MaaT Pharma SA (MAAT) Earnings Call Transcript & Summary

Good evening. I'm Herve Affagard. I'm the Co-Founder of MaaT Pharma, and I'll be the host for the discussion today. In terms of the logistics, there will be a Q&A session at the end of the meeting. You can use the questions button on the bottom of the presentation, and they will be sent to us and we will answer your questions. So I'll start with the introduction. I'm together today with, if we can -- I'm together with Professor Mohamad Mohty and also Professor Florent Malard. They are both working at the Saint-Antoine Hospital. Mohamad is the Head of Hematology and Cellular Therapy Department; and officer Malard is also on the Hematology and Cellular Therapy Department of Saint-Antoine Hospital. So I'll start with the introduction of MaaT Pharma. So MaaT Pharma is today the leader in the field of hematology-oncology when it comes to microbiome modalities. We have developed a platform, which is called MET, Microbiome Ecosystem Therapies. And our niche market entry strategy is focusing on hematology-oncology. And our objective is really to enhance patient survival. We have been very fast in terms of the execution regarding the inception of the company back in December 2014. We are a 9 years old company. We have been created in December 2014. We have treated our first patient in 2016. We developed a technology which is leveraging on the concept of the pooling so that we can achieve a high level of standardization of the product. And this is the first FDA-approved authorized pooled microbiome product. We have taken 7 years to enter in the Phase III. That's the data we're going to be presenting today on the Phase III for ARES. And also more recently, we have built our manufacturing facility that has been very fast as we have taken only 12 months to complete this new manufacturing facility. In terms of the way our drugs are working, here, we represent the gut of a patient. And you'll see that the blue layer is the gut microbiome. And as you know, 80% of the cellular host defense, they reside within the gut. And what our drug would do is that we will reset the blue layers. So what we mean by resetting is really about increasing the diversity of the microbiome because we have evidence showing that you need to be diverse to get a good clinical response for the patients. And our drugs will be targeting this blue layer and the mode of action basically to restore the microbiome -- microbial homeostasis and network so that it will increase diversity, eradicate the bad bugs. And in turn, it will also restore the immune homeostasis. That's the way we're going to be improving overall survival in patients. Focusing in HSCT on the left-hand side, you see that that's an illustration of the benefit of the diversity. You see that the highest the diversity in patients, the highest the survival. If we focus on the left graphic, you see that you can improve that by like 50% of the survival of the patient if you are diverse at the time of the engraftment of neutrophil. So this is a pretty significant evidence that we are leveraging on. The different products that we are developing, that's 2 range of products, MET-N and MET-C, and that's because they are native products. They come from donors, [ see it ] because they are co-cultivated products. We don't rely on donors. Today, we will be focusing on the MET-N products, which are MaaT013 and MaaT033, which are the products that we are evaluating into the clinics in the hematology-oncology setting. We use our data science platform to better understand the mode of action, stratify patients, but also develop the different products. In terms of the pipeline, we have 2 projects for different clinical trials. 2 are on the field of hematology-oncology, that ARES and PHOEBUS that we will be discussing today. And we also are expanding in solid tumors with metastatic melanoma patients, where we use MaaT013 in combination of immunotherapies. And we have also launched recently a proof of concept in neurodegenerative disease. With that introduction, I will now let Professor Mohamad Mohty introduce the work that we are doing with MaaT013 in GvHD.

Thank you very much, Mr. Affagard, and good evening, good morning, good afternoon, everybody, wherever you are. It's a great pleasure to be with you, and I've been asked for the next few minutes or so to give you a brief summary about the results we have generated from the Early Access Program using one of the MaaT assets, namely MaaT013 that was mentioned by Herve. And this is in the setting of refractory GI acute graft versus the host disease. So let me start first by highlighting what is this product, what is MaaT013? Actually, it is a maximum density product, which would allow for fast engraftment of the microbiota in acute situations. And this is definitely what we need when we are facing a life-threatening condition like acute GvHD. So in contrast to a single donor homemade product, this is a true drug made from a pooled microbiota with high richness, very well-characterized high diversity, a sort of a full microbiome ecosystem treatment containing exactly the beneficial effect of the Butycore. And it is administered in the form of enema, and I'll show you here in the studies we are performing, usually we would go for 3 doses. And the current indication is actually gastrointestinal acute severe graft versus host disease. And our initial results were published as part of a seminal Phase II trial called HERACLES, which included 24 patients, and this was published a few months ago in eClinicalMedicine, a very high-impact factor journal from the Lancet series. And today, what I'm going to present to you are the results of 111 highly advanced patients with GI acute GvHD who actually received the MaaT013 product as part of an Early Access Program in France and across Europe and the world. But these are 111 patients with mature and well-characterized data. But I must confess that we have already more than 200 patients being treated today. So for those who are not really familiar yet with acute GvHD, actually, this is one of the most serious complications of allogeneic stem cell transplantation. And allogeneic stem cell transplantation is the only curative treatment option for many patients with leukemias, especially myeloid leukemias, because despite the advent of novel therapy, cellular therapies, unfortunately, the outcome of these patients is very dismal. And unfortunately, one of the severe and key complications of allogeneic stem cell transplantation is the development of acute graft versus host disease. And this could affect the skin, the liver, but also the gut. And actually, the gut involvement is usually the most life threatening, I would say, condition. And that gives you around 22,000 patients per year receiving transplant and you end up actually with around 10,000 patients who are candidates to some curative treatment. And out of them, 1/3 of them are going to be steroid but also ruxolitinib-resistant and refractory, but I'll come back to this in a few seconds. But the bottom line, why MaaT013 is a key drug for treating these patients with very dismal outcome. It is because we have a very strong body of data highlighting that the loss of the microbiota diversity, in another word, what we call the dysbiosis, is a key initiator and the trigger for these severe cases of acute GvHD. And this is favored by the chemotherapy, the irradiation, but also the multiple courses of antibiotics that these patients are receiving. And once they develop acute GvHD, you usually treat them with steroid, corticosteroid. This is the best we can do since now more than 40 years. But unfortunately, not all of them will respond to steroids, but also some patients may not tolerate steroids. And until recently, the outcome was very dismal. The mortality was over 80%. So you would imagine a terrible situation. Recently, we had ruxolitinib, a JAK2 inhibitor, which has been approved for those patients in steroid-refractory acute GvHD. However, one should bear in mind that, unfortunately, not all patients will respond or are able to receive ruxolitinib. And most importantly, some patients are even resistant to ruxolitinib. And in this situation, there is a clear unmet medical need. And this is where comes the MaaT013 use and story. And this is about this Early Access Program that is still ongoing today in Europe, and I mentioned more than 200 patients were already treated. So this is about patients who are steroid-refractory or even steroid-dependent with a very severe gut acute GvHD. Usually, it goes from grade II to IV, but most of them are grade III and IV. And actually, this is used as a monotherapy or even in combination because as you may guess, in an Early Access Program, it's not a prospective control the trial, it's just according to the attending physician decision. And obviously, these are patients who are not eligible to our ongoing registration pivotal trial Phase III trial called ARES. And usually, the administration would require a few hours of discontinuation of systemic antibiotics. So you can see here the characteristics of the patients. The median age is 57, but you can give it with no age limit, the older patient was age 74. And actually, these were really highly advanced patients who received a median of 3 lines of therapies for their acute GvHD. So I can assure you, these are patients who are in theory is supposed to be in supportive or palliative care. And you can appreciate that the majority, 85%, were steroid-refractory. And as I mentioned, the majority, 91%, had the most severe, I would say, advanced cases of acute graft versus host disease. So these patients received the MaaT013 drug as an enema, and the results are quite astonishing. You can see here on the left-hand side, the GI overall response rate of 53%. But what is really even more important than these 53% is that the majority of the patients are going to be in complete remission or even very good partial remission. And we know that this is a key and mandatory step to improve the survival and the outcome of these patients. And actually, this is what you can see on the right-hand side of the slide, where those patients who are responding to the MaaT013 therapy are actually enjoying a 67% probability of survival at 1 year. And this has never been described in the past, and this is highlights -- actually highlighting the huge benefit of this life-saving therapy. And if you focus actually on the most advanced patient, which means these are the patients who are not even only steroid-refractory, but also ruxolitinib-refractory because ruxolitinib is an approved and widely used drug now in acute GvHD. And these are patients similar to our ongoing Phase III registration trial. And the results are even more amazing, I would say, because you have a 61% GI response rate, including almost exclusively a complete remission. And this will translate into an incredible, really astonishing overall survival rate and responders, 81% at 1 year. And please don't forget, I mentioned to you that the mortality in these patients at 2 months or 3 months would be more than 80%. Now we have a probability of survival of more than 80%. And you can achieve these amazing results actually with an excellent safety profile, 16% of the patients reported an adverse event, which was probably related to the product. But actually, there were no pathogen transmission because that was some concern initially because these patients, they do have a fragile gut and there were no deaths attributed to the drug itself. And currently, 55 patients are alive at last follow-up. So one would reasonably, I would say, conclude and with strong confidence that MaaT013 is a safe, effective drug for steroid, but also ruxolitinib-refractory acute GvHD, given the very high response rate and the positive impact on survival. And that has set actually the stage, although the Early Access Program is ongoing, to run this Phase III clinical trial, which aims to include 75 patients across Europe. So with this, I will stop here. I think we'll take questions later, but I'll hand it over again to Mr. Affagard.

Thank you very much, Professor Mohty. So just to remind, I see there's already questions, but for the benefit of the audience, you can ask your question as we speak, no problem, we will be dealing with the questions at the end. So now we have finished with the presentation of the Early Access data with MaaT013. Now we're going to be going to the next project, MaaT033, and that will be with a presentation of Professor Florent Malard. Thank you very much, Professor Malard, if you want to continue the presentation.

So thank you, Mr. Affagard. And we are now going to discuss the PHOEBUS trial. So this is a multi-center, randomized, double-blind Phase IIb trial that evaluates MaaT033 to improve the outcome in patients receiving allogeneic stem cell transplantations. So I am going to present you what is a rationale to develop this MaaT033 in allogeneic stem cell transplantations. We know that in patients that are going to undergo allogeneic stem cell transplantations, they have at baseline a healthy microbiome. But before we start allogeneic stem cell transplantations, they receive some high-dose chemotherapy, some antibiotics that will induce some dysbiosis because of the treatment, in particular, for the treatment of acute myeloid leukemia. And when we are going to perform the allogeneic stem cell transplantations, again, they receive high-dose chemotherapy. This is part of the transplantation platform. They need to receive this high-dose chemotherapy for disease control and engraftment for the success of allogeneic stem cell transplantations. And almost all patients also will have to receive some antibiotics with a broad spectrum so that it will have an important impact on patients' microbiome and it will induce an important dysbiosis. And in fact, over the last decade, a lot of study clearly demonstrate that this dysbiosis have an important impact on patients' outcome. It will, of course, induce a higher risk of infectious complications. This is easy to understand. We have some dysbiosis. We have more bad bug, and it will lead, of course, to more infections. But we have also some data that showed that it can increase the risk of relapse of the underlying disease because it will interplay with immune systems. And probably, it will lead to a decrease efficacy of the allogeneic stem cell transplantation on an increased risk of relapse of the leukemia. And as Professor Mohty just told you, this microbiome is closely related to this graft versus host disease to these life-threatening complications. And in patients with this low bacterial diversity, it will increase the risk of graft versus host disease and increase the risk of graft versus host diseases mortality. And this dysbiosis is also associated with a delayed adaptive immune recovery that will also contribute to the increased risk of very severe infection after stem cell transplantations and that will overall lead to reduced overall survival. And in fact, this reduced overall survival was confirmed in a very big study that included more than 1,000 patients that were not treated in single centers, but in some -- it was some patients treated in the U.S., in Europe, in Japan. So it was some patients treated all over the world. And with more than 1,000 patients, they were able to demonstrate that patients that have a higher diversity at engraftment after stem cell transplantations have a significantly higher overall survival. So it was a very powerful finding because we are speaking about patients with acute myeloid leukemia, very serious disease. And in fact, this gut microbiome dysbiosis was a very strong predictor of patient's survival. So based on these findings, we need to develop an intervention to restore this gut microbiome dysbiosis to prevent the dysbiosis and to improve the patient's outcome. And this lead to the development of this MaaT033. So this is similarly to the MaaT013, this is a pooled microbiome with a high richness, a high diversity, full ecosystems that which contain a high number of butyrate-producing bacteria, so the so-called Butycore. So this butyrate-producing bacteria, some bacteria with some immunoregulatory properties that are being shown to be protective and to be associated with a good outcome after allogeneic [indiscernible] stem cell transplantations. What is very interesting with this MaaT033 is that it can be given as an oral product, and this is lyophilized capsule so the patients are able to take their capsule at home, and this is a home delivery, very easy. So what is a treatment schedule plan in this Phase IIb clinical trials? It will be a first treatment for 1 week before we start the conditioning regimen. So before we start the allogeneic stem cell transplantation. So they are planned to receive 3 capsules per day for 1 week, and we'll stop at day 7 before allogeneic stem cell transplantation because this is the time where we're going to start the chemotherapy. And after neutrophil recovery, so this is after allogeneic stem cell transplantations, we'll again give 3 capsules per day. So it will be around day 18 after allogeneic stem cell transplantations and we'll pursue the treatment for up to 90 days after allogeneic stem cell transplantation. So this is a very long-term treatment aiming to have a full microbiome diversity recovery to improve the patient's outcome and prevent allogeneic stem cell transplantations complications. So these dose are 3 capsules per day were based on the Phase Ib CIMON study that was conducted in 6 centers in France to establish what was the right doses of MaaT033 to have an engraftment and to restore gut microbiota diversity. And in fact, we use some patients that have diagnosis of acute myeloid leukemia that receive high doses chemotherapy, a lot of antibiotics that induce some important dysbiosis. And when patients recover, when we stopped all the antibiotics, they were included in these Phase Ib clinical trials, and we have several cohorts. In the first cohort, we give only 1 pill of MaaT033 weekly for 2 weeks or 2 pills. In the cohort 2, it was 1 per day for 1 week. Cohort 3, 1 -- 3 per day for 1 week. And in the last cohort, it was 3 per day for 2 weeks. So it was this dose escalation clinical trial that is typical for the Phase I clinical trials. And in fact, as you can see here, this is baseline. So this is when we are going to give the first MaaT033 treatment. This is 1 week after, 2 weeks after. And here, this is after patients receive further chemotherapy that are planned for the treatment of acute myeloid leukemia. And as you can see here, in all cohorts, we see a significant increase into patients' microbiome richness, so that is to say that we find more bacteria 1 week after the treatment, and it was further increased 2 weeks after in most cohorts. It was only in the first cohort when we give only 1 pill per week that we don't have this strong persistent into the increased richness, but we have a very low doses of treatment in this case. And when we look at the engraftment, we are also able to see that in all cohorts, we have a strong engraftment that is to say that we find the bacteria that are within the MaaT033 in the stool of the patients. So we have an increase into the richness of the product that were associated with the good engraftment of the product, including this Butycore. So this beneficial butyrate-producing bacteria. So overall, we find a robust and persistent engraftment. We see that the engraftment follow MaaT033 treatments that correlated with an increased anti-inflammatory markers, and we have a very good safety profile since we have 22 patients exposed, 22 that completed and that received the entire treatment, it was a very good compliance because it was some small pill that was easy to take for the patient. So all patients takes all their pills, and we have some very positive DSMB meeting regarding the safety of the treatment, [ which each time go ]. So based on these Phase Ib clinical trials, we're able to design this Phase IIb randomized PHOEBUS clinical trials. And we have a very good primary objective since we aim to improve the overall survival in patients at 1 year after randomization. We have some very important secondary endpoint, of course, regarding the safety of the product, of course, also the GvHD free survival at 12 months. So we expect also to reduce the incidence of graft versus host disease with MaaT033. We'll, of course, look at the incidence of grade II to IV on grade III to IV acute graft versus host disease and of chronic graft versus host disease that is another kind of graft versus host disease that we can see after allogeneic stem cell transplantations. Overall, we also want to evaluate non-relapse mortality, infectious-related mortality, graft versus host disease-related mortality and also the survival without relapse and without graft versus host disease. We also want to assess infectious event. It will be part of the safety analysis also on patients' quality of life. And finally, we'll, of course, assess microbiome compositions to evaluate engraftment of the product and the increase in richness that is expected in patients that receives MaaT033. So here is a study flow chart. So we plan to include almost 400 patients, [ 397 ] patients in these international studies. So patient will be screened, of course. It will be the first screening visit and inclusion visit that will be between day minus 21 and day minus 14 before the day zero of the allogeneic stem cell transplantation, then we'll be able to receive the treatment for 7 days, and it will stop at day minus 7 to start the chemotherapy for 1 week before patients will receive allogeneic stem cell transplantations. After conditioning regimen, there is a decrease into the neutrophil that is expected on at engraftment. So when neutrophil go up, we'll be able to start the second treatment period, so from neutrophil recovery up to 3 months after stem cell transplantations, and we'll have some follow-up visits at 3 months, 6 months, 9 months and 12 months when we will assess the overall survival that is the primary endpoint. We'll have a stratification to be sure that the groups are balanced. Of course, we'll stratify based on the disease -- underlying disease severity using the disease risk index that is an internationally validated stratifications parameters to assess the risk of the different kind of acute leukemia that are going to receive transplants, and we'll also stratify the patients based on the HLA compatibility within 1 month of patient that will have some HLA identical donors and the other on the patient with some kind of HLA incompatibility. So where we have some HLA mismatch just to be sure that the groups will be perfectly well balanced. So regarding the inclusion criteria, we decided to focus on patients age over 50 years because this is where we really have an unmet need to improve patients outcome. But of course, if it works in patients over 50 years, of course, it will work in younger patients with hematologic malignancy that need to receive stem cell transplantation. Of course, with the neutrophil level above 0.5 because we don't want to give the treatment in patients that have very low neutrophil level per regulatory guidelines. And of course, we will only include some patients that received some broad spectrum antibiotics within the last 90 days prior to inclusion because we want to be sure that we are going to treat some patients that already have some dysbiosis where we will have a true benefit from the use of MaaT033. We will, on the opposite, just exclude patients that receive antibiotics at time of the inclusion because otherwise, we'll have directly a detrimental effect on the treatments and we'll also be sure that the patients have a good general condition that we have a donor that we can perform the stem cell transplantations, but this is some very classic inclusion criteria for protocol related to stem cell transplantations. Regarding the inclusion criteria, we decided to exclude some patients with non-myeloablative conditioning regimen because this is some patients that almost no have any neutropenic phase, did not receive antibiotics with very low dysbiosis, so there will be no benefit to give MaaT033 in those patients, and also the patient that received some very high, very intensive myeloablative conditioning regimens with high-dose TDI, with high dose busulfan combined with cyclophosphamide because this is some conditioning regimens that are almost everybody stopped using because of the toxicity, and we think that the toxicity of this conditioning regimens will be too high for our patients. We also exclude several kind of patients regarding different graft versus host diseases prophylaxis with alemtuzumab, vedolizumab, abatacept for the purpose of the homogeneity of the cohort and, of course, some patients that have some contraindication to allogeneic stem cell transplantation will be excluded, but anyway, they will not [ resist ] stem cell transplantation so they should not be included. So what is the study status? So I am very happy to tell you that the first patients were included on dose in November 2023. And so far, we have France and Germany that have active countries with some inclusion and the next step will be to open United Kingdom, Spain, Belgium and Netherlands. So now I will give again to Mr. Affagard for the conclusion. So please.

Thank you very much to you, too. We are lucky to have two pioneers on the field of microbiome and hemato-oncology. So thank you very much for sharing your experience on this field. So I'll go to the conclusion. We have a lot of questions, so I'll try to be fast. In a nutshell, we have 2 different sequences. The first one is MaaT013. So the first step for us would be to complete the European part of ARES with MaaT013. We expect to have enrolled all the patients and then get the primary endpoint because as you have understood, this is day 28 after the treatment of the patient that we evaluate the primary endpoint, so it's pretty short. So we expect to have by mid-'24 the primary endpoint. Because it's a first-in-class product, we will also follow the patients during the year, even if now with the Early Access data, we know that we have a pretty significant safety database. But as per protocol, we will follow the patient during the year, and that will be the end of the clinical trial by mid-'25 from that. We will then -- if the results are good enough, which is what we hope, we will then fill for a marketing authorization in Europe. For MaaT033, we -- it's a longer clinical trial that's in total 387 patients. We expect to have in the second part of '24, the first DSMB, which will be taking place, then we will continue the enrollment of the patient. In '25, we're going to have the second safety interim analysis, safety analysis, and the results will be known by '26. Here again, we're going to be following the patient during a year after the treatment of the last patient. Coming back to the initial slide, MET, Microbiome Ecosystem Therapies. We are leading the field in hematology-oncology. We have demonstrated as part of the Phase II in ARES that we can modulate the immune activity in very severe conditions, such as GvHD. And now we are pursuing the Phase III with ARES with the endpoint, which will be mid-'24. So we are in a good direction with that, and we have accumulated very strong data. I would say that's the most important. And now we are expanding with the capsule, which allows also for ambulatory treatments, and that's also ongoing. Focusing on the EAP, it has also helped the company to generate revenues. They are all revenues from France, which is in Europe the only country where it's feasible to generate revenues. So we have been generating close to EUR 2 million as of September, and that continues on the fourth quarter. We expect to have a very good year in terms of demand. Our cash position is close to EUR 32 million as of end of September, and that is taking us to the second quarter of '24, as we speak today.

So there is a lot of questions. We are on time. We have 20 minutes, and I'll take your questions. Name the person who asked you the question, and I'll assign one of the speakers to the answer. The first 2 questions would be for you, Professor Mohty. One is from Dr. [indiscernible], the other one is from Jacob from KBC. The first question is, do your results of microbial therapy in marrow transplantation allow us to consider it in all iatrogenic alterations of the intestine in oncology? And the second question is that based on the data set that you presented today, 111 patients, for the -- do you think this data set could be a benchmark for what we could expect in the Phase III?

Yes. No, excellent questions. Thank you very much, and they are absolutely relevant and timely. So the first question about whether we can extrapolate the benefit of MaaT013 and MaaT033 eventually for other disease conditions, the other -- the short answer is yes. Actually, in every single disease condition where you would expect dysbiosis because of antibiotics, because of chemotherapy, radiotherapy, any condition leading to dysbiosis actually would benefit. And for instance, we have already some evidence in the literature about dysbiosis in the setting of CAR T cells in the setting of bispecific antibodies, but in the solid tumor and oncology in general. So actually, this question sounds like music to my ears. And actually, I believe today, we have sufficient evidence to consider that the modulation of the microbiota with products that like the one manufactured by MaaT actually can be an excellent partner for any treatment in cancer, I believe, and probably beyond, but this more in the cancer field, I would say. The second question is about what can we glean, I would say, from the current Early Access Program results and whether this can give some good indication for the ongoing ARES trial. Actually, these results are really excellent. So in theory, it gives you a flavor on what to expect from the ARES Phase III trial. Obviously, we don't know what are the results of the Phase III trial yet also the latest DSMB and the press release that followed from MaaT suggested that the results are excellent and even beyond expectations because, obviously, in the ARES trial, the population is very homogeneous in contrast to the Early Access Program where you cannot control. The inclusion criteria are clearly about those patients who are ruxolitinib and steroid-refractory according to the official and I would say, universally admitted definition. So in summary, I think the Early Access Program results are already excellent and I'm extremely positive about the rest of the story.

So the third question is from Jacob. It's related to a potential baseline characteristic of the patients so that we can predict who's going to respond to the treatment or not. So what we have seen in the Phase II is that the more dysbiotic you are, the better and it makes sense. It was not obvious to us. But at the end of the day, it makes sense because the more you have the broken the ecological niche, the better it is for the product to engraft. So what we have decided with the Scientific Advisory Board is to -- for the Phase III to add a pretreatment of vancomycin for 2 days so that we can break the ecology for all patients. So that's another way to answer the question. So yes, the more dysbiotic you are, the better it is, but it's not that we are taking only those with a dysbiotic microbiome. We are also like making an average microbiome for all patients and by giving antibiotics to all the patients. We need to free up the niche for the patient to be the most efficient. The question is still valid when it will not be iatrogenic dysbiosis, but I would say, more functional dysbiosis, where you have limited dysbiosis. That would be a different question. And here, the biomarker question will make sense. But here in the field of hematology-oncology, that's the choice we made to make sure that the ecological niche is freed up and that's improved the level of response. Then we have a question from Christophe Dombu from Kepler. That's for you, Professor Mohty. Here, that relates to the fact that we are selecting the patients based on their GI status. And the question, would your treatment be efficient also beyond GI patients?

Well, obviously, again, this is an interesting and important question. Based on the mechanism of action, our first target is the GI, of course. And especially that in acute GvHD, the life-threatening organ is actually the gut. Having said this, what we have noticed, at least empirically from the Early Access Program, some of the patients is that the other organs are also responding. So probably, there is a sort of a systemic effect and a clear benefit irrespective of the organ. But definitely, the target organ based on the mechanism of action of the drug is the GI.

Thank you. The next question is from Jacob, KBC. Can you share any updates regarding the status of your interaction with the FDA with regards to initiating clinical activities in the U.S.? And what are the time lines? So today, there's nothing preventing us to open centers in the U.S. We have been discussing last week at ASH, San Diego with a lot of investigators and they are already willing to help us with the expansion in the U.S. So the IND is cleared. As you know, we have been on hold with the FDA during a certain period of time. We get out from the hold. When we get out from the hold, it's because also we have done some modifications on the CMC process. Those modifications have been made. The products have been produced. So there is nothing preventing us to continue the clinical trial to expand the clinical trial in '24. The time lines will also depend on the financing of the company, of course, but there is nothing preventing us to expand in the U.S. The IND is clear. The centers have been identified. The products are here. The CRO has been selected. So there's nothing preventing us to expand in the U.S. but also we have been focusing in Europe. And we have the capacity in Europe to recruit all the patients we need. But of course, we would like to go to the U.S. So that will be an activity for '24. So then the next question will be for you, Professor Mohty. What was the main reason why ARES like patients were not eligible for ARES trial in the EAP?

Yes. Very good question. Well, first of all, and the most frequent one was about those patients who were treated in centers who are not participating to the ARES trial. And obviously, given the brilliant results that we already had, it was ethically mandatory almost, I would say, to make such an Early Access Program available for patients everywhere in France and across Europe and even beyond Europe. Also, there were patients who did not fulfill some of the criteria of ARES because ARES is really a very well-defined population of steroid and ruxo-refractory patient. But most of the time, it was about the participating centers.

Another question for you, Professor Mohty. What was the feedback from the medical community at the ASH conference regarding the data you presented?

Well, I would say, the feedback was extremely positive, and Professor Malard can confirm this because he was also attending. I think the community was extremely e enthusiastic because these are unprecedented results we see in such a life-threatening condition. Nobody ever saw such a high response of CR with such a high level of survival. Obviously, it's not randomized data, it's an Early Access Program, but these results were very, very well received by the community. I don't know, Florent, whether you would like to comment on this.

Yes. I completely agree with you, Professor Mohty. It was very well received. We had a lot of questions. It raised a lot of interest. And the centers, including in the U.S., are very interesting to have access to this drug. We also have some people, for example, from Australia, that say, can we participate in the clinical trial? Can we have access to the product through an Early Access Program? So for all over the world, we have this strong interest and people are very excited about the results. So it seems very promising.

I can even add one example, I experienced myself. Immediately the day after the presentation of the data, I received a case by e-mail from the Netherlands, for instance, for a patient, a young lady struggling with the GI acute GvHD since several months says -- asking desperately to take advantage and get access to MaaT013. It gives you just a snapshot of the enthusiasm of the community. Thank you. We have 2 questions on MaaT033. The first -- so that will be for you, Professor Malard. The first one is from Jacob. Can you please shed some light on the rationale behind choosing overall survival as the main endpoint for the PHOEBUS trial as opposed to a GvHD related endpoint?

So yes, thank you for this question. And this is an important question, of course, because this is always an important question, are we going to choose the primary endpoint in the clinical trials? In fact, it was based on all the data available. First of all, we have this very important multi-center study that established that this gut microbiome dysbiosis was associated with overall survival and not only with some GvHD-related impact, not only with the incidence of GI graft versus host disease or with graft versus host disease mortality, for example. So this is the first answer to this question. The other thing is that beyond graft versus host disease, we know that the microbiome is linked with all complications we can see after stem cell transplantation, including the risk of relapse of the underlying disease and the risk of infectious complications. So really have the feeling that using MaaT033, it will improve low -- decrease the risk of graft versus host diseases, but also decrease the risk of infectious complications, decrease the risk of relapse, and at the end, have a very good effect, not only in some graft versus host disease related endpoint, but with the overall survival, and this is why we decided to choose the overall survival as a primary endpoint.

So second question -- thank you. Second question on MaaT033, despite [ 100-person ] compliance in the Phase I, you could expect some non-adherence during the 90-day post-HSCT in your view? Is there a risk of a lowering of your study power?

So yes, this is also an important question because it is really, which dose of treatment patients are going to take during the course of the treatment, if it will have an impact on -- of course, of the feasibility to achieve the endpoint if we have an [indiscernible] study. So several answers. So the first thing is that we have 2 sequence of treatments. A first sequence of treatment that will be very short of only 7 days before we start the conditioning regimens. And for this phase of 7 days, we'll have a very good compliance because this is a very short period of treatment. Regarding the compliance, regarding the longer phase of treatment from day around 18 to day 90, of course, there will be a few patients that may not take the entire equipment. But we must highlight that when we are speaking about allogeneic stem cell transplantations, compliance is a key issue because patients need to take their immunosuppressive drugs, need to take some prophylaxis. And when we decide to perform an allogeneic stem cell transplantation to one patient, this is something we take into account. for example, we have a patient 2 months ago with a very bad compliance, and we decided not to perform allogeneic stem cell transplantation because of that, because there was 2 important risk of disease complications after stem cell transplantation if you don't take the immunosuppressive drug. So patients are already selected to have very compliant. So this is the first answer. The second answer to the question is that we plan a longer period -- treatment period from day 18 to day 90, and we can expect that already, maybe the first 15 days will be very important to restore the gut microbiome dysbiosis will lead already to a beneficial effect. And we decided to give the treatment for a long period of time because we know that patients can have some event, maybe have some new infections, receive some antibiotics. So this is the reason why we plan for these long treatments. But we know that already, the patients take a part of the dose, we already expect that it will be enough to achieve the endpoint of the study.

Thank you very much. There was one question, and I don't know who to assign. It's assuming you have competing data with MaaT033, do you think you could switch from MaaT013 to MaaT033? So I don't know who is going to answer that one. It could be both.

I can start. In theory, I would say, yes, because the starting material is the same. However, we need to bear in mind that severe refractory acute GvHD is an acute, I would say, life-threatening condition where you would like to achieve almost a rapid immediate, I would say, instantly correction and recovery of the dysbiosis. And if you just consider a dosage issue, obviously, the MaaT013 product is more adaptive. Having said this, it doesn't mean that we cannot envision that MaaT033 would become a sort of a maintenance treatment. And that is exactly the concept Professor Malard was explaining about why we took overall survival in the PHOEBUS trial because actually, we do expect a benefit on different outcomes. And just to add on this because the question was about compliance, actually, the results in PHOEBUS will be analyzed on an intention to treat. So there is no risk. But I don't know, Florent, if you would like to add something.

No, I completely agree. I think we need these high doses of microbiome, so we need this MaaT013, at least for the first dose of treatment with this GI acute graft versus host diseases. But of course, we can use this kind of maintenance of MaaT033, and so far, we are dosing 3 doses of MaaT013. So maybe we'll be able to do only 1 dose on MaaT013 and after switch to MaaT033 to have this maintenance. As when we are going to treat, for example, for CMV, we have this induction treatment after this maintenance. So I think we'll have the same kind of model with the combination of some very induction with high doses of MaaT013 combined with MaaT033 and that it will further improve the result, I would expect that.

And question on MaaT013 from a partner, what would be the historical data you would have expected if you compare to the population you had in the Phase II?

Yes. Another important question. And obviously, as you may guess, given the dismal outcome of this condition, we cannot ethically randomized trials. So we have to benchmark with historical data. And actually, compared to historical data, the figures are almost like 180 degrees different because with historical data in steroid-refractory acute GvHD, the survival would be less than a 10% at 6 months. it's probably worse if you consider the both steroid and ruxolitinib-refractory patient. And now I'm showing you in the responding patient more than 70% or 80% overall survival. So although this is not randomized and a controlled Phase III, but still, I think the difference is huge between what we see in -- we used to see in historical cases and routine practice and now when patients are able to access such innovation like MaaT013.

Thank you very much. There's only one question we have not answered, so I'll follow up with the person who asked the question. However, we have -- we are at a time limit. So I'll conclude, we want to restate your time, of course. Thank you very much. We will continue to communicate any time we have new data and new developments. So thank you very much for following the company. Thank you for your interest. And thank you to our two pioneers with us today. Thank you very much, and talk to you soon. Bye-bye, and happy Christmas and a Happy New Year.

Merry Christmas, happy holidays.

Thank you. Happy Christmas.

Thank you.