Laurent Levy, Nanobiotix 🇫🇷 | Nanoparticles, Radiotherapy | E45

When you look at our industry, it's a lot about biology and chemistry. And we thought that we should bring something different in the game. Not just to be different, but because we think there's many people and enough people working on biology and chemistry and not enough people working on the physics side of things. So the key question is how do we improve the dose in the tumor without improving the dose in surrounding tissue. So when those particles in the cell the patient is getting the usual X-ray, the particle will absorb the energy of X-ray and will deliver much more damage like how often you had to reinvent yourself. It's not always an easy task because if you did something that was really useful in the past, to understand first that may not be the best thing for the future and to actually apply it requires some internal motion. That's what makes this venture very interesting.

Thank you.

Yeah, it's been a while, isn't it?

Well, I think we feel just as we felt before. I think until we reach our goal which is to be able to treat millions of patients and really help and make a change, we just continue our journey and what I told to the team is you know when we are really low in market cap we just continue to work and continue to deliver what we have to deliver, then we should do it even when the market cap is higher. At this stage we don't think that's the best surrogate of what we are.

I think we look at this results as an add-on to everything else we've been showing. And starting with the first randomized trial we have done in soft tissue sarcoma which was really the basis to show that our product is working. When you compare the standard of care versus the standard of care plus our product and you see a delta, a significant delta, and you hit all the primary and secondary endpoints, that's really what established the basis for this product. And then every other trial we've been running has added some more things about efficacy and safety and feasibility, just opening and opening the potential for this product.

Well, I think this deck was fun for two reasons. And there was the first deck we used to pitch the story to investors like more than 20 years ago. And what is good is the goal did not change and the goal never changed at Nano. But the way to reach the goal has been changing because you have to adapt as a small biotech and even as a biotech to make sure you can continue to survive, continue to develop and bring new things. And it is really rare to know exactly which pathway you're going to take when you start the company. So that's completely untrue from a pathway perspective but 100% accurate from a goal perspective and from a vision, I guess.

Yeah, maybe we can talk about the fundamentals of what we are doing. I think when we say we do nano physics applied to healthcare, that's one way of looking at it but more fundamentally, when you look at our industry, it's a lot about biology and chemistry and how do you bring something that will interact with the biology of the body to produce an effect. That's the basis for most of the development we have in the biotech and pharma companies. We thought that we should bring something different in the game. Not just to be different, but because we think there's many people and enough people working on biology and chemistry and not enough people working on the physics side of things. So we decided to see how can we bring something new and for that looking at a cell not from a biological perspective but from a physical perspective. And when you start doing so, you don't see like a molecule you want to target with a drug. You start seeing the cell from a different perspective and you can redefine the notion of target. And then you can start developing small objects that will interact with the physics of the cells. And when you do that, you can have product that could be useful across all variability of biology. And maybe we talk about that later, but for me that's a big fundamental thing that is shaping our industry, probability of success. And if you can develop technologies that move this probability of success, then that's opening many doors.

Yes, it was from the beginning even when I was doing my PhD I should say working on the nano physics at that time I thought that if we could change the way a cell can feel the physics then that will open many many doors.

And I think that's the first product we have. We have other platform that we can talk about but from this perspective maybe we can go back to what is the need we're trying to solve. We made an observation which is a very basic one: at the time of diagnosis, cancer patients most of them have a local disease even before having metastases. If there are so many patients having metastasis, it's because a lot of local treatments will fail. Our industry usually is taking care of those patients having metastasis, last line of treatment, try to bring new drugs and eventually if it works then try to go to the early lines. But if we think about patients, if you can cure them at the stage where they have a local cancer, then you'll have a big impact. But for that then you need to go back to fundamentals of oncology which are surgery and radiation therapy and some chemo. So those are the pillars that are treating patients front line when they have a local disease and we have targeted radiation. Radiation is probably one of the biggest tools used in oncology; more than 60% of patients will get radiation. Radiation basically you send X-rays that will go through the body and through the tumor and you will deposit some dose that will kill the tumor. And the problem is it's a very powerful technique meaning you put a cell you will find a dose of radiation to kill it regardless of the cell. And your side effects – the thing is because the tumor is surrounded by healthy tissue, you are always limited by the dose you can deliver in the tumor because you're creating damage in the surrounding tissue. So the key question is how do we improve the dose in the tumor without improving the dose in surrounding tissue and we've been developing a product to exactly answer that question. So those are nanoparticles that we inject directly into the tumor and those particles have been designed with a very specific material to be the most inert possible but also to be a super strong X-ray absorber. So when those particles in the cell, the patient is getting the usual X-ray, the particle will absorb the energy of X-ray and will deliver much more damage than the radiation alone can do.

That's one of the possibilities but not always the possibility. I mean basically if you can remove a tumor by surgery you try to do it because that's a big benefit for the patient but many patients and majority of patients depending on the indication will come with a locally advanced tumor that you cannot remove by surgery. Then that's where radiation will play a similar role in trying to sterilize the tumor and kill the tumor and often used alone or in combination with chemo or some other molecules.

I think not really. Surgery and radiation therapy are deeply rooted in the treatment paradigm. You cannot just remove one strong technology to replace it by something else. So that's true what you're mentioning about all those drugs they are complementary. And most of the drugs that you are mentioning they're also starting last line of treatment and if they come back into front line usually they add to what existing already front line. If not that will mean that you have to reshape the entire way patients are treated. And if you go back front line and you want to see if you can replace one of this old wellestablished technology and treatment, the time to get some endpoint or the risk you may bring the patient into is really big.

Yeah.

No, did not change. That's a conclusion. But what we can say maybe is if we improve the way we diagnose cancer to be more proactive in the way we can prevent cancer, there will be more and more patients that will be diagnosed with a local disease way before it can become metastatic and therefore local treatment is going to continue to play a key role in the treatment.

Yeah, maybe there is a misunderstanding of what early means and what late stage in the sense that it's not because you treat patients early that they don't have a high unmet medical need. If I for example take the example of head and neck, the vast majority of patients 90% of head and neck cancer patients they have local disease at diagnosis. The ones that have a small disease like small tumor can go for surgery, they are the ones having the better outcome. So they get surgery plus minus radiation and chemo as an adjuvant treatment and they usually have a good outcome. There's still few relapse here. The vast majority of patients will get either radiation plus chemo or radiation alone depending on how frail they are. And for those patients there will be more overall 60% of the patients that will relapse over time so it means that they have a need to get a much better local control. And if I think for example about the frail elderly patients, the ones we are treating in our ongoing phase three, what they need is local control and if you look at the literature, you should expect for those patients a median overall survival of 12 months, which is not that big. So if you take OS as an endpoint, then it's not that long to get an answer.

Well, first of all, now J&J the partner we have for this drug is running the phase three and also other programs. But initially we've been testing in head and neck because we thought first of all that's an indication where patients have a big need. There is a big number of patients with local disease and head and neck could be a good surrogate of what's happening in another indication. Also head and neck being an indication which is less competitive than other like lung and some other at least at the time we started it would be addressable for a small company like we were in the past when we started this trial. But basically what we wanted to prove and what we still want to prove with head and neck and other tumors is you take the patient after diagnosis they have local disease. If you can bring a good local control in the number of CR complete responses then you will improve the PFS and the overall survival for patients. This correlation exists for local tumors much more than what you can find in the metastatic disease.

Yeah.

Well I think first if we look at the fact today we've been treating hundreds of patients across different indications. So we've been injecting patients in head and neck in sarcoma in rectum in lung in hepatocellular cancer in esophageal and some other tumors. So it's feasible and I think that there's like some kind of fantasy around intratumoral injection. If you look from an oncology perspective, it's something that hasn't been developed a lot because what we were saying previously, we try to treat a metastatic disease. So it's going to be hard to treat a metastatic disease with a local injection. So when you first look at oncology it's IV injection and then you try to get a systemic effect but for local treatment which is what the vast majority of patients need after diagnosis, local approach makes a lot of sense and it's not something new. If you think about biopsy, we do biopsy for most of the tumor and the way to position a needle when you're going to make a biopsy could be the exact same path where you're going to use to make an intratumoral injection. So it's more about who's doing what in the hospital. Is it the surgeon? Is it the interventional radiologist? How do you position the product and the practice with it? What exists in the hospital?

Yes, for sure. And we can see that globally intratumoral approach in oncology is something that really increased and has increased a lot over the past 10 years.

Well I think first maybe this was to go back in time. So at the time we did our IPO on the NASDAQ. Things were moving in the right direction. The market was good. People could find money and continue to develop. But rapidly at the end of the COVID period, we've seen the biotech market crashing and a little and we thought that with the lack of visibility about the market, it's going to be hard to predict how much we can continue to grow and develop the company and finance the company with an asset in phase three. So that's where we decided as we can't plan and anticipate the market, let's find a partner because you didn't partner before. Yeah, correct. We did partner but from a local perspective we had this deal with Lian Bio for China and some other countries but globally the product was not partnered. And then at that time we started looking to different partners and we said no to some of the partners because we thought they were not the right match in terms of strategy and values for the company. But then we discussed with J&J teams and not only we share this vision of treating patients early in oncology would be of a great benefit for them but also we like the people we've been talking to and the philosophy and the values of those people. So altogether we brought this deal to life.

And you mentioned the 30 million upfront but we should go back in time to understand why. At the time we were negotiating this deal we were a sub-100 million market cap company so it was really hard to negotiate a high upfront without triggering like a bid discussion or that kind of things and as a company we felt there's much more value to create and that's point one. Point two I think when you look at the potential of the product and what we believe is the potential of the product we did establish a deal which is backloaded to make sure we can capture what we think is the biggest value of this product which is helping potentially millions of patients with radiation therapy. And also we did structure this deal a little differently because there was the 30 million upfront, there was 30 million in equity, there was also some short-term milestones that were planned and there was some in-kind contribution also from J&J. So altogether that was a much bigger deal.

Our vision about this approach of using radio enhancer in oncology is if you use a physical mode of action at least from a primary mode of action perspective then it is something you can apply broadly into patients right and that's why we started doing it and we hope that's why also J&J will continue to do. But the fundamental of this and I want to come back to some of the comments I was doing about biology and chemistry is when you think about it, when you inject a product like a biological product in a patient, you never know if the target is going to be rich, you never know if the target is fully present in the patient and you never know, for example, in oncology if the target will be expressed in every cancer cell or if the target is not going to increase then decrease and that's why we see so many resistance appearing in some of the cancer treatment and so on. It means that the mode of action you're using with sometimes the biological molecule is uncertain depending on where the patient is sitting and which patient you are treating. If you use a physical mode of action you don't have all this variability. So at the very basic level you have a product that could work in every patient. It doesn't mean that you will bring the same benefit for all patients because they have their own biology. But at a primary level, you have a mode of action that could work for all patients and that makes a big difference when you think about probability of success when you think about universality.

And that's what we see with radiation, right? We don't screen patients to see if they express a specific biomarker before getting to radiation.

From now that's J&J that is going to communicate on that product especially the advanced program but Nanobiotics continues to run some of the programs like in combination with PD1 and radiation in head and neck and we also have a big alliance with MD Anderson Cancer Center that are running. So from now on we'll continue to talk about what we are running and J&J will start communicate on what they do as they do usually.