MaaT Pharma SA (MAAT) Earnings Call Transcript & Summary

Good afternoon or good morning depending on where you are. Thank you very much for attending this webcast of MaaT Pharma, where we will be presenting the data that we presented during the ASH conference. I'll be doing this introduction and opening remarks. Of course, I'd like to start with the disclaimer. I'd like to remind you that today's discussion contains forward-looking statements that are subject to various risks and uncertainties. The agenda for today is that I'll be starting with introduction, presenting the company and providing you with a big picture on where we are and what we are doing. Then Professor Mohamad Mohty will be presenting the first presentation that we did during the ASH, which is an oral presentation, talking about GvHD and new data sets that we are providing with regards to MaaT013. Then Professor Florent Malard would be also presenting the first data that we are sharing with the community today on MaaT033, our second product that we have tested as part of a Phase Ib study and which was subject to a poster presentation during the ASH, and I'll come back with a presentation and sharing with you the needful as well as the ending remarks. And there will be room for a 15-minute Q&A session. So just to introduce you to MaaT Pharma. MaaT stands for microbiome therapy. We are developing microbiome-based drugs using a platform that we call MET, Microbiome Ecosystem Therapies, to address severe disease in the field of hematological malignancies and oncology. Our pipeline is made of several assets that are late stage and also preclinical. We have MaaT013, which is under assessment today as part of the Phase III in acute GvHD. And also, we have another program, MaaT033, which will be soon be started as part of potentially another pivotal study in stem cell transplantation patient that provides investors with news flow, including late-stage clinical milestones. Our MET platform is made of 2 key pillars. The first one is the data science platform that we call gutPrint, which is about assessing the dialogue between the gut microbiome and the host part of the patient using metagenomics methods, mainly. And also the second part, which is very important because of the biological nature of the product that we are developing, which is the cGMP facility that we run by ourselves. The company is made of 50 people as we speak today. We have raised more than EUR 80 million. And also we have treated more than 200 patients since the inception of the company back in December 2014. The overall concept of what we are doing is that we want to address the host microbiome interaction. That's the dialogue between the microbiome and the host part, which is very important regarding the mode of action that we are targeting and which will be presented by Professor Mohty during his presentation. However, the overall concept is really to deal with this blue layer, which is a network of bacteria talking together, but also talking to the immune system. As most of you would know, 80% of the immune cells reside in the gut microbiome. So it's understandable that by dealing with a microbiome you have an opportunity also to modulate the activity of the immune system. And there's also now a good evidence is showing that when there is an alteration of the microbiome, there's also hyperinflammation or a dysregulation of the immune system. So that's exactly what we will be developing. We will be developing drugs to address this very important issue of what we call the dysbiosis, which is when the gut microbiome is altered. One very important concept to go straight to the point, if you want to achieve a good clinical result or benefit for the patient, you need to restore the diversity. All the studies that we have seen so far are showing that 1 key element in achieving the different primary endpoints in clinical studies is really to restore the diversity. This is evidenced here on the left-hand side, for example, with a publication which is coming from the Sloan Kettering Center. This is not our studies. They are third-party studies. And the first one on the left-hand side is coming from the Sloan Kettering Center, and that's showing that at the time of the engraftment of the neutrophil when patients are undergoing stem cell transplantation, if you have a high diversity, you increase by 50% your chance of survival at 3 years. The second graph is basically saying the same, diversity is very important. Interestingly, we see also the same phenomenon in solid tumors, where the rationale is a little bit different here because it's more about cooperation between immune checkpoint inhibitors and the microbiome. And here, again, you see the higher the diversity, the most the patient will be responders to immunotherapies to ICI here in that context. So it's very important to make the anti-cancer drugs efficient to have a good microbiome. So to address this important issue of the disequilibrium of the microbiome, we have this AET platform, and that has helped us to generate several candidates. We have a native product that we will be presenting today. And we have MaaT013 and MaaT033. MaaT013 is what we call enema. This is a liquid formulation we use for administration as an enema as a lavage. So that's very powerful for patients that are in very severe conditions. And we have also MaaT033, which is a capsule which you will use when the patient conditions is a little bit less severe. MaaT013 is under evaluation in GvHD and is also under evaluation in combination with immune checkpoint inhibitors, whereas MaaT033 has been evaluated as part of the Phase Ib study, and we are hoping to start very soon a potentially pivotal clinical trial to evaluate MaaT033. We have another generation of products, which we call the co-cultured product, where this product, they are donor independent, the native product, they come from donations from healthy donors that we have selected based on safety criteria. The co-cultured product is a different product. We go with master ecosystem being that we use to define a specific product, and we are considering using that product in solid tumors, mainly because the size of the market is bigger. Then it translates into the go-to-market strategy where we start with the GvHD, 2,000 patients, then we go with any patients receiving stem cell transplantation, 22,000 patients. That's for Europe and the U.S. And then we go with MaaT03X, which is 10x the size of the stem cell transplantation market, 200,000 patients. And then we go potentially to any immune-mediated disease. Our objective, as I said, MaaT013 is evaluated in GvHD with interim analysis for this clinical trial, the Phase III by the first part of '23. We will be also proposing a Phase IIb in Europe using MaaT033 in hematological malignancies. MaaT013 is also under evaluation as part of Phase II clinical trial that's ongoing in France, MaaT03X, that's under assessment at the preclinical level. And also we are optimizing and scaling up the CMC manufacturing to support the entry into the clinics. And last but not least, we are setting a new GMP facility, which will be based here in France, and that will be, of course, fully GMP-compliant. So we'll be presenting the data on MaaT013 and MaaT033, both in hematological malignancies. ASH is a very important conference, and we are happy to share that. That's the third year in a row that we have been accepted on oral presentation, and that's the sixth year in a row that we are presenting data. So we see that now the microbiome has a strong recognition within the hematological community, and we are very happy with that, of course. So I'll introduce the presentation of Professor Mohamad Mohty with regards to MaaT013 in the context of GvHD. So the GvHD and MaaT013 data, they are made of 2 kind of data. On the left-hand side, you have the results from clinical trials. We have achieved a Phase II clinical trial, and now we are undergoing Phase III in Europe. And we're going to see also the data from the early access program that is accessible within Europe. We already treat patients in several countries in Europe as we speak today. With that, I'll leave the floor to Professor Mohamad Mohty, who will present to you the data on MaaT013.

Thank you very much, Herve, for the kind introduction, and it is my great pleasure to be with you today to present the data that we have just presented at the American Society of Hematology Annual Meeting in relation of -- with the pooled microbiota product for refractory gastrointestinal acute graft versus host disease. And these are the results of the early access program in France. So I'm Mohamad Mohty from the Sorbonne University in Saint-Antoine Hospital in Paris. For the sake of introduction, I would like simply to highlight that acute graft versus host disease, especially steroid-refractory acute graft versus host disease is a huge unmet medical need. Needless to say that allogeneic stem cell transplantation is the only curative treatment for many blood diseases today. Unfortunately, 1 key limitation is graft versus host disease, especially acute graft-versus-host disease. And beside high-dose corticosteroids until recently, we had limited option to treat these patients, especially when they become steroid refractory. In terms of pathophysiology, we know very well that actually the chemotherapy we use in these patients as part of the treatment of their malignant blood cancer, the irradiation, the immunosuppressive therapy, but also the broad spectrum antibiotics are going to generate a significant loss of diversity. This is what we call dysbiosis. And this status of dysbiosis is going to initiate to be a trigger for acute graft versus host disease. And when you look into the numbers of transplanted patients every year in Europe and across the globe, you would easily imagine that this is a problem we need to handle, and we need urgently to develop solutions. And this is where I think we are already fortunate enough to have this MaaT team, drug or product, which aims to restore the interaction between the gut microbiome and the immune system to treat acute GvHD. Because actually, when it comes to the target organs of acute GvHD, we have the skin, we have the liver, but most importantly, the prognosis is related to the gastrointestinal localization. And this is why actually the MaaT013 product is able to bring a high richness, high diversity, Butycore-rich product, which would allow to restore -- to increase the diversity that would help to restore the GI barrier integrity and true, for instance, some immune regulatory mechanism, we have a complete restoration of immune homeostasis. You can see here the characteristics of the product that we are currently using, and we have now a very important experience with this, especially that this is a pooled microbiota product that can include a high richness, high diversity sort of a full ecosystem containing Butycore. And if you compare it to a single donor product, I don't need to spend a lot of time, highlighting the major differences in favor actually, of the pooled MaaT013 product. In terms of administration, we have validated through previous clinical trials, especially the HERACLES Phase II clinical trial, the 3 doses to be administered. And in general, since we're talking about GI acute GvHD, the evaluation is about the overall response usually at day 28. And here, my focus is going to be about the early access program in France. This has been authorized by the French regulatory agency. And actually, we have treated, I think, more than 100 patients. But here, I'm showing you the data from the 81 patients treated between July 2018 and May 2022 in 17 French sites. All of these patients, you can see the characteristics are adult patients with GI active GvHD Grade 2 to 4. The majority 84% are steroid refractory. A small number, 16% are steroid-dependent. And when you look to the characteristics of GvHD, you would appreciate that the majority of these patients are the severe patient. And besides the GI localization, there are also other organs being involved. And the primary endpoint, of course, for us, is to look into the response rate at day 28, especially that these patients have received and failed a median of 2 prior lines of treatment. Here, you can see the responses in the oral population. And what is really very important is the high rate of complete remission but also VGPR and PR. And you can appreciate that we are talking about a 49% response rate, 56% when it comes to the GI. And I do insist, it is a GI which really drives the prognosis of these patients. Here are the overall survival curves and data. And again, although this is not a randomized trial, of course, it's an early access program, but still, these results, 51% survival at 6 months, 39% at 1 year compare favorably to what we know from the literature. And what is really amazing is that when you concentrate on those responding patients, this is a blue curve, almost 70% of the patients are alive at 6 months, 59%, 60% at 1 year. So this is really, in my opinion, unprecedented and clearly showing that clinical response to MaaT013 would translate to an increased overall survival. Let me dig a little bit deeper into these results, for instance, comparing the steroid-dependent versus the steroid refractory patient. Well, obviously, although the numbers are smaller, actually, the steroid-dependent patient are doing really very nicely with the MaaT013 administration, 92% GI response rate, whereas in the steroid refractory as you may guess, because these are the most advanced and most difficulty hard-to-treat patients, it's only 49%. What I would like to highlight again is the 69% CR rate in the steroid-dependent and 31% CR rate in the steroid refractory patient. Another important feature that I would like to emphasize and insist upon is the response in the ruxolitinib refractory patient and why we believe that this group of patients is important because ruxolitinib has been recently approved as a treatment for steroid-refractory acute GvHD. So what does that mean? Well, if patients have received and failed ruxolitinib, we are totally in a hopeless and desperate situation. So ruxolitinib refractory patient are really in a very terrible situation. And the good news we can see here is that the MaaT013 administration can also salvage these patients who are ruxolitinib refractory. And you can appreciate the GI response rate is around 56%. And if you use MaaT013 in the third line, which is immediately after the failure of ruxolitinib, you can go up to 65%, again, 61% of CR really amazing results. If you look to the overall survival in this group of patients who are steroid and ruxolitinib refractory, well, 74% are surviving at 6 months among the responders. And it looks like there is a plateau because we have exactly the same rate at 1 year. So in this population, where we have nothing to offer to propose, MaaT013 is leading to some incredible results with an excellent safety profile. I will not go through all of these details, but there is no report of pathogen transmission. We do have only 2 cases of nonpathogenic commensal bacteria associated with an infectious event, but the procedure is very safe and very well tolerated. So in conclusion, based on this early access program, we could show, and this is a very decent number, 81 patient being analyzed very precisely. MaaT013 is a highly effective treatment for steroid-refractory or steroid-dependent. We're talking about a 56% GI overall response rate at day 28 after administration of the product, 49% overall response rate. These excellent responses are also specifically seen in the ruxolitinib refractory patient, which means when MaaT013 is used as a third line with 65% GI response rate. And all of these responses, as I highlighted, are translating towards an increased overall survival with a very good safety profile. And as you can guess, such very nice, very good results warrant further investigation and this is why we launched recently the ARES Phase III study of MaaT013 as a third-line therapy in GI acute GvHD. It's a pivotal single-arm study. The primary endpoint is the GI response at day 28, and the first patient was included in March 2022. The centers participating are in France, Germany, Spain, Belgium and Austria and there will be some future expansion to other EU countries. So with this, I'd like to thank you all for your attention. Of course, I'd like to acknowledge all my colleagues who contributed and generated these data, the patient, the care caregivers, the healthy donors, which allowed to manufacture the fantastic MaaT013 product. And of course, I'd like to thank the whole MaaT Pharma team for their great efforts and dedication to find solutions for patients who are really desperately in need of a treatment for their GI acute GvHD. So thank you very much, and I'll hand it over now to again to Mr. Herve Affagard.

Thank you very much, Professor Mohty for this very, very well-made presentation and very interesting data that you shared with us today. So with that, we will be transitioning to MaaT033, which is the next product within the pipeline. MaaT013 will be used in any patients receiving stem cell transplantation. Leveraging on the concept of diversity and based on observations that we have made on our data but also on data from others, we have seen that the diversity after stem cell transplantation is very important with regards to the overall survival of the patients at 2 years. And that's exactly what we want to do as part of our next clinical trial. We want to restore the diversity with the gut of the patient to improve the survival of the patients. And the way we're going to be improving the survival is really by dealing with the reduction of the prevalence of GvHD with the infections. We believe there will be less infection in patients that have been treated regarding their microbiome. So this is what we will be presenting today. This is really the first step in terms of the clinical development. If we look at who is receiving stem cell transplantation, there are many leukemia patients. You see here that half of the patient, there are acute myeloid leukemia patients. And that's where we have done our first clinical trial because the conditioning is very similar to the conditioning that is received for stem cell transplantation patients. And also, we have a long story in terms of clinical trial in the field of acute myeloid leukemia, where we can compare data that we have obtained in the past being on the same setting. So those data are very interesting and Professor Florent Malard, will be presenting the poster that we have presented during the ASH. So with that introduction, I'll leave the floor to Florent Malard.

So thank you, Herve, for this introduction. And now I will have the pleasure to present you the result of MaaT013 for at gut microbiota diversity restoration in patient with acute myeloid leukemia, and this is a result of the Phase Ib CIMON trials. So MaaT013, what is MaaT013? This is optimized oral capsule that restore and maintain a healthy gut microbiome in patients with severe dysbiosis. Here is a characteristic of the product. This is an oral fecal microbiota that is produced for a strict screening process from healthy donors with high richness, high diversity, full ecosystems, which -- this is very important and ileocecal delivery and with more than [ 10 to the 9 ] bacteria per capsules. So this is oral on lyophilized capsule. So this is very important because patients can have the capsule at home. So this is very easy for administration and as indications developed so far, this is to improve the survival in patients that are planned to receive Allogeneic stem cell transplantation. So as I just said, this is intended to be an adjunctive on maintenance therapy for patients with hematological malignancies and in particular, for patients that receive allogeneic stem cell transplantation. Why? We want to focus at the moment in those patients because there is some very strong data in particular, this analysis established in The New England Journal of Medicine that included more than 1,000 patients that demonstrate that patients with lower diversity after engraftment have lower survival compared to patients that have a higher microbiome diversity. So it seems very important to restore microbiome diversity to improve the outcome. Why these patients have a decreased diversity because they receive chemotherapy and a very large spectrum antibiotics. And this will induce dysbiosis that is associated with complications such as infectious complications, obviously, but also acute graft versus host disease, that is a life-threatening complication of allogeneic stem cell transplantations. So how do we expect MaaT013 to work? So we expect that MaaT013 will allow immune hemostasis restorations, in particular, induced regulatory T cells. It will, of course, induce increased diversity of the microbiome. It will inhibit pathogen growth and production of metabolite that will produce some beneficial bacteria that will produce Butyrate, short chain fatty acid, [indiscernible] on immunoregulation that will allow this immune homeostasis restorations. And it will also have a direct effect of the barrier integrity of the gut epithelium. It will restore this higher integrity and prevent infections, and it will allow the prevention or the remissions of symptoms, in particular, of graft versus host disease. So, so far, this MaaT033 capsule was evaluated in the CIMON Phase Ib open level dose finding study, including 21 patients. Patients were included in 6 different hospitals in France. It was a dose escalation design with 5 cohorts. In the first cohort, we give the capsules only once a week. So they received 2 capsule of MaaT033. Cohort 2, 6 patients included. It was planned to give once a day for 1 week. Cohort 3, 6 patients included, also it was 3 capsule a day for 1 week. On Cohort 4, it was 3 capsule a day for 2 weeks. And Cohort 5, what now is performed because we have already enough data from previous cohort. So patients were receiving induction chemotherapy for acute myeloid leukemia. And after neutrophil recoveries, they were included in this clinical trial. They received 1 to 2 weeks of treatments, and we assessed biome diversity at baseline after 1 week; after 2 weeks, so before the consolidation chemotherapy. And again after patient received this additional chemotherapy, we assessed the outcome on the microbiome diversity. Here, as a result for getting gut microbiota diversity and the engraftment of the MaaT013 product, so we have different colors. It corresponds to the different cohort I just presented to you. As you can see here, in the first cohort, we already have a good engraftment in patients but with around 40% of engraftment of the MaaT033 product as early as V2, at V3, and very importantly, at V4. So that means that also when patient receives some additional chemotherapy and of course, antibiotic, we maintain this good engraftment of the product. When we look at the further cohort, we again improve the MaaT033 engraftment because it reached 60% of engraftment and also, it was maintained up to visit 4, so after the consolidation chemotherapy. When we look at the richness, this is even more interesting because in addition to the engraftment, the use of this MaaT033 capsule allow good, increased richness of patients microbiome as early as V2. It was even increased at V3, and we see a small decrease at V4, but it still remains significantly higher compared to baseline. So this is after induction chemotherapy. And this is a third consolidation chemotherapy. So we don't have the same decremental effect of the consolidation chemotherapy of the microbiome diversity when patients receive MaaT033 capsules before the consolidation chemotherapy. So MaaT033 induce an increased microbiota richness at the OTU levels. MaaT033 display a strong and persistent bacteria engraftment with higher in Cohort 3 and Cohort 4 that was with 3 capsules per day for 2 weeks compared to Cohort 1 and 2 with only 1 capsule per week on 1 capsule per day. And MaaT033 bacterial engraftment, inversely correlated with patients baseline microbiota richness. We have some preliminary results regarding the [indiscernible] analysis. So this is some PCR analysis. So it can be a bit complex to just understand. But just to clarify, we were able in the same statistical analysis to look at production of short chain fatty acids. So this is some products that are produced by the microbiome and some chemokine, also some inflammatory parameters, such as proinflammatory cytokine, such as IL-18, TNF-alpha, C-reactive protein. And we see 3 different patterns depending on the visit of the patient. So V1 this is at baseline. So right after the induction chemotherapy and before we give MaaT033 to the patients. And we find that the patients have some very pro-inflammatory parameters with some increase into the inflammatory, so CRP, IL-6, IL-18, TNF-alpha at V2 and V3, so this is at the 7-day and 14-day after the MaaT033 administration. We see that patients are less inflammatory. And in the contrary, we find some increase into the short chain fatty acids produced by an healthy microbiomes. At V4, we have a small shift to baseline with more inflammatory parameters, but still we maintain some protective short chain fatty acid production. So overall, we find that MaaT033 engraftment correlate with anti-inflammatory markers, levels on inversely created with inflammatory marker such as IL-2 on [indiscernible]. So MaaT033 treatment was also safe with a good tolerance. We have only 4 adverse event reported in 4 patients. Only 1 was considered as possibly related by the investigators. We have only 1 febrile neutropenia in Cohort 2, none in the Cohort 3 or 4 with more capsule given. One neutropenic colitis in Cohort 3 and 1 DRA infections and 1 hyperkalemia. But that have some difficulty to directly related to the product given. The next step now is to go to a randomized clinical trial to evaluate MaaT033 to prevent infections and complication of allogeneic stem cell transportation, including graft versus host disease. We plan to introduce 389 patients. It's a randomized double-blind placebo-controlled study. The primary end paint will be the efficacy of MaaT013 to improve overall survival at 12 months, a very ambitious primary endpoint. We'll also evaluate safety and tolerability before allogenic stem cell transplantation. And we'll, of course, evaluate engraftment of MaaT013 on activity to prevent complication, so infections on graft versus host disease. We will give pre-phase, so before the start of the conditioning regimen with 1 to 2 weeks of MaaT033. After, we stop, of course, because it will be the neutropenic phase. And around day 15 to day 21, we will start again to give the MaaT033 daily up to 3 months and will, at the end, evaluate overall survival at 1 year. So to conclude, MaaT033 appear to be safe and effective for gut microbiota restoration in acute myeloid leukemia patient that received induction chemotherapy and antibiotics. We have a good tolerance with minimal toxicity after treatment on post neutropenia. We think that 3 MaaT033 capsule per day for 1 week is enough to induce an increase in microbiota, which nice and effective and persistent MaaT013 engraftment acute myeloid leukemia that was maintained after further chemotherapy and use of antibiotics. And now we plan to evaluate in this Phase IIb trial as an adjunctive on maintenance treatment in patients with hematological malignancy that receive allogenic hematopoietic stem cell transplantations. So I would like to thank you and I will give now again to Herve for the next step of the meeting. Thank you.

So thank you very much, Professor Malard, for the presentation of the data. So now time has come to go to the -- back to the company and the ending remarks. So I'll be sharing with you the key takeaways as well as the next milestones and provide you with an update on where we are with the manufacturing facility. So the key takeaway message here, we have showed, once again, we have treated more than 200 patients and that's ongoing. We are continuing to recruit pretty well in our clinical trials that are ongoing. So MaaT013 has a significant data set now coming from the EAP program but also from our clinical trials. And it has shown to have a good overall safety and a high effective therapy in steroid refractory mainly, but also steroid-dependent GI predominant acute GvHD patients. So to us, it's very promising. And this, I would say, Phase 3 is -- really the results from these studies expected soon. Further investigation in steroid refractory and steroid-dependent GvHD is ongoing with the Phase III. We will go through the milestones on the next slide. And the next product, MaaT033 has also showed to be safe in patients where leukemia patients where their immune status is pretty bad because when they get the chemo, they are immunocompromised, they receive antibiotics. So the status of their immune system and also their microbiome is pretty bad. And we have showed here again to be safe and effective in terms of restoring the microbiome. [Technical Difficulty] Now we are considering going to the next step, which is about having a significant Phase IIb clinical trial, which has the potential to be pivotal, assuming the results are good enough. And the objective is clearly -- the objective you are looking for in oncology, that's to improve the survival of the patients receiving stem cell transplantation. So we have generated and we continue to generate promising clinical data to improve patient survival, which is at the heart of the DNA of the company. In terms of the more precise milestones within the next 12 months, MaaT013 expected interim results in half of the patient by the first semester of '23. We are on track. We do not report any delay here. We will continue the early access program in France and in Europe. For MaaT033, the capsule, we are planning to start early '23, a significant randomized controlled trial in any patients receiving stem cell transplantation. MaaT013, which is through partnership with the Hospital of Paris, AP-HP and institute, Gustave Roussy, the largest anticancer center in Europe. We have a partnership with them. We are evaluating MaaT013 in combination with immune checkpoint inhibitors. And here also, we're going to have internal data read out in the first semester of '23, and that will be very important. Those data, they will be very important to inform us regarding the next stage of development in melanoma. And regarding solid tumors and the 3X product, which is just to remind the co-cultured product, we are expecting to enter into the clinics in '23 with this very disruptive technology. All of this is possible because we master the GMP manufacturing of full ecosystem microbiome, which is a pretty complex biological process. But since 2016 now, we are dealing with the production by ourselves of those products. Now we have reached a point where we need to expand. So we will leave the manufacturing location where we are today, and we will go in more -- a larger facility, which will be also more convenient to support our R&D activity because the MaaT03X product is even more demanding regarding the complexity. So we need to expand to have enough space to continue the development of the company. So the first step of this manufacturing location, which will be up and running in '23 as well, would be to produce, of course, native product, but also we will be able to work on the design of the bioprocess for the 3X program. So that will be ready by '23. The way we are dealing with this new facility is that we are established a partnership with an existing CDMO, which is named Skyepharma. They are our partner. We are working with them since 3 years to establish, I would say, the setup of what it is we want to do together. And at the end of the day, they will be taking care of about everything related to the facility itself, the GMP and quality system that will be with them, whereas we will be taking care of buying or sell the equipment. That will be our staff, our people. We will continue to control everything which is related to the development of the bioprocesses and also the execution of the process when it comes to the GMP production. So that's the way we have set the deal. And because of that deal, which I believe is really, really modern, each of us, we will be able to concentrate on where we are good at, and we will not be defocusing on stuff where we are not good at. So that's, I think, a very well-balanced deal that we have established with Skyepharma. So in summary, the 40 plans of the company, we are a full ecosystem company. We are not focusing in one strain or several strains. We have taken the challenge to restore the diversity. That has proven to be efficient and safe. So we will continue with that. We are focusing in oncology. We have established a proof of concept in a very complex disease, GvHD. Phase II by dealing with the microbiome, you can deal with the immune system. And the data that we are accumulating are still confirming that Phase II study. So the concept is established. And also, we continue to master the field of the bio manufacturing with both the R&D activity and the GMP facility to the best of my knowledge of our facility when it will be up and running. That will be the biggest facility in Europe to deal with full ecosystem products. So we have the capacity to go even further to support our development and potentially additional developments. So I want to thank you for this first part of the presentation and now it's time to go through the Q&A. So feel free to ask any questions you might have, and we'll be happy to answer those questions. Thank you very much.

Okay. So now that we have been through the different data that we have presented during the ASH meeting, that's going to be the opportunity to answer your questions. So in terms of the organization, I'm together with my team and Sian here will be asking the question that we have received. There is already several questions that are on the list. So let's start, Sian.

So the first question, can you comment on the recent Rebyota approval?

Yes. Good question. So recently, Rebyota, which is a product developed in another indication, in Clostridioides difficile, has been approved by the FDA, that was November 30. And it's the first ever FDA-approved microbiome product. And what is important is the fact that this product is a fecal microbiota transfer product. So this approval is very important because one of the challenge of this nascent industry of the microbiome is really to make sure, especially for investors and for pharmaceutical company, it is important to show that we have a clear regulatory path. And this approval is establishing like a building block. Based on what we have learned from this approval, we have a very good understanding now on what you need to do in terms of donor selection, in terms of duration of follow-up of the patient. So this approval was very important in terms of the go-to-market strategy and also for us at MaaT Pharma and other competitors, it's also very important because we have learned a lot on what the FDA is expecting. So it's pretty positive for the field, and we hope there will be several additional approval soon. Next question.

Yes. So a question for Emilie in terms of the MaaT013 results from an investor. How are MaaT013 responders versus non-responders defined?

Good question. Thank you. Indeed, responder to MaaT013 were defined as patients who achieved a complete response or a good partial response or a partial response of the GI at day 28 after first administration of MaaT013. Other patients, non-responders were patients with stable disease progression or death before day 28.

And Mohamad, a question for you. What are the differences between GI ORR and overall ORR? Why are overall ORR rates generally lower? And do you see an impact of MaaT013 on liver and skin?

Yes. Very good question, indeed. Well, obviously, as it is suggested by the question, acute GvHD can have 3 major target organs, GI, liver and skin. And the most life-threatening and serious one is about GI. Obviously, if you're assessing the response at the GI level exclusively, then this is usually different from the overall assessment when you consider all organs. And given the mechanism of action of the microbiota modulation, of course, it's important to consider the response at the GI first. However, the good news, what we have seen in the MaaT013 data is that the other organs usually also respond when they are involved.

Thanks. And just coming back and looking at the early access program results and the ongoing Phase III trial, a few questions from Jacob from Kempen. How does the EAP data set compare to the Phase III trial of MaaT013? What sort of responses could we expect to see in the Phase III trial on MaaT013? Couldn't the EAP program be -- the data set be seen as a benchmark? Emilie, can you comment on those questions?

Yes, sure. The early access program, as you know, include more heterogenous population. But indeed, the high number of patients we include, we have now 31 patients corresponding to the exact population of the ARES trial, which is patients who are refractory to corticosteroids and ruxolitinib. And MaaT013 is now -- have third-line therapy. So we have 31 patients in this setting, and we have very good results in terms of ORR, of course, but also in terms of survival and which is more important. And we expect to have comparable results in the ARES trial because we are -- I mean, this is the same population.

And I would like to add to this that 31 patients actually for this population is really a significant and meaningful number of patients and that would give us quite a good confidence that in the ARES ongoing prospective trial, the results are likely to be as good. So to make it short, is it a good benchmark? I think it is a good benchmark and Emilie emphasized also that in addition to the response rate, what is really amazing is the high survival rate in the responders, 74%. Never seen this in my practice in the last 25 years.

Thanks. And just a further question, Mohamad from Thomas Franklin from KBC. Is there any expected impact of EMA's recent half review of JAK inhibitors for the use of ruxolitinib in a GvHD in Europe?

I guess the question relates to the fact that ruxolitinib has been recently approved for steroid-refractory acute and also chronic GvHD. And I believe this is rather good news for the field. As a transplanter, I'm not going to complain about it. And the other good news is that the development of MaaT013 and the ARES trial is exactly targeting the population of patients who have failed actually ruxolitinib. And unfortunately, despite the enthusiasm we have all for ruxolitinib, we know very well that there is a significant proportion of patients who will not respond or cannot receive ruxolitinib or even will lose the response to ruxolitinib. So the post-ruxolitinib, I would say, population is a truly huge unmet medical need, and this is why new options like MaaT013 are eagerly needed.

Now moving on to MaaT033. Florent, I've got a few questions for you. Firstly, again from Thomas, the decrease in the OTUs between visit 3 and 4 related to consolidation chemotherapy or does the treatment effect always fade slightly?

So I think this is indeed a very good question, and this is a very important point. In fact, during the consolidation chemotherapy, patients received, again, high-dose chemotherapy on large spectrum antibiotic. So we expect the impact on the microbiota, impacting decrease into the number of OTU. So in fact, the small decrease we observed is a very important visit since it highlight that with MaaT033 treatment, we have a long-term effect, and we'll preserve the microbiome during the further chemotherapy and despite the use of antibiotics. So we expect this small decrease. But in fact, the small decrease just highlight that we have a long-term effect of the treatment.

And just another follow-up question again from Thomas. What is your current hypothesis on the origin or source of the EPA bacteria leading to the SAE?

So yes, this is a good point to raise the issue of this adverse event. So in fact, we are able to look very closely into the MaaT033 product, and we don't find the effect within the product. So we are able to completely roll out that it was transmitted by MaaT033. And in fact, in these kind of patients that have acute myeloid leukemia receive chemotherapy, this kind of side effect is very frequent. We have very frequently this kind of infectious complications, so we can suppose that it was a bacteria that was present within the patients, and it was clearly not related to MaaT033.

Again, sort of following up on the MaaT033, I've got a question. For how they now, what do you believe the greatest challenge to be in the development of MaaT033?

I believe the difference between what we are doing since year with MaaT013 and MaaT033 is really the volume. Because here, we are considering a larger clinical trial, especially with the next clinical trial for all patients receiving stem cell transplantation. So one challenge was the supply chain because we needed to scale up the supply chain to make sure we have enough volumes for the production. Today, we do not report any issues on that one. But we had to for the scalability to be the supply chain process for the -- upstream supply chain process to getting of donors.

And just generally talking about the timing of the Phase IIb trial of MaaT033. Can you comment on the timing?

Yes, that's true that we have announced initially that we will be starting the clinical trial within Q4 '22. So we only have 18 days now. So it's important to say that we are on target to start very soon, and we confirm that we will be starting soon. However, we have taken a little bit more time to discuss with certain stakeholders, including regulatory bodies, but also potential partners, just to make sure what we are doing is appropriate for the next step. So a little bit of delay, but nothing significant at the end of the day.

And sort of looking about broadening the pipeline, I guess, this is a question on the landscape. How do you see the promising data that came out on EO2401 from Enterome in glioblastoma?

Yes. So they are competing indeed. But here, we are -- we can't really compare with them because this modality is very different. That's proteins that are generated by bacteria, and then they are developed as a small molecule, which has nothing to do with us as a biological. So neither in terms of the therapeutic area, nor the modality it's comparable. So probably I will skip any comment on that one because for us, it's not something you should be comparing to.

Okay. And I guess, just sort of coming -- wrapping up, there's a few questions wanting an update on the status with the FDA from both analysts and investors, a status on the clinical hold, but equally how the Rebyota approval has or doesn't influence, in your opinion, the hold of MaaT Pharma?

Yes. So the hold, we have made a significant progress on responding to the FDA. Just would like also to remind that the microbiome product, they are hosted by the Office of Vaccine or VRR in the U.S. We feel there was a deep prioritization process in place at the FDA to put priority on vaccines and not on other products. And so today, we believe there is more traction with the FDA. We have submitted our answers to the FDA. We are waiting feedback from them. So I can't comment that much both in terms of the process, the timing of the process and the results of the process, of course, but we have made good progress in terms of the interaction and submitted additional data to the FDA. So let's follow the situation. And regarding the approval of Rebyota, of course, that has helped us because even if they have been approved in November 30, there was already in September, the advisory committee, and we have learned from that, and that has helped us to refine the proposal that we have made. For example, we know that the ground team that has been proposed by Rebyota, just to make sure there is no new pathogen emerging all of a sudden, so you will put the product in quarantine. We have been able to compare what we are doing with what they are doing. So we have a very good understanding of what is reasonable for the FDA in terms to get an approval. We have been able to bench our process against that and sometimes improve our process. So that was very useful to have this transparent process starting in September and ending in November with the approval of Rebyota. So that does help a lot in terms of the way we have responded to the FDA, yes.

Thanks. I don't believe we have any questions. So do you want to wrap up?

Yes. So thank you very much. You were -- that was many of you today participating to this conference. So thank you very much for your interest into the company. Thank you for the new participants as compared to the previous presentations. And thank you again to all of those who are present at each conference, thank you very much for that. So the '22 has been very intense with a lot of programs starting with the ARES study Phase III, the PICASSO study, Phase IIa and also the conclusion of the MaaT033 CIMON product. So that was very important. We have accumulated a lot of data. We can have additional data soon for the first part of '23 with the interim analysis of MaaT013 in GvHD. We can have also a biological readout in the PICASSO advanced melanoma patients with MaaT013 again. We'll be starting MaaT033 in all patients receiving stem cell transplantation. We can have also the new factory, the new manufacturing location that we are starting. We do not report any delay today. So it's also on track. So we continue to establish the foundation for the company. We are getting close to the end of the first Phase III for the company. So we are pretty happy with the progress that we are doing today. And we want to thank all the investors that are supporting the company to where we are today, and we hope that we can continue together to develop the company.

Yes. And I'd like to add that we are here live from ASH 2022 in New Orleans with Emilie. And I can assure you the excitement about the microbiome modulation and the MaaT Pharma work is amazing. It's incredibly exciting.

Thank you, Mohamad.