Beyond biology: Nanobiotix's physics-first approach to cancer

0:05Hello, and welcome to Beyond Biotech, the weekly podcast from La Biotech. I'm Dylan Kassane and this is episode 211 for the podcast. What if the key to beating cancer wasn't a new drug, but a new way of thinking about matter itself? That's the question Laurent Lévy asked when he co-founded Nanobiotics over 20 years ago, and it's a question that is now producing some genuinely compelling answers in the clinic. Nanobiotics is a Paris-based biotech pioneering what they call physics-based nanomedicine. Their lead asset is a radio enhancer made of hafnium oxide nanoparticles designed to be injected directly into a tumour and amplify the destructive power of radiotherapy from within without ever increasing damage to surrounding healthy tissue.

0:55It is currently in phase three trials in head and neck cancer. But that's only half the story. The company's nanoprimer platform is now emerging as a potential new engine for growth with the promise of making an entirely new class of genetic medicines work better. I hope you enjoy my conversation with Laurent Levy, right after this word from our friends at Inside Biotech.

1:22Hi, everyone. My name is Karish Manjigani, and I'm the co-host of Inside Biotech, the official podcast of Biotech Connection Los Angeles, or BCLA. For those who may not know, BCLA is a nonprofit organization dedicated to inspiring, educating, and connecting emerging scientists, students, and entrepreneurs to help grow and diversify the biotech ecosystem in Los Angeles. On Inside Biotech, we invite you to get a behind-the-scenes look at one of the fastest-growing biotech hubs in the country. Each month, we sit down with scientists, founders, investors, and industry leaders to talk about the cutting-edge science inside their companies and the personal journeys that brought them there.

2:02From breakthrough therapeutics and AI in healthcare to career transitions beyond academia, we explore how science, business, and storytelling intersect to shape the future of biotech in SoCal. If you're a student exploring careers in STEM, a young professional navigating the industry, or simply curious about the people driving innovation, this podcast is for you. Search Inside Biotech wherever you get your podcasts and give us a listen. We'd love to have you join us.

2:33Lauren, welcome to Beyond Biotech. Hello. Lauren, let's get started. Tell me a little bit about who you are and how you came to found this company, Nanobiotics. Well, maybe we can start with my training. I've been trained as a physicist mainly. I did some biology too, but my main stream learning was physics. And I did my PhD in nanophysics, trying to understand what's happening with the laws of physics when you start reducing the size of the material. When you come to nanometers, laws of physics may be tweaked, may change. And that was the basis of my thesis. And later on, I did a postdoc. And in between, I was wondering what I should do with my life.

3:18Should I go to semiconductor industry? Should I do something else? But I always wanted to have an impact for people. So what better field than trying to improve health of people? That's why I'm starting to think about how can we apply all this new emerging field of nanophysics into doing something to cure people from different disease. And I was there at the beginning of the whole story. You know, the tagline on the website there is building new therapies atom by atom. Where did this idea come from? What was the original insight? Was it back in that doctoral work? Well, I mean, technically, that's what we do.

3:58You know, we do bottom-up approach, meaning we have to start with atoms that we assemble, not one-to-one exactly, but few-to-few, in order to build those nanoparticles to have very specific physical properties. If you start from a big material, try to reduce the size, you will obtain something very different. So the ability to build complex objects, complex nanomaterial, has to come from building almost atom by atom. So that's technically what we do. Nanobiotics, it's not a new company. You were founded in 2003. You've got more than two decades now of building something that is genuinely new and really on the cutting edge.

4:42How does it feel to be at this point where you've got clinical programs, you've got a major partnership with J &J, you've just closed an 85 million euro raise as well. How does it feel to be 20 years in and hitting these sort of targets? Well, I mean, 10 years ago, I would have told you who cares. I mean, we still have so much to accomplish. But today, I'm still focused on the goal. And I think the whole team is also that we are very keen into helping millions of people. And we always look at the future in that way. But I also step back from time to time and say that the team can be proud of what they have achieved over two decades, It's building this very specific knowledge that make us unique in our industry, but also achieving step by step all the key milestones that transform an idea into a product that could be useful to people.

5:37So that's a mix of let's stay focused on the goal and also let's celebrate step by step the journey. You know, these products that are for people, most people who are working in oncology, they use the drugs that are working chemically or biologically. they bind to a target, they block a pathway. You're doing something different, and I think it's because of this physics here. Can you explain what a physics-based approach to cancer treatment actually means? Yes, you know, I think that's where we can make the biggest difference. Not that biology and chemistry is not good. I mean, obviously, it does save billions of people when you look at how important is the field we're working in.

6:21But it was something with biology. Biology is hard to scale up. It's very valuable. If you think about an individual, between two days, it could be different. The biology could be different in the morning, in the afternoon. It could be different when you're a baby, when you're an elderly. Also, two individuals are very different. And what we try to target with the biology and chemistry at some point, as you said, is a molecule somewhere that we want to interact with or a biological process. And it's very hard to be certain that you will interact in the right way with these biological pathways.

6:58Also uncertain that if this biological pathway will stay the same over time in one individual. So biology by essence is complex. Now, if you step back and think about physics, physics has something different. Physics is really reproducible, scalable, and it's the same everywhere. physics will not be influenced by the biological viability. If you think about gravity as an example, we all feel gravity, regardless of our biology. And that's true for every single human. That's also true on every planet, true for every species. So there is something constant in physics that we can use, meaning that when we develop a product, in a sense that it is a small object that is small enough to go into the body, to go at the cellular level, let's say at the biological level, but this object delivers a physical effect.

7:56So we are sure that in every single patient, it will deliver the exact same physical effect. So we have a first layer of a mode of action that is universal for every patient. It doesn't mean that the benefit would not be influenced by biology, but at least at the first level we are not influenced by the biological viability and we think that's where we can make the whole difference. This is something you've been working on like we said for more than two decades now. Were there moments early on where people pushed back against this idea of using physics in drugs and drug discovery? People said it wasn't going to work or nanotech was something separate to healthcare?

8:42Well, story of my life. I mean, not anymore, obviously, but when we started, clearly there was some question around, I mean, that's science fiction, why this should work. I mean, and why no one has done it before, that kind of things. But the more you progress, the more you show data, the more you get into what people are used to see, like clinical data or different in vitro, in vivo experiment that you can show and fit into an existing framework, then the more believer you get. And at the end of the day, the clinical benefit that you can measure into patient is the goal. And that's where you can make a difference, and that's where people start to see that it's working.

9:29I remember the first data of the phase 2-3 randomized trial in soft tissue sarcoma has been the first time for this new class of product we were showing it does work in patient. When comparing the radiation alone versus radiation plus the product, we did meet all primary and secondary endpoint. And this trial has been a critical step in our development, not only to convince the medical community, but also to get more and more investors on board. So even if you develop something really different, at the end, getting to some of the usual framework does help. Just out of interest, who are you hiring to work on these projects?

10:10And are you drawing in physicists? Are you taking biologists and teaching them something new? Who are the people who are actually doing the work? It's a mix of people. We have different chemists, biologists, engineers, physicists, physical chemists. And all together, we've been building for the past 20 years this very specific knowledge. Because you have the basic science that you need to handle, but also the interfaces of the science together. And that's where the innovation occurs. That's where the discovery occurs. that's also where we can file very broad and large patents to literally patent new fields of applications for healthcare.

10:55Let's talk a little bit about your lead program. This is MBTXR3. It's now partnered with J &J as J &J 1900. It's a radio enhancer made of hafnium oxide nanoparticles. Walk me through, what does that mean? How does it work? What happens when these particles are injected into a tumor? Maybe we should start by the goal of this product and why we've been developing this product. And I think we can again start with the patient. A diagnosis, cancer patient, for most of them, they have a local disease. They don't yet have metastasis. It's around 75 % plus of the patient diagnosed the cancer that have a local tumor.

11:39And for those patients, if you want to bring a large level of cure, you need to kill this primary tumor before it's getting to a more spread disease. Nevertheless, when you look at our industry, most of the time, people will start the last line of treatment, post every known treatment, try to make a difference here, then come back into the earlier line of treatment. But again, if you want to bring a large rate of cure, going early in treatment where the cancer is local, that's where you can have the biggest impact for cancer. And that's our target. Talking about local control or local treatment of cancer, surgery, radiation therapy are two of the big treatments, sometimes combined with chemo, with some other biological approaches.

12:29but literally radiation and surgery are really two key pillars of treatment. And if you think about radiation, it's more than 60 % of all cancer patients that are receiving radiation during their treatment, and most of the time when you have a local disease. So that's our target. If we can improve radiation and make it much more efficient, then we could potentially improve the rate of cure for patients. So how can we improve radiation? For that, maybe we need to step back and to look at what is radiation. Technically, you send ionizing radiation, but when you want to irradiate a tumor, it's surrounded by LC tissue.

13:11Therefore, sending ionizing radiation will create damage in the tumor, obviously, but also in surrounding tissue. And then you're always limited by the dose you can bring into the tumor because of those damage you're creating in the surrounding tissue. Regardless of the technology you're using, regardless of how fancy is the equipment, you don't change the fact that you have to cross LC tissue. So there is an intrinsic limitation of the dose you can deliver in the tumor, and therefore the efficacy of radiation. So the question we ask ourselves is how can we improve the dose in the tumor without changing the dose in surrounding tissue?

13:48That's what led us to develop this drug, NBTXR3 or GENG-1900, which is a small particle that is made of a crystal, afnium oxide, that we inject directly into the tumor only one time before the first session of radiation. And when those crystals, they float into the cell, the patient is getting the usual radiation therapy, but the radiation will be highly absorbed by those particles that will deliver a high quantity of damage around them and kill more cells. So that's the basic principle of what we are developing. The question for me then becomes, if it's putting all of this extra energy into the tumor, it's killing the tumor cells at a much higher rate, why doesn't the energy spill over into the healthy tissue?

14:35Is that just a function of the physics? yes when the particle absorbs the energy they will deliver their damage in a very short range you can go more than one or two cells so technically the particle will provide additional efficacy versus radiation where they are there's also this other component the immune component in the data it says you can also prime the immune system against the tumor cells beyond on that primary site. Honestly, it's one of those things that sounds almost too good to be true. Can you explain what's going on there? Sure. Well, first of all, the primary mode of action, absorbing energy, killing more cells, that's what brings a good local control.

15:21You literally kill more cells. But by killing cells, you also make visible part of the cells that are usually not visible that allow the immune system to start recognizing the tumor, getting equipped against it, and having a potential impact not only for the primary tumor, but for some metastases that are distant from the treatment. So that's something we've been showing in different clinical settings like head and neck metastatic patient or melanoma patient that are resistant to multiple line of treatment, including immunotherapy, where we clearly see the injection and irradiation in one lesion not only have an impact on this lesion but has an impact on distant lesions that haven't been treated so this head and neck cancer i think you're also looking at lung cancer these are areas where the patients can be elderly they can be more frail they're not going to tolerate really aggressive treatments including things like chemo you know did you start there because you can have that really big impact right there in the tumor well head and neck lung cancer prostate some of the breast cancer and so on all those tumors mainly start from a local perspective and that's where radiation tries to play a key role and if you improve the local treatment you may improve the pfs the survival of the patient and the quality of life head and neck is one of those tumor where local treatment is a very important thing if you want to bring cure.

16:54And looking at diagnosis of head and neck patient, it's 90 % of them are diagnosis that have a local disease. So the primary treatment is surgery when you can do it, or if you can do it, that would be radiation, either alone for frail patient or in combination with chemo. So head and neck is one of those tumors, among many others, where local treatment is so important. And we started with ZNNEC, especially frail elderly patients, because the only treatment they get is radiation. So any addition of benefit that we will show in our trial will be linked to the addition of this product. There's no crossover, no confounding factor because they don't get like immuno for most of them or chemo or other treatment after that.

17:42So we wanted to not only help this patient population, which is underserved, no one is trying to help elderly people, but wanted to make sure that what we show is due to the product, and therefore we can establish a strong clinical benefit. When it comes to head and neck, you've got your phase three registration trial, which is underway. Lung cancer, you just presented the phase two data. Where are these programs standing today? What are the milestones that you're looking for, for those head and neck and lung treatment programs? Well, in the coming year, we have a good number of key milestones.

18:22If we go backward, there's the phase three that now J &J is running in head and neck cancer. And we expect the readout of this phase three first half of next year. Before that, we should get the first outcome of the randomized phase two in lung cancer, which is a very key milestone, obviously. And even before that. We will have the completion of our pancreatic cancer trial, another in lung cancer, which is a different population than the one J &J is running for. Also melanoma cancer and esophageal cancer. So those are phase one, two that are either run by nanobiotics or MD Anderson Cancer Center.

19:06So we'll have a busy year in front of us. A busy year, an exciting year. the partnership with J &J I just want to dive into that for a second how did that relationship come about and what do they bring to the development that you couldn't do alone or didn't want to do alone I think the nature of this product is tumor agnostic patient agnostic combo agnostic so the potential for application is tremendous so at the time we started the phase we thought that it would be a good thing to find the right partner to amplify the development of this product, but also to prepare the market in order to reach much more patient, more efficiently and maximize the impact of what we do.

19:52So at the time, we've been looking at different partners in pharma, but also other type of industry. And we found out that G &G probably will be the best partner for us and for this product, not only because of the culture of the company that we like, but also the fit in terms of strategical thinking. J &J has launched a few years ago now what they call interventional oncology, which is how can we address the tumor at the local stage to have a big impact for patient. And our product, that's exactly what it does. And that's one of the strategical acts for J &J. So we had a very good strategical fit with a good culture of company.

20:34So that's why we did choose J &J. J &J is working on that asset, but maybe we could talk a little bit about your platform as well. It's the Nano Primer platform. This is quite different from the individual asset there, MBT XR3. Can you explain the problem that the Nano Primer platform is set up to solve? Sure. Here, we still try to look at an issue that our industry has. but from a different angle. And here we've been looking at some of those very innovative objects and therapies that people work on, like cell therapies, oncolytic virus, some RNA-based system, in vivo CAR-T, all those things. When you think about it, all the subjects, they share an issue.

21:26They share a limitation, which is the following. When you inject the subject IV, because they are different from what the bodies used to see, they are eliminated, sometimes close to 100%, sometimes less, by the reticuloendothelial system. So, for example, the liver is playing a key role to eliminate the subject to the point that when you inject sometimes one of the subjects, out of one million objects injected, you will find one in the target. So, you have a big loss that either brings lack of efficacy or sometimes increases the the liver toxicity, that kind of things. And it's not one product.

22:06That's literally hundreds of products that are under development, if not thousands. So the question is, shall we do like the industry is doing, which is trying to tweak the subject to make them escape the liver while they also try to optimize the pharmacokinetic, also the delivery, also the transfection in some cases. So in one object, they try to do everything. And then you make more and more compromise. So instead of going that direction, what we decided is to create a second object that we call a nanoprimer. This nanoprimer is made to be injected before the therapeutic agent, and the nanoprimer being injected IV is going into the liver, keep the liver busy for a certain amount of time, and when you inject your therapeutic object, it's going through being less captured by the liver.

22:56Therefore, you can increase circulating quantity of product and efficacy, but also reducing toxicity when it comes to liver toxicity. That's, I guess, a theory, but you had your first preclinical data presented at AACR just recently. What did the data show in this case? In that case, we had a product that allows to deliver DNA or RNA, and the idea was to improve the delivery of it in the target, but also to reduce the liver toxicity, which we did demonstrate. But at Stechnik, just one of the things we have done, we've been showing for oncolytic virus, for RNA, LNPs, for some cell therapies that by adding the nanoprimer, you can really improve the benefit-risk ratio of that.

23:51Improve it to an extent sometimes that you make possible something that is impossible without the nanoprimer. and maybe as a surrogate of the interest of industry with this technology, we today have signed more than 20 material transfer agreements when pharma and biotechs are testing this product with their product and here we're targeting oncology, CNS disorder, rare disease, some vaccine also with different type of technologies. you're describing this platform elsewhere as the next major growth engine for the company how does it sit strategically alongside drugs like mbtx r3 is this a completely separate business is it something you want to spin out or do these platforms actually reinforce each other there is something that is common with the three different platform and the last one we did not talk about is about the CNS disorder.

24:49There is something very transversal in it. It's the very specific knowledge of designing nanoparticles to interact in a certain way with the biology and can provide some physical effect that will do something good for patients. And in terms of manufacturing, regulatory development, characterization, in vitro, in vivo efficacy, there's a lot of shared knowledge across this platform. When it comes to clinical development, there we go into usual pathway with the usual demonstration of the benefit-risk ratio for patients that are very disease-oriented and less nano-oriented. So if we keep it on the business end, you keep all of these programs, the three programs, all together.

25:38You've also just closed an oversubscribed€85 million global offering I mean, this is a time where things have been a little bit difficult for the last couple of years for biotech. To have a nice fundraising like that is great. It's a real statement. Do you think that investors are confident? Is there something else that's driving their confidence? Well, I think, again, if we look at the attention around the company for the past 18 months, I think people start to see the value of what we create. Obviously, some have seen that before because they are shareholders for quite a long time. And Believer, if I think about Inverse or QIA, for example, that have been a long-term supporter of nanobiotics.

26:22But there's more and more biotech investors coming in, also some very long-term sovereign fund that we have seen joining the band. So it's time. When you do something disruptive, there are pros and cons, or at least advantage and disadvantage. The advantage is that you're alone. So you have time to bring something very established, but it takes more time. It takes more time and it takes more time to convince people that this could be useful and valuable. But little by little, we're getting there. What are you going to spend the money on? What do you do with it? Is it enabling something, a new trial or something that wasn't there before?

27:07yeah something that there was two um two purpose uh of that uh fundraising first of all is to accelerate the different platform and now we have visibility into 2029 and this without any milestone payment or revenues coming from jnj so we have time to build not being dependent on the money coming in from J &J, but more importantly is to accelerate what we are doing, like the development of the nanoprimer and some other projects that are cooking. Let's zoom out for a second. If NBTX-RF3, if it achieves what you hope it's going to do across these different tumor types, head and neck and lung, what does it mean for roughly half of the cancer patients in the world who are getting that radiotherapy?

27:58Like you said, how does their world look? What does the treatment landscape look like? Well, first of all, I think that would be a very good thing for patients if we can bring more cure with radiation therapy. But think about it. It's 60 % of all cancer patients getting radiation. So let's say out of the 20 million diagnosed every year, that's around 12 million. So it'll be hard with just one company and one product to address 12 million patients, even a tenth of it. If you think of NTPD-1 as an example and the Merck product, I think just recently hit the 2 million patients, but after more than 10 years of usage into clinic.

28:42So that will help patients, at least part of them. But in any case, for us, it means that it will, first of all, validate the concept, the overall concept of using nanophysics and helping patients with that. that will also bring a large quantity of revenues for nanobiotics and sustainable revenue that will allow us to develop many, many other things in our pipeline. Like you say, getting people just to understand that nanophysics is an approach because it's still sort of a niche idea or a small idea in the field. But do you feel like that's starting to change? Are you starting to get the recognition that you think it deserves?

29:23well that that would be for the world to judge but we continue our work and we see more and more people working on that there's more and more academic work also so it takes time if you think about biotech itself between the first concept of biotech the few first companies and where it is now it has been a few decades to get there so we think with nanophysics we we can also create a new industry that is not in competition with the biotech industry per se but i will bring new type new class of product to to patients and finally for people who want to learn a little bit more about nanophysics or nanobiotics where can they go to learn more where's the best place that they can go to follow your progress well i think there's two big differences i mean two places here all the medical conference.

30:18If we think about oncology, we are often at ASCO, ESMO, but also Astro and Estro, which are the radiation equivalent of ASCO and ESMO. And then for all the investor field, we go to many conferences like the Jeffreys or the JP Morgan and many others every year. So we'll be happy to meet people that want to learn more about what we do. That sounds great. I'm sure you'll have people lining up, Laurent. thank you for joining us today on beyond biotech thank you that's it for this episode don't forget to check out all the latest news and analysis at labiotech.eu i hope wherever you are in the world you have a great week ahead thanks for listening and i hope you'll join us again next time for another Beyond Biotech.