Good morning, good afternoon, everyone. I'm Laurent Lévy, CEO of Nanobiotix, and happy to welcome you here to present to you our company and what we see for the future in terms of development of new therapeutics to bring that to millions of patients. Before getting into the meat of this meeting, which is about the new platform Nanobiotix is developing, I just want to step back and come back to the fundamentals we've been using to develop our different product and platform in the company. For the past decades, we've been able to develop three platforms for different purposes: one in oncology, one for the CNS disorder, and one with multipurpose. All those platforms, they have something in common. They are not purely based on biology or chemistry; they are based on physics. And why that? The whole idea of Nanobiotix was to think about the question: Can we bring the physics at the subcellular level to bring new mode of action into patients to help them? And that's what we've been doing with the different platforms we are developing today. What's the advantage of this? There's something fundamental with physics: the mode of action that you can produce with it will be much less influenced by the viability of biology. And therefore, you can have products or approaches that could be shared by millions of many patients. And that has been the motto for years at Nanobiotix: to develop only products that are first-in-class and that can be used in many patients to help all those patients. And today, we're going to talk about Curadigm. But before that, I would like to come back to the priority of the company, which is to bring to life and to bring to market our first-in-class radioenhancer NBTXR3. The idea with this product is really to address one of the largest untapped markets in oncology. And we do that with Johnson & Johnson, which is the partner we've been choosing for more than a year now, and we've been licensing our first product to them. So what do we think about when we say oncology? We're thinking at a particular aspect of oncology. And as you can see on this slide, we're looking at interventional oncology, but more precisely at patients at the time of diagnosis. What is clear with the numbers you can see is most of the patients having a cancer at the time of diagnosis, they have a local problem. Only a small part of them have metastasis. As you can see also, most of the pharma in the biotech, they try to tackle this problem of metastatic patients. And there's not much development, not much research done to how can we help those patients when they are still at the early stage of the disease and when they have a local disease. Because if you can do so, that's where you will have probably the biggest impact in oncology. And that's where we focus our attention. That's where we focus the first development for the company. And talking about local control or talking about local disease, there is one tool that is widely used in oncology, which is radiation therapy. As you can see here, it's all patients getting radiation. More than 60% of all cancer patients are getting radiation at some point. All the big cancers, like breast cancer, lung cancer, prostate, they all use in the vast majority radiation therapy. Nevertheless, you have some limitation with this tool. And the limitation is due to the fact that when you try to irradiate a tumor, you also have to irradiate surrounding healthy tissue. Therefore, you're limited by the dose you can deliver in the tumor versus the side effects you will create. That's what led us to develop a unique drug, which is called NBTXR3, and now JNJ- 1900, which is a product that has been designed based on crystalline inorganic nanoparticles. So some tiny objects that are small enough to go into the cell. And while they are into the cell, thanks to the specific design of this nanocrystal, they are able to absorb the energy of radiation therapy. So after a single injection, those particles will diffuse in the tumor, will penetrate the cell, the patient will get the normal radiation, and the particle will absorb the energy and will create a high quantity of damage around them. So it's a physical mode of action that will lead to the destruction of the cell. The way we want to apply that is the following. For many patients, there is a need of better local control. So we have this injection in the tumor that we irradiate, and then we provide better local control to patients. And there are subsequent biological consequences of that, which is the physical destruction of the cell will trigger also a priming for an immune response that could be useful for the treatment of the primary tumor, but also for systemic disease. So as you can see here, we have a product based on the physical mode of action that triggers some biological consequences that could help a lot of patients getting radiation. And here, what you see is the first pass to get there. We have a large number of clinical trials ongoing, including two late-stage programs, one in lung cancer stage III, one in head and neck frail patients ineligible to cisplatin. And we intend to develop this product with our partner, J&J, for the larger number of patients to reach as many patients as possible. So just in a nutshell, what we intend to do with this first product and this collaboration is really addressing and helping the maximum of patients in oncology. That's why we've been signing in the recent past a $2.5 billion deal in milestone plus royalties. When you look at just the two first indications we want to target, like lung cancer stage III and head and neck, it's around 100,000 patients we could help per year, only in the U.S. and EU. That's potentially a big market. Associated to that, we also will have a substantial amount of milestones that will lead us to financial sustainability and will allow us to continue to develop. When I think about continuing developing things, the next big step for us is to develop this new platform, Curadigm, this platform that should lead to many new first-in-class products. Here, what we are doing is really the idea that we can transform the way we design drugs and the way we apply them. This could be applicable for many products that you see every day, like RNA DNA-based products, oncolytic virus, and many more. Just to give you a glimpse about what this technology is and what is the potential. I'm going to turn now the mic to Matthieu, our head for the platform Curadigm, that is going to explain what it is, how it works, and then we'll go back all together for a panel discussion. Matthieu. Thank you, Laurent, for the introduction. I'm going to introduce the Curadigm platform. And to start this introduction, I would like to mention a fact. If we look at the therapeutic landscape, especially at the innovative therapeutic, it's very dispersed in terms of the nature of therapeutic agents, ranging from lipid-based, polymer-based nanomedicine loaded with small molecules, nucleic acids, viruses, inorganic nanoparticles, recombinant nanoprotein, protein, and so on. But all this nature of therapeutics shares a common challenge. When you want to deliver by intravenous route of administration a treatment, they will need to reach their target at a subcellular level. Meaning, to reach this target, they will have to overcome different barriers. The first one being at the organ level, then, once in the right organ, they will need to address a specific cell population, and then reach their target at the subcellular level. At each barrier, you will have off-target losses of your product and degradation of the therapeutic agent. And if we look more specifically at the first barrier, the organ level, an analysis has been performed and shown that for nanoparticles in oncology, the median accumulation of the nanoparticle in the tumor is less than 1%. Of course, it's better than a small molecule injected as such, but still, there is some room for improvement in the field. Why such a low amount accumulated in the target tissue? The first, the main challenge at this organ level for a therapeutic agent is the liver. The liver is the main organ of the reticuloendothelial system, a system which is dedicated to the clearance of endogenous waste, such as cellular debris, dead cells, and so on, but also exogenous materials, such as pathogens. Why? How does it work? The liver has a specific structure allowing to decrease the blood flow within this organ, maximizing the interaction with specific cells which are dedicated to recognize and clear endogenous cellular debris, external pathogens, but also a large part of therapeutic agents, including the one I was mentioning previously, and at the end, if we want to illustrate the impact of the liver, if we take a mouse and we inject a fluorescent nanoparticle to mimic a therapeutic agent, as you can see on this picture of this mouse, as soon as you inject intravenously the nanoparticle, all the fluorescence is localized within the liver. There is no more fluorescence in the rest of the body of the animal, meaning everything is in the liver, and a very tiny portion of the dose will be able to reach the target. Why? Where does it come from? This situation is coming from a combination of different physicochemical attributes: size, surface charge, hardness, and shape, and this specific combination of these parameters will drive the recognition by the liver cells involved in the clearance of therapeutics, and all the therapeutic agents I was mentioning at the beginning of the presentation have this combination of parameters leading to the internalization by the liver. This is why we decided, leveraging this knowledge, to design this concept developed by Curadigm, which could be summarized in one sentence. It's really to prime the body to receive the treatment. By priming, I mean, we design a nanoparticle which is called the Nanoprimer, which is dedicated to be intravenously administered just before the therapeutic agent. The Nanoprimer will reach the liver, and it will occupy transiently the cells involved in the clearance of the therapeutic agent. Meaning that when in a second time you inject intravenously the therapeutic agent, there is less recognition by the liver. You increase systemic viability of the therapeutic agent, allowing a higher accumulation of this therapeutic within the target tissue, which could be a tumor if we are talking about oncology, or another organ or tissue if we are talking about another therapeutic area. So if we come back to a mouse injected with a fluorescent nanoparticle, let's take another mouse, and we treat this mouse with the Nanoprimer first, and then we inject the fluorescent nanoparticle. As you can see, even one hour administration of the fluorescent nanoparticle, you can still see the whole body of the animal, which is still fluorescent, meaning that the nanoparticle continues to circulate within the blood and is available for subsequent accumulation in the target tissue to deliver the treatment more efficiently. Of course, this approach has already been tried using different approaches in the past. The first approach which has been developed was the use of conventional liposome. Conventional liposome means they use the same liposome that is used to deliver the treatment within a tumor to ensure the pretreatment of the liver. You cannot ensure both aspects. You cannot deliver with the same object the therapeutic within a tumor, and at the same time occupy the liver, meaning that the effect is moderate, and you will need to use a high dose of the liposome, potentially bringing toxicity. The second approach is the use of lipid emulsion, which is used for parenteral nutrition. The approach is to deliver in the patient body a high dose of lipid, an emulsion of lipid, but this emulsion leads to a high polydispersity of the lipid nanoparticle, different composition in fatty acid, and so on, meaning that you will also need a very high dose to generate a moderate effect and potentially bring in toxicity. Then finally, the third approach is to use a small molecule to decrease clearance by the liver. So this approach uses molecules such as clodronate, which is toxic for the Kupffer cells in the liver, meaning you will kill these Kupffer cells, so there is less clearance by the liver, but you have the toxicity of the small molecule. This is why we really think we've got key differentiating factors with the Nanoprimer. Why? This Nanoprimer is a lipid-based nanoparticle, and the mode of action is related really to the physicochemical parameters of the nanoparticle of the Nanoprimer itself. There is no API, no small molecule encapsulated in the Nanoprimer. We optimize the physicochemical properties of the Nanoprimer to ensure the specific interaction with the cells involved in the clearance of the therapeutic agent. The effect is transient because the Nanoprimer is biodegradable, and as soon as the Nanoprimer is eliminated by the liver, the liver will come back to its physiological function, trapping again the remaining therapeutic agent. And of course, we checked preliminary safety with the Nanoprimer, and the first result confirmed that we are safe with our Nanoprimer. The beauty of this concept resides also in the fact that you could, with the Nanoprimer, answer different needs of the therapeutic agent. If we come back to the fact that the therapeutic agent, the major part, is loose or could bring some toxicity, and only a small portion will deliver the efficacy, we can see it in a different way. A product could be limited by the lack of efficacy. In this case, when you combine the Nanoprimer, you can increase the efficacy of the treatment for the same dose administered. But for some of our products, you are not limited by the efficacy, but you are limited by the toxicity of the therapeutic agent. So when you combine the Nanoprimer with this product here, you can preserve the same efficacy, but for a lower dose administered of the product and a lower toxicity. Also, our Nanoprimer is a strong opportunity to be a game changer in the way some treatments are administered to the patient. For this, let's use an example: RNA-based therapeutics. These treatments are very efficient. Everybody's aware of the impact of RNA-based therapeutics for COVID vaccines. There is an approved product for liver-related diseases. But when it comes to using these RNA therapeutics by IV route of administration for extrahepatic delivery, it is still a challenge for this nature of therapeutics. And we really think that the Nanoprimer could unleash the power of RNA-based therapeutics. And to demonstrate the impact of the Nanoprimer on RNA-based therapeutics, we had the opportunity during our collaboration with the Langer Lab in MIT to evaluate the impact of the Nanoprimer on the accumulation and bioavailability of small interfering RNA loaded in lipid nanoparticles developed by the Langer Lab. On this graph, you've got the impact of the Nanoprimer on the accumulation of the siRNA in the liver on a mouse model. What you can see is that when we add the Nanoprimer to the treatment, we decrease by 40% the accumulation of the siRNA within the liver. It's correlated with an improvement of the bioavailability of the siRNA in the systemic circulation of eightfold. Clearly, we increase the systemic bioavailability of the therapeutic agent with the Nanoprimer. At the end, what we want to obtain is an improvement of the efficacy of the treatment. For this, during another collaboration, we combined the Nanoprimer with an siRNA-based therapeutic agent, siRNA loaded in lipid nanoparticles, during a tumor growth delay experiment on a mouse model. We use a triple-negative breast cancer tumor model, and we follow the tumor growth during the experiment, depending on the treatment administered to the animal. On this graph, the yellow curve corresponds to the response obtained with the therapeutic agent alone at a defined dose. You can see we obtained a tumor growth delay inhibition of 36%. When we add the Nanoprimer, you obtain the pink curve. And this, for the same dose of the therapeutic agent administered, we increase the tumor growth inhibition to 80%. So clearly, we significantly increase the efficacy of the treatment when we add the Nanoprimer. We also evaluate the impact of the Nanoprimer on the efficacy of small molecules loaded in the medicine. For this, we used irinotecan-loaded liposome. We first evaluate the impact of the Nanoprimer on the tumor accumulation of the drug loaded in the liposome, CPT-11, the pro-drug, and the active metabolite SN-38. We evaluate the impact of the Nanoprimer on a colorectal tumor cancer in a mice model. What we obtain is that when we add the Nanoprimer, we increase by three- to fourfold the accumulation of the drug in the tumor. We make the correlation between the tumor accumulation and the efficacy of the treatment generated with irinotecan-loaded liposome. For this, we perform a tumor growth delay experiment. What we obtain is that the red curve corresponds to the response of the tumor group with the irinotecan-loaded liposome alone at a defined dose. The blue curve corresponds to the same dose of irinotecan-loaded liposome, but with the pretreatment of the Nanoprimer. As you can see, we significantly increase the efficacy of the treatment with the Nanoprimer. We generate similar efficacy results by combining the Nanoprimer with Onivyde, which is approved in the treatment of pancreatic cancer. Finally, a last example of what we could achieve with the Nanoprimer by combining it with a recombinant protein, asparaginase. asparaginase is used in the treatment of acute leukemia. The mode of action of asparaginase is localized within the blood. This recombinant protein will degrade asparagine, asparagine which cannot be synthesized by the tumor cell as opposed to healthy cells, so by depleting asparagine, you will kill the tumor cells, so blood bioavailability of the recombinant protein is very important, but the half-life of this recombinant protein is also very short, so we perform an experiment to evaluate the impact of the Nanoprimer on the systemic bioavailability of asparaginase in a mouse model, and what we obtain is that when we add the Nanoprimer, we increase by threefold the AUC curve, so the bioavailability of the asparaginase. This is a great opportunity to improve the duration of the effect of this recombinant protein, potentially decreasing the number of injections required for the treatment and potentially decreasing associated toxicity. Now, to finish, let's come back to the therapeutic agent. If you look at the therapeutic agent, you will see that you will have to ensure different functions to deliver the treatment in a single nano object. You will have to take care, of course, of the systemic bioavailability, which is a very big portion to ensure to deliver the treatment. But you will have also to ensure drug loading, tissue targeting, cell uptake on the molecular scale, drug release, and so on. So a large number of functions to be regrouped in a single object. You cannot ensure an optimization of each function. There is a notion of compromise in the design of the therapeutics. Here, the Nanoprimer could really be a game changer because we could rethink the design of the therapeutics. Because this Nanoprimer will ensure the systemic bioavailability, meaning you will remove the function of bioavailability from the therapeutics to the Nanoprimer. So you create a space to improve existing function, such as on the molecular scale, for example, or you can create a new function in the therapeutics itself. So clearly, dissociating the function into independent objects is a strong opportunity to boost overall function of the therapeutics and deliver more efficiently the treatment to the patient. And now I'm going to leave the floor to Laurent to give you an overview of the business opportunity associated with this Nanoprimer. Thank you, Matthieu. As you have seen, this is a new concept that will bring many opportunities, many potential product developments. We're starting at Nanobiotix to think about how can we use that not only for our own purpose, internal development, but also to help the industry out there. When you look at the first approach we could go for, you have many approved products that could benefit from this by improving the benefit-risk ratio they exhibit in some indication, could get to label expansion or improvement of safety of those products. You have also many other products under development that could be benefiting for this new approach, making it more efficient. Or it could be for late-stage products, but for preclinical products too. If you think about the industry, about the past, about the number of products that have failed, not because of a lack of efficacy, but because of some hepatotoxicity. So that's also here a big area where this product can revive some of the products and make them use for the benefit of patients. When you look at those three first buckets, you already have many things to do. And that's probably where we're going to start looking at partners or looking at licensing out this technology to help the industry to get better or a larger number of products. What we're going to do also is developing our own platform that will provide products for Nanobiotix to develop. And here we're going to focus on what Curadigm platform can bring that you cannot do without. It's very important. Matthieu was mentioning RNA-based delivery product. If you add this Curadigm or Nanoprimer into the game, then you'll be able to deliver RNA IV. And that's opening a new field for this type of product. It's true for RNA, but it's true for many other approaches. The history of medicine is full of products that could not be developed because of this barrier. With Curadigm, the possibility to overcome this barrier allowed Nanobiotix to be able to develop many products for its own benefit based on this platform. But we will have time later to talk about that. What I would like to do now is to introduce some of our colleagues and discuss about this technology and open the panel for discussion. For this panel, I would like to welcome two members. I will first introduce Dr. Margaret Liu, who is a seasoned scientist and entrepreneur that is starting now working with us at Nanobiotix as a new member of the supervisory board and soon to become a full board member. We've been having a long discussion with Margaret about this technology and how this could help patients and how this could help industry. That's the reason why I invited her to participate in this panel, for her to be able to share her thinking and how does she see what we try to develop with Curadigm. On the other side of the screen, you can see Dr. Jeff Bockman, which we've been working with for quite a long time now on different projects trying to help to shape this industry with new products. Jeff has also helped us to animate many panels in oncology in different setups for different technologies. We thought that it's always good to have an external view on what we do and some challenge that Jeff always brings into the game. Thank you for being here. And Jeff, if you want to start shooting questions and asking things and challenge us, free to go. All right. Great. Well, it's an honor to be participating and moderating once again. Yes, it's been a long time, Laurent, going back to early days of Nanobiotix. And excited to hear Dr. Liu's comments. Very, very honored and esteemed guest. So let's just start off at the highest level here, given the slides that have just been presented, kind of giving an overview of Curadigm and this platform. So this Nanoprimer approach, how would you say it's differentiated from other approaches in the industry that are designed to improve bioavailability, whether bioavailability of small molecules, large molecules, etc.? I'll pose that to you first, Laurent. Well, I think what Matthieu did present at the end of this presentation is the key thing. Most of the products we are developing in our industry, we're thinking about one object, one object that will do everything, and when we start doing so, it's the science of compromise, and you do those compromises even before injecting this product into a patient, and we know how important bioavailability is, but also efficacy and many parameters that are embedded in one object, so as soon as you start releasing one of the constraints, that's where you're opening many doors and many opportunities, so I think that's the beginning of a new story for our industry to start developing new types of treatments that are not only based on one thing doing everything, but maybe different approaches to fulfill different functions that are needed by the patient. Great. So I think one thing I'm curious about is that clearly there are various approaches that address some of these various elements that have been talked about that can compromise, let's say, the therapeutic window for drugs, right? And there's use of ritonavir, for example, to block liver metabolism and increase the drug levels in certain cases. And of course, there are all sorts of delivery platforms which are designed to address some of these issues of increasing accessibility. Maybe you can just talk a little about either you, Laurent, or Matthieu, about kind of how the Nanoprimer is either an alternative to those or may actually be useful in combination with some of those other approaches, whether those are physical approaches like a pump or a subcutaneous device or something, or some of the currently used kind of drug approaches to modulate activity. I could start if you want. I think we could identify synergies between Nanoprimer and some other approaches delivered to optimize the delivery of therapeutic agents because the Nanoprimer will improve liver bioavailability by decreasing the liver clearance. But after this, biodistribution typically remains related to the physicochemical property of the therapeutic agent. There is a lot of different approaches designed to optimize the therapeutic agent to enhance the delivery within a targeted specific tissue organs. So really, there are synergies between these approaches to deliver more efficiently the treatment. And after, I come back to what Laurent was mentioning, really to rethink the design of the therapeutics when you add the Nanoprimer to these treatments. So I can see it really as a synergy, especially in the nanomedicine field, to have a better delivery of different cargo small molecules, nucleic acid, and so on. Definitely. Margaret, did you have any comments, sir, at this point? No, I think that those are really the key things. But I did want to add something slightly different that's complementary to what you're mentioning, which is that using the Nanoprimer means that one can still add on other targeting moieties to whatever you're delivering. So it is good in that it helps to get rid of the non-specificity of the uptake in the liver. But at the same time, it doesn't preclude anyone from developing other rationales, other parts of the molecules for targeting, whether it's targeting a receptor on a tumor cell, for example. So it's a very synergistic approach that can really help to augment then whatever additional approaches people are using for designing targeting specifically. And I think that that's one of the advantages. It's a little different issue than what you mentioned, but I think it's important to point out that you can still then have this synergy of using additional targeting rather than this just being the one thing that you do, which is to decrease the hepatic delivery. Great. Yeah, thank you. So curious about kind of the residency or half-life or how long that Nanoprimer kind of remains in the body. And then I do have a related question to that, which had been touched on in the slides, but I'd like to probe a little bit more in terms of kind of the effects on the therapeutic window. But maybe you can just take the first point first. Yeah, sure. This is a very important question. It's related to the duration of the effect of the Nanoprimer, also the residency of this Nanoprimer in the body. Clearly, if we go step by step, I mean, as soon as you inject the Nanoprimer, accumulation within the liver is very short. I mean, it's very quickly accumulated in the liver due to the physicochemical properties of this Nanoprimer, and now, right after accumulation, you will have an interaction with specific receptors on macrophages and Kupffer cells, then the Nanoprimer will be internalized in the endosomal-lysosomal pathway, and since this is a lipid-based nanoparticle, it will be metabolized by the phospholipids in this lysosome, and it's related to the duration of the effect of the Nanoprimer because the time for the cell to ensure the metabolization of the Nanoprimer, it will slow down the rate of internalization of the therapeutic agent within this pathway, and as soon as the Nanoprimer is fully metabolized, the effect is no more present and the liver will come back to its physiological function. The duration of the effect is about 24 hours, the time for the cell to ensure this metabolization. So this is the time of residency of a Nanoprimer within the body. So kind of curious about the kind of what you can say about the translation of the preclinical results, which mostly you've shown are in cancer models, how you anticipate or what evidence or clues you have about that translatability into humans as you anticipate going into kind of some type of a first-in-human study. Well, I think, as you know, there's a big difference between animal model and human, especially when we look at some targeted molecule. We design the model to respond to a molecule and the model works, and it's different when it's in human. Here, I think there is a different level of correlation we can think about because every mammal has a system with a liver. Of course, they are different. There's different volume, different species and things, but still the concept is the same. At some point, the liver will capture some of the substance. And we know from the literature and all the clinical trials that have been done that some of the objects that Matthieu has mentioned in the presentation, they are captured by the liver in humans. So if we can just go to the first step of this process, which is to bring an object that will mimic the object you want to avoid to be captured by the liver, we think the translation between an animal and a human is very, very high. Now, of course, we'll have to adjust a number of parameters like concentration, etc., etc. But the concept itself should be highly transferable to a human being. And I want to ask a follow-on question, and it may be to both of you, but I'd also be curious for Margaret perhaps to weigh in. So I think when you just think about this in the presentation, the first thing you say is, "Wow, it's very cool. You can increase the activity." You certainly talked about the ability to conceivably address the safety tolerability by reason of increased activity for the same dose or maybe even able to lower the dose. But certainly, there are on-target, off-tissue toxicities that one might presume with just greater circulation time could still result in problems. And I'm thinking really through a cancer lens at the moment. Can you comment on that at all and to what degree you think that is or is not relevant? Yeah, I can answer this question. Of course, yes. Off-target toxicity is very important since with the Nanoprimer, we'll modulate the systemic bioavailability. We'll have to ensure that we preserve the biodistribution. We had the opportunity to evaluate on some of the products we combine with the Nanoprimer, especially on liposome. What was the impact of the Nanoprimer on the biodistribution profile of the therapeutics? And what we obtain is that typically, we increase the accumulation within the tumor by three- to fourfold, probably due to the enhanced permeability and retention effect in this tissue. For the healthy organs, I mean, the biodistribution remained quite similar compared to the one without the Nanoprimer. There's still a small portion in some secondary organ of the reticuloendothelial system, which contains macrophages and so on. So we are focused with the Nanoprimer on the liver. But the increase is quite small, if I may say. It's 1.5-fold compared to the therapeutics alone. So it doesn't really change the biodistribution profile and off-target toxicity of the therapeutics. And if I may jump also on a very important aspect regarding the safety, there is the safety of the Nanoprimer itself also, which is very important because we cannot have any sign of toxicity due to the Nanoprimer, I mean, since we are not a therapeutic agent in itself. And we had the opportunity to explore preliminary safety with the Nanoprimer by performing in vitro and in vivo experiments and in rodent models. In vitro, we didn't observe any sign of cellular toxicity even with maximized dose of the Nanoprimer. No immunological toxicity. I mean, there is no activation of the complement, no modification of the cytokine-interleukin expression profile on human blood. So typically, the first results are very good. And they have been confirmed by an evaluation performed by the NCL, Nanotechnology Characterization Lab in the U.S., which is an organization dedicated to promoting nanomedicine development. And they generated the same result, confirming the safety of the Nanoprimer. And in vivo, on the rodent model, we didn't observe any variation in terms of hepatic enzymes such as ASAT, ALAT, hematobiological parameters, and so on. No sign of toxicity at this stage. Of course, we'll move on in deeper exploration of the preclinical safety package, but first results are very encouraging from this side also. Yeah, and this may be something that you'll be doing down the road and certainly would need to be thinking about. And that is, since certainly oncology, we're mostly talking about combination therapies. You would need to be thinking in a more holistic way about the impact on the regimen of the multiple agents. There might be some small molecules, cytotoxics. There might be a biologic antibody, something else. And all of those are conceivably going to be affected depending on the timing and the regimen and when the Nanoprimer gets used. Yes, but the good point also is here that the Nanoprimer is really focused on the reticuloendothelial system, Kupffer, and liver sinusoidal endothelial cells. So if you have a co-treatment involving a small molecule injected as such, the metabolism pathway is going to be through the cytochrome within the hepatocyte. And the Nanoprimer is not dedicated to interact with cytochrome metabolization pathway. So it won't impact the metabolization of the small molecule. It's very dissociated. This is a good point also for multitherapy treatment. Yeah. Yeah, that's a good point of clarification for everyone, I think. Thank you. Margaret, any comments, thoughts? I just wanted to add that I think that when one thinks about it, fortunately, there are tools to determine what the impact is. You do your normal pharmacokinetics, for example, during the administration of a drug. What may happen is the effects will be distinguished both by longer presence of your drug potentially because you don't have all of this absorption in the liver. That may differ then as well depending on what the entity is. For example, mRNA molecules need to be formulated in lipid nanoparticles precisely because they're so easily degradable. And so besides the issue of being able now not to get stuck in the liver, you have the issue of you have more in the circulation, but the persistence then may differ between a molecule like that or a virus, which may target other cell types, for example, if you're delivering some kind of virus as your vector for killing cells. So the issue is that you can measure the impact depending on what the entity is that you're delivering because you'll have this primary effect of not being trapped by the liver, but then each entity that you're looking at has its own particular targeting and pharmacokinetics and other ways of binding that may take it to the tumor or to other cells, etc. But these are all things that get evaluated anyway for each product. And so the tools exist in order to determine exactly what the impact is that might affect dosing or even regimens. Great. Thank you, Margaret. Maybe if I can. Please. During Margaret's talk, it was ringing a bell. There is also an important aspect of the Nanoprimer mechanism is transient, as we were discussing. And clearly, I think this is an advantage regarding the safety aspect also. If you look at current nanomedicine, I mean, everybody is using pegylation to extend the systemic viability of the therapeutic agent. But at the end, let's take an example, Doxil typically. Doxil has been generated to decrease the cardiotoxicity of doxorubicin by encapsulating the drug within the pegylated liposome. The pegylation means that you will keep your therapeutic agent in the blood for something like a week. And at the end, you will have a modification of the biodistribution in other tissue, I mean, in the extremities and the feet and in the end, bringing a new limiting toxicity. So you replace the toxicity by another one. With the Nanoprimer, the improvement of the systemic bioavailability is transient. I was mentioning approximately 24 hours. That's enough to accumulate your therapeutic agent in a tumor, typically. But that's short enough also to prevent accumulation in other tissue due to a very extended circulation time. So I think we have an advantage from this side also. Great. Great. And actually, we'll come back to that shortly, I think. But, Laurent, just to kind of pull us a little bit out of the weeds for a moment, how is the company thinking of developing Curadigm? I mean, from a kind of a corporate development BD standpoint, bring it forward on your own, doing partnerships, plural, and that may tie back to the issue of different applications of even the Nanoprimer, let alone any follow-on nanoprimers. But, Laurent? I think with this concept, what we do is two things. First, we could solve some of the problems of our industry today, problems that people have developing some of the drugs. So I think here there's a big opportunity to develop partnerships with different types of partners for different types of applications with different types of products. That will be definitely part of the job we're going to do. We already have a good number of MTAs that have been signed and products being tested in many combinations. That's part of the job. The other part is really building in-house our own platform and products so we can have the ownership of a full product, the Nanoprimer plus the other, to develop that and to bring that to humans as far as possible in our development up to market. So that will be the mixed business model we're going to use. And this is needed because there's a lot of applications. So we can do everything, that's for sure. And so finding partners, validating the technology, developing with us, increasing the use of this product for patients will be the right path. So, in fact, you've just kind of alluded to it as, although the presentation does focus on oncology, clearly, the applications are beyond that. Can you speak a bit to that, either Laurent or Matthieu? I think the application is not necessarily linked to a therapeutic area, obviously, but more to the type of object we develop. If you just take RNA, for example, it can be used in many indications. If you took drug delivery systems, that's the same. There are many products that exhibit that kind of physicochemical property that we can help. Yes, it's going way beyond oncology. Nevertheless, the company has already developed knowledge in oncology, and that should be logical for us to continue in this field, at least for a while. This has all the appearances of being quite transformative. I'm just curious kind of what type of reaction you've had from anyone externally that you might have spoken with, whether early partners or financial folks or others in terms of kind of how they're viewing this. Well, I think we have had different types of things. What is sure is, because, as I said, it does solve some of the well-known problems of our industry. There is a natural, okay, it has value. That's the first thing. And it's interesting. And after, it's different. So how does this work? How do you sell that? How do you reimburse this? How do you develop it? Is it a combo? Is it two different products? So the natural question when you develop something new. But we have an answer for all that. And I think in a broad view, we found many if not only people that think there is a big opportunity here, but it's the beginning, so we need to push and to make that happen. Yeah. So given the diverse applicability across therapeutic areas, specific diseases, different types of therapies, how are you thinking of prioritizing? I mean, you mentioned oncology, obviously, as kind of leveraging the resident knowledge from Nanobiotix work. But how are you thinking about kind of diversifying or de-risking or increasing the optionality given that this can be applied to areas that are kind of well-validated that involve, as you said, kind of RNA or nanoparticles like some of the gene therapy or related areas or vaccines that are in nanoparticles and others that are, let's say, not so well-validated, including still, sadly, as a lapsed virologist, oncolytic viruses and other places. So how are you kind of weighing that? And I'm sure Margaret would like to kind of comment as well, but I'll start with you, Laurent. So in terms of priorities in the company, we have a well-defined pathway to develop our own product and platform. So that's something we will disclose later next year. But we have a clear pathway moving forward. On the other side, from the BD perspective, that will be more based on the partners' need. As I mentioned, we have different MTAs ongoing, different tests with this product. It's a lot in oncology, but not only. So we will see how things move forward and we'll go step by step. Great. Any comments there, Margaret? In terms of flexibility? I think that oncology is an obvious place to start because there's been so much focus on how do you take treatments from intratumoral injection to intravenous injection because of the issues of not all tumors are accessible or the challenge. Having something that could be given intravenously for oncology, whether it's a drug or whether it is a virus that can kill the tumor cells, is a very obvious and, I think, a big opportunity as a first step. What I think is really important, though, is that other arenas, let's say gene therapy for inherited disorders, where right now the viral vectors that are used for delivery have to be given in huge numbers. The thing about that is this, to me, seems like an area that really is ripe for exploring. But what it will take is it'll take people in those areas to recognize that instead of just focusing on how do you make a vector, what's the payload, how do we manufacture enough of this to say, "Oh, this is actually the same issue that confronts oncologists every day." And so it's important then to get people in other arenas to recognize that this same type of technology is really addressing a similar problem, which is if you're losing a lot of your vector to someplace like the liver, you have less vector that's going to the intended targets to make your therapeutic product, regardless of what that therapeutic product is, whether it's for treating cancer or whether it's treating an inherited disorder. I think that one of the keys is actually just to get people who are in these other fields to think outside of the box that they've been working in, which has been payload and maybe stabilization of the vector or manufacturing, which, of course, can be a challenge when people are manufacturing viral vectors. Some people have accomplished the numbers, but I think that that's the issue: having people understand the value for other arenas as well as for cancer. Absolutely. I think, of course, just from personal experience, having started in the dark side of industry at a biotech working on delivery of ribozymes and other agents and working with nanoparticles and 30 years on, people still trying to optimize lipid nanoparticles or related LNPs that will avoid the liver for delivering the active to places other than the liver where you want to go. Still does remain a challenge. This does look like a very transformative approach that, at least to some degree, and maybe to a significant degree, might obviate some of those limitations. I'm curious then, Laurent, what's next for Curadigm? I think we have a lot to do when you see the potential of this. As I said, there's a big part for us now. The team is focusing on developing our own product based on this platform. That's something we'll be able to talk about the second half of next year. I think for the first part of next year, we'll be able to show some new data coming out from these nanoprimers and how we could apply that in some of the situations that could be very beneficial to patients. But we'll make an update to the rest of the world and the market soon to explain how we're going to develop that and, more importantly, what's coming in terms of news flow about this technology. Absolutely. And of course, NBTXR3, which kind of started this story many years ago with Nanobiotix. Correct. And there's a lot to do here too. There's a big collaboration with our partner, J&J. And we need to make sure that this is a success and we can bring this product to market. Great. Any further comments from any of you? I think we've covered a lot of ground today. So, Laurent, we've had a great discussion. Clearly, a tremendously interesting and quite potentially broadly utilizable, transformative, if we may say, and we've used that platform technology that you have here in Curadigm. So how would you kind of summarize kind of the benefits, the potential, kind of the so what, if you will, for Nanoprimer? For us, it's like the continuation of the Nanobiotix story. We've been always looking at how nanophysics could help patients and preferably millions of patients. So that's a good step two for us. This technology offers many opportunities that we're going to explore step by step, having BD activities, but also having internal activities, developing our own products. And we're going to start delivering that to the patients. So there's a lot to do, but we think we have a unique opportunity to change the face of the industry with this. So that's where we're going to go. Great. I want to thank everyone for the time today. Thank you for those overviews, Matthieu and Laurent. Thank you for your comments, Margaret. Thanks, everyone. Thank you, everyone. Thanks, everyone.