 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 August 2021. We have submitted a type A meeting request by the end of the year, as it was announced during the IPO. Since then, we have ongoing conversation with the FDA, with the support of well-respected regulatory consultants supporting 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 more detail on square that's ongoing. Regarding the single arm, it has been discussed with the European agency as well as part of protocol scientific advice. They have endorsed the design of a single arm clinical trial. For Europe, that was agreed with the EMA before we submitted and then authorized in several countries by national agencies as a single arm.
Thank you. A question for Professor Holler, from Jakob Makowka. What are other examples of future indications that microbiome therapies could be applied or expanded towards, please?
I mentioned at the end of my talk the CAR T cell therapy, which is the new approach in oncology, a more specific therapy than 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. I would say this is the next step. I also would like to make the point that we have a lot of problems in our hematological patients with resistant bugs and resistant infections. I think modulation of resistance could be another aspect which is important for hematology patients.
Thank you, Professor. Another question for Hervé from the same person, actually. What are the advantages of the co-fermented product versus MaaT033?
The co-fermented product shares similarities with the native product, where what you want to do in patients, whatever the kind of patients it is, you want to restore functional microbiome. That's true for hematological malignancies, and it's true also for patients undergoing immune checkpoint inhibitor. Moreover, the way we design the co-fermented product allows us to bring more specificities in the immune in the mode of action to trigger certain immune pathway. That comes in addition to what we have done so far in hematological malignancies. This product, on that aspect is more designed. 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? This, I guess, was more about MaaT03X, but maybe also MaaT013 and MaaT033.
Thank you, Savita. Yeah, for this new range of products, it's the 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, well, data 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.
We have already mimicked the process, the future process so that we could parametrize or work on, fine-tune the parameters so that we would be able to work in the future with larger scale. We have already made several scale-ups, which was satisfactory.
Thank you, Carole. Next question for Hervé. It was actually asked in France, in French, sorry. « Envisagez-vous de faire des partenariats pour cibler des maladies touchant un grand nombre de personnes ? La dépression, par exemple. » In English, do you envisage to partner in other indications, larger indications such as depression and maybe partner that?
Nous sommes toujours ouverts aux discussions sur les partenariats. MaaT Pharma se spécialise actuellement sur l'oncologie. Le potentiel va bien au-delà, comme indiqué par le docteur Joël Doré. 25% de la population mondiale a une dysbiose, le potentiel est quand même relativement large. Néanmoins, pour ce qui concerne la dépression, on n'a pas de plan actif aujourd'hui sur ce sujet. Si un partenaire voulait tester nos produits, j'ai envie de dire via un partenariat avec MaaT Pharma, on en serait tout à fait heureux. Notre focus restant bien sûr l'oncologie. Do I need to say the same in English or? We always welcome collaborations. MaaT Pharma is today focusing on oncology mainly. The question was on depression.
We know there's a strong link between dysbiosis and depression as it is for other psychiatric or neurological diseases. We would welcome distribution with partners in that field, but there's no plan to do it by ourselves today.
Thank you, Hervé. Another question for Emilie, and we're going back to more technical questions, and I think there will be two more questions, and then we'll have to conclude our session. From Anthony Williamson, "How does the human gut engraftment observed with MaaT033 compare to that observed with MaaT013, Emilie?
We cannot compare directly the engraftment of MaaT033 versus MaaT013 because we did not test those products in the same population. For example, MaaT013 was tested in GvHD patients, which are quite different compared to AML patients in MaaT033. We cannot compare directly. I mean, the engraftment is the magnitude of species colonizing the patient. Since the baseline characteristics of patients are not the same, we cannot compare directly, unfortunately.
Okay. Thank you, Emilie. One last question, a very general one, but one that can open perspectives. Excluding money, what are the current slim limits to the approach explaining that it took so long to add a new pillar to oncology? Is AI changing the rules? I think this one is for you, Hervé.
Yeah. Thank you. The potential is huge. Indeed, I think there was some very important milestones in oncology treatment since surgery, chemotherapy and everything. The most recent one being immunotherapies, probably. 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 observe 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, is not an easy science, because there's many parameters that comes into play. A normal microbiome, just to remind you, it's 350 species, so once you are playing with data, it's immediately huge.
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 one bacteria or the other. It's breeding, it's growing all those bacteria together so that you can maintain the functionalities and all of that. It's very important. I think today we are at a stage where AI and also the bioproduction there 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 gonna have a lot of products on that field. I mean, it was not so long.
If you think about the first catalog of genes, I think it was in 2010, something like that, if I'm correct, Joël.
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. We need to be a little bit more patient, but that's coming. Thanks to company like us and also the others from the field, I think we are going on the right direction. Just want to remind that there's a potential BLA that will be submitted or that have been submitted in the U.S. with potentially the first product approved within a year from now. I think we are getting close to the level of maturity that everybody is expecting.
Well, I think that's a very good conclusion. Thank you, Hervé. Just to remind everyone who's connected that the slides will be made available on the website. It's a question that has been asked. Thanking everyone, all our professors gathered here and all the people inside of MaaT Pharma who contributed to this R&D Day.
Yeah. 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 for MaaT Pharma, and our path is clear. We are aiming to be the global reference in the microbiome for the benefit of millions 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 indication, leveraging our on.
leveraging on our MET Microbiome Ecosystem Therapy platform, and building our new GMP facility, next year. 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.