Sanofi (SAN) Earnings Call Transcript & Summary

Good morning to those of you in the U.S. Good afternoon to those in Europe, and good evening to those of you in Asia. I'm Peter Verdult and on behalf of Citi's Global Healthcare team delighted to introduce our next speaker Giovanni Abbadessa. He heads up Oncology Early Development at Sanofi and is the global project head for SAR'245 the non-alpha IL-2 program. As I always say on these events, I'm here to moderate the next sort of 55 minutes rather than monopolize. It's not an open line forum, but there is a chat room functionality on your webinar. So I'll be keeping an eye out if you have any questions you want me to put through to Giovanni, just use that functionality. Now one thing I'll just address straight away as I'm sure many of you have questions on upcoming and [indiscernible] data, but this is not the forum for those questions. And I think the only update from Sanofi is what we said previously that we're expecting the data in Q1. So with all those formalities done and without further ado, Giovanni, maybe over to you. I know you have a few slides before that because this would probably be the first time that many people are meeting you. Perhaps you could give a bit more of an introduction of yourself and introduce yourself, and then we'll go through the slides and then the Q&A. So over to you, Giovanni. Thank you very much.

Yes. Good morning, Peter, and good afternoon. And thanks for having me at this summit today. It's a pleasure for me to share some insights into Sanofi's early development programs in oncology. As a background, I'm an oncologist by training, I then enrolled in PhD in genetic oncology, while I was working in a lab in Philadelphia, and I moved to industry in 2007. After a few roles, leading roles in small biotechs, both in development and in preclinical research, the last one at ArQule. I joined Sanofi where since late 2019, I lead the oncology early development team. My focus is any non-myeloma oncology asset in the pipeline prior to proof of concept. And together with my team, we're also actively engaging in the progress of experimental drugs at earlier research stages. I'll give you some introduction about our pipeline, early development pipeline here. Can you see my screen?

Yes.

So my comments obviously may contain some forward-looking statements. So please take a note of this standard disclaimer. As you will remember, Sanofi strategy to succeed in oncology is based on 3 pillars: building on recent launches, such as for refractory multiple myeloma and Libtayo for non-melanoma skin cancers and for lung cancer; second, expanding on what we believe will be the next generation of standard of care backbones, such as amcenestrant, tusamitamab and SAR'245; and third, driving innovation by leveraging new technologies and our momentum keeps growing. At the end of 2019, when I was tasked with building a strong early development portfolio in light of strategic focus, our new strategic focus for Sanofi in oncology, we just had 5 ongoing Phase I, Phase Ib clinical projects on hand. The shift towards a truly innovation-driven company have been already initiated, but the oncology early development portfolio was pretty different from what we'll discuss today. Today, with 11 drugs in the clinic, and our ambition to bring up to 4 more molecules in development to patients this year, I think Sanofi oncology pipeline looks much more promising than any time in the recent past. In fact, I think this is one of the most interesting early pipelines in the industry, not just by the numbers but also in terms of diversification of technologies and mechanisms of actions being pursued. In particular, we are uniquely positioned to leverage both the T cells and the NK cell mediated antitumor activity with multiple assets that can play those roles. We have modalities and tools to strengthen our mid- to late-stage pipeline and to collaborate directly with any external partner and even in the future to strive for innovative proprietary combinations. Now the pipeline we have today, it's really the work of -- hard work over the last 2 years by a number of skills colleagues and team members, both in terms of what we call the 'what' and the 'how', meaning technical and soft aspect of our work. Each of our project teams is constantly challenged by the ambition to accelerate development, effective resource allocation, careful assessment of what's best for the patients with upfront criteria for stop or go that are followed rigorously by all new functions and which enable regular reassessment and refocus of prioritization, which for other development is today, in today's environment is really key, I think. Also, what changed is that clinical input is now given very early in the life project before a drug candidate is selected, and at the same time, translational teams are embedded in the clinical conduct of trials. All of this is only possible because there's a radical commitment to a solid how and I stress the how break silence, gain trust, collaborate, assess data honestly, communicate transparently, learn from each other and everybody in the team staying humble while being hungry. These are at the core of our development team, which is today, substantially more powerful than it used to be in 2019, and it keeps growing. And I believe this is a great foundation to drive innovation and growth but also to make them sustainable for the longer-term success. So I hope you can see what drives my ambition to grow Sanofi's early development pipeline in oncology and to bring first-in-class and best-in-class therapies to patients rapidly. I think the experience that I gather from key roles over 10 years in small biotics, makes me feel privileged to be an active part of this type of transformation. And of course, excited to be where I am, sharing this journey with people I'm blessed to work with every day. And I'll open up for questions now.

Thank you again. So before we dive into the weeds that perhaps -- let's just stay on that topic, which is, I'm sure you're aware of this that Sanofi did have a legacy in oncology. It hasn't been a player in oncology. And since the new strategy came out, the company is clearly over delivered on many metrics. But if you ask many investors, the big question mark still is, how Sanofi -- has Sanofi improved that kind of improved its R&D productivity? And of course, that kind of really be answered with clinical data. So we're at this point now where we're about to see a lot more data coming from the oncology portfolio. And I think you've already talked a bit about some of the processes that have changed in the time that you've been at Sanofi. But if we do assume that there's a degree of skepticism out there, what would you point to in terms of particularly that you've seen changing in the last couple of years? How you go about development? Is it personnel? Or is it just a process that you alluded to from your opening remarks? Or is it the quality of assets that you have acquired plus what are you bringing internally? Just a bit more about what the -- what's changed in your view in Sanofi oncology development?

Look, I think that 2 things go together, the what and how the personnel process -- actually 3 things: personnel process and then the quality of the drugs. You can't have high quality of drugs if you don't have -- well, you can acquire always a good quality drug, but then to drive them through and make these innovations sustainable, you need good processes and good how, good personnel. And yes, of course, again, as I showed you before, 2019, Sanofi oncology pipeline was limited. I truly think the people and not just in terms of skills but in terms of culture, can make all the difference. And that's what actually -- that's what drove me after 10 years is in biotech to take that challenge in 2019. Working for so long, different roles maybe -- having worked with people coming from large pharma is, maybe be always skeptical, in general, of some large pharmas where silos and factors that are not maybe science-driven with influence than what they were doing for the patients. So the ability to build an early development team from scratch, and the team is now composed of over 25 people, and we have several positions open, allowed me to embed the collaborative and productive culture into the team. When you have so many skilled team members and each one brings a different background and their different cultural background and professional background, you generate a collective knowledge and expertise, which is really hard to find already made. And that is -- we're already seeing the benefit of that because the new drugs that we bring into the clinic now benefit of learnings from other projects and other people and the quality of the work being done is substantially better. So your question is what makes me believe in this? Sure. We have improved the quality of the assets. But I think for the mid and long term, I believe in this because of the people that we have and the leadership guidance that we have.

Got it. Okay. Let's get our hands dirty with the products. And then we've already realized that there's not really much new to say or additional sale on Amcenestrant in the AMEERA-3. But the CEACAM5 ADC. It's on the horizon. I just wouldn't want to get a sense of, I think mono and combo data with pembro. I just want to get a sense of your involvement in that program, how you're thinking about the readout, what profile you're looking for and level of excitement into that data readout?

Well, so I oversee early development of proof of concept. Tusa which makes it easier to pronounce, is in a late-stage path now. When a product or drug goes to a stage, we set up team with the project head and so on. And I'm not the person head of Tusa. There's a very smart colleague who is and it wouldn't be fair for me to steal his thunder and talk about it with you. But in terms of the target, which is relevant for also maybe our future plans. CEACAM5 is an interesting target. It is expressed by lung, gastric, colon. And so depending on the -- on how you tackle it, it can be a very precious one. So Tusa is, of course, the drug I think, the target is relevant. Let's see how the late-stage trials go.

Okay. Well, let's move in quickly to something that is close to your heart, the non-alpha IL-2. I mean, I believe there's a 300-patient basket study. I mean, if you think about pools take there's sort of big deal that was announced along with the CMD 2 years ago since , we're now going to see the first data. So can you again outline the data, what data readouts we expect to see this year? And then if I could layer on top, speaking to -- or Genmab had their results, their quarterly results last night. They mentioned a recent change in FDA guidelines. I realize it's not a small late-stage development, but FDA now acquiring the drugs of interest in oncology, once you've done your dose escalation. If you then want to subsequently move into combination studies like you're probably going to do with , the FDA now wants more dates or at least some combination data at lower doses before they will sign up for moving into Phase III. So just can we talk about the data of the program as of today and the future development and the path you're going to take it through as it relates to combinations of this?

Yes. I mean what you're mentioning now, I'm glad the Genmab press released it, but it's an FDA guidance that has been out for a while. They've had multiple interactions. You can imagine, given now the number of assets that we have, and we've been well aware that you need to have an established a combination dose before moving to a Phase III. They are asking, in fact -- besides that, they're asking the companies meet with them to discuss the combination dose before you move to Phase III. So maybe a couple of things. SAR'245, THOR-707 is now -- from the get go, it's been a high priority for our company because it's -- we believe it's a best-in-class. And so I remember, we were at ASH in Atlanta when the acquisition deal was signed -- with John, and we had the discussion about how we really had to plan big and bold for these assets given the qualities. So you mentioned the 300 patients. I think -- maybe if you look at the SITC poster from November and clinical trials, you realize that there's a potential for something even bigger than that, and that's coming. And as a result, we recently appointed also a new GPH for the asset. There's -- I wouldn't say they are basket trials, I would call them platform studies because we're -- so in the spirit of laying the groundwork for being confident when we move to Phase III, besides the FDA request for those, what we've done for the last 2 years is designing in another way of allowing a project to have multiple statistically independent cohorts, where you test both novel combinations and novel indications, that's why platform rather than basket. And you can slow down or accelerate based on a continuous assessment of performance independent for all the cohorts. So you've noticed how we have gone from acquiring a Phase I drug with few patients treated to very rapidly enrolling -- in that Phase I study, both monotherapy and multiple doses in combination with cetuximab combination with pembrolizumab and then just this year already launching 5 platform studies: one in skin cancers, first line melanoma and CSCC; one in lung cancer and mesothelioma. And in lung cancer, that gives you the idea of how thorough groundwork we're doing. The lung cancer study has independent cohorts for PD-1 progressors, chemo-free, chemo combo, PD-L1 high, PD-L1 low. Each subset of population is being tested independently. So we're really going to have a strong confidence when we decide which one to move fast to Phase III or who knows? Maybe -- let's see, for the post PD-1 indications, you can imagine if you can make a good response rate and rational response with a chemo-free or a minimal chemo combination that could be very beneficial for patients. We're doing the same type of approach for head and neck cancers, gastric, post-PD-1 HCC, colorectal and recently on clinical trial lymphomas. So you've seen also at SITC, we presented an update from our AACR poster with the drug. And you must have seen how, unlike other IL-2s, this one -- well, first of all, it has one PEGylation only, and we were able to dose it up to 40-microgram a kilo which is still well tolerated, so the escalation continues, by the way. And we're able to see expansion of NK cells and T cells, the poster shows you up to 28 fold in NK cells. That's without major toxicities, that gives us a lot of confidence in this drug.

I realize that it's a bit unfair me asking this because it's a function of obviously getting the data and getting it accepted for presentation at scientific congresses. But the question is going to come in already about just what data do you expect to be able to show the market -- everything is according to your plan, what data we'll be able to show the market this year? And is there any -- are you saying that there will be Phase III enabling data this year? Or do we need to be a bit more patient before we can get more excited on THOR707?

I think the place I see today is different than when I was in a small biotech where we needed to release data continuously to keep the stock going, right? I think here, when you have this such a valuable asset and there's competition. And I do pray that the most advanced competitor keeps giving good results because it's a validation of the target. But with such competition out there and such value of the drug, I think the most important thing for us is to prioritize our choices before making them public. And so I do think we're going to get some possibility to assess initially on initial subsets of patients -- assess some of this activity, but I'm not sure it's in our best interest to tell everyone what we're going to do before we are ready to launch the next step, right? This is -- we have over 25 cohorts open with this project. And as I said, we do continuous assessment of efficacy so that we can stop or accelerate each one. And it's not just the matter very important to me and that's what I'm so proud of being in this organization today. It's a matter of doing the right thing for the patients. You don't want to keep treating patients with an experimental combination. That is not the best you can offer them. If you're asked today, lung cancer patients have lots of options, and there's drugs that work. I'm just giving lung cancer as an example. So if you -- I think it's our duty to continuously check and allow those patients to go on something else if we don't think that, that particular cohort is the best one. But that also means that with this environment and how fast things are moving, it is also our responsibility for our drugs to move as fast as possible as soon as we see a signal. And I don't think it's in our best interest to tell people that in 8 months, we're going to do a Phase III trials, right? Let's tell people once we're actually ready to launch it. So I don't know if we're going to make public something this year. We are assessing every month or more the activity, and let's see how it goes.

Sorry for being a dog with the bone, are you saying that we should not expect any data of note from this program this year -- or are you saying we'll decide you keep your cards close to your chest, but I just want to understand, I mean, should investors expect anything this year? I know you don't want to talk about what, but just the high-level question, won't there be any incremental data from this program that should?

There will be incremental data that we will see. Sharing it depends on which cohort, right? Because if it's a cohort where there's less competition and we can move fast to expand, it's a different thing than if it's -- let's say, a first line lung cancer cohort where you need to plan a big Phase III and there's a lot of competition. So -- and if I had the crystal ball and was able to predict which cohort will succeed, then we wouldn't need to run the experiment. So I don't know which cohort is more likely to give results this year. I think we have to wait. And that really is in the best interest of the patients, the drug and maybe even the investors, right? Because if we mess up the Phase III plan, then it's a major problem.

And then in terms of understanding, I mean, the sort of mindset from your team, you alluded earlier that you're not the only ILT player out there and you're not in the lead. Given the engineering, given the sort of [indiscernible] platform, is it about tolerability that you think you can differentiate? Or are you arguing that you can differentiate on both efficacy and tolerability. Just the sort of target profile you're seeking and how you sort of answered the question well, you're not first in class here. So why should we give this asset a particular amount of credit? Just how you sort of talk -- think about the asset in the competitive landscape?

Yes, I think you said 2 relevant things. The first is, we're not the first. And the other one is, is it going to be differentiated based on efficacy therapy. True it is not the first-in-class, and that's actually what makes us more confident about the agent because we think it's a best-in-class. But the amount of planning, which is this year now finally showing in the starting of the execution shows you, we can be first in a number of indications. We're testing this drug in combination with cetuximab in colorectal cancer, I haven't seen that. And post PD-1 HCC, I haven't seen it. In PD-1 low gastric, I don't think we're going to be second to anyone there. So again, I am very happy that some other IL-2s are showing good efficacy in melanoma with a dose of 6 microgram a kilo. One of my favorite mentors keeps reminding me, it's all about the dose, and there's also a song about it and the ability -- having worked on a few drugs and as multi kinase inhibitors, where your window of efficacy and safety small -- having the ability to dose a 40-microgram a kilo, which all includes 1 PEGylation. I keep reminding that and being well tolerated and having efficacy at 8-microgram a kilo when combined with PD-1. And as we anticipated in the AACR poster, assuming we have a Phase II dose of 24, that allows you a margin of between -- window, which I've read about for years for other drugs. It allows you -- see, today, it's not only about the response rate. That's the quick assessment that allows you to believe in the drug and go forward, but you need to go for the long run because patients have many options. So you want the patient to tolerate your drug for over a year. And today, we have patients on THOR707 in combination with pembro or monotherapy who have been well tolerated in the drug for over a year and they're doing well. So that gives me -- so the safety profile, the dose that we're able to give and the initial efficacy -- they all go together and they're a very powerful hope. And when you think that we've done all that groundwork and now we're over 25 cohorts testing this drug in multiple combinations and indications, I think that's the way you plan an important immuno-oncology agent today, and we're doing that. And I don't know if this would have been possible 3 years ago at Sanofi, but it is today.

Got it. Okay. I'm going to move on now. And I'm going to ask a question on your SHP2 because we've seen some initial monotherapy data. It hasn't set the world on light, but there are combo studies ongoing. I also had a question from a client, which I'm going to read out to you. What is Giovanni's view on developments and the unmet need in the KRAS RAS mutation space at this point? And what is Sanofi doing in this area? So perhaps we can combine that sort of discussion in terms of the whole KRAS RAS space, lung and your SHP2 -- whether your infusion for that program is increasing or not and future plans? So hope you don't mind me just throwing on your plate.

No, that goes well together. Thank you. So if you look at -- if you just Google the SHP2 picture and you see where it falls, it falls under so many pathways each [indiscernible], EGFR, VEGFR, PI3K, MEC, KRAS. There's many packages that can involve SHP2. And when having worked with small molecules in the past, when a target is so promiscuous means, it has, of course, a key role, but it makes it a little bit harder to understand which one is the best combination, the best partner target to it. KRAS seems to be, at this point, the most hopeful one. And -- but I wouldn't discount the idea of PD-1s combining. So what we've been designing already over a year ago and now getting into execution is, again, a wide catch but with independent ways of accelerating or stopping where we have Amgen, and Amgen collaboration where Amgen is testing this SHP2 inhibitor in combination with AMG510 in their own study. We have a study that just started at the end of last year and enrolled first patient round by Revolution Medicine, our partner, where we're combining the SHP2 with the AMG510 with the call of accelerating the enrollment in that setting. And then Sanofi has already initiated a year ago, a combination core with PD-1. We know that SHP2 inhibition changes in the immune filtration. And so -- but we've planned that cohort with long-term plans to then test also a [ kinase ] combination and potentially if we have a good signal, expand with both. So then -- what happened is last year, as we press released, I think, in October, we were able to strike a partnership with Mirati as well. Their KRAS may be a little bit different from the Amgen one. And I think it's just fair to test the SHP2 with either one to see which one combines better. So we will soon be launching a Sanofi run KRAS, Mirati combination KRAS in the same study where we have the PD-1 combination, which then would allow us to expand even further. So yes, I think the KRAS pathway is the one to pursue, probably with this type of drug, at least with the data we have at hand at the moment, and we're running multiple options so that we're going to be best positioned later this year to know which one does better.

I just come back to a comment -- a passing comment you just play in treatment. You said there may be differences between the 2 KRAS, the Mirati and the Amgen compound. Could you expand on that a little bit?

First, you wanted to get me into fight with my friend who runs Tusa. Now you want me to get myself between Mirati and Amgen.

Just to help a general comment. I don't want definitely that would be trouble. I do want to make a...

Yes. I only know what each company says, right? And then what the 2 companies publicly say is that their drugs act differently based on the confirmation and when they hit the target. And we've seen data presented recently, Mirati showed some very nice activity in colorectal. So outside maybe also lung cancer, that's another avenue. With lung cancer, it's going to be really hard to know how to compare with each other. Once you have a 40% response rate, you need quite a number of patients to establish if one is better than the other. So maybe there, we're going to go back to a safety question, which drug will be better tolerated in the long term for patients. Because again, if you have a 40% response rate, you expect 40% of those patients to stay quite a bit on the drug possibly. So the one that will be better tolerated maybe will stay there for longer. But that's going to take a while to understand. That's why we really want to test our SHP2 inhibitor with both.

And I don't want to get into fight with me. But when it comes to the monotherapy data that we've seen, I mean, the market was hardly -- didn't set the world alight. So how would you -- given that again, the SHP2 space is also competitive. What do you say to the doubters out there that say, well, why should I get excited about Sanofi SHP2 versus the competition? What would you point to? And then also, when -- as I asked you on the IL-2 program, can you just give us or sketch for us like a time line for incremental data?

So we have presented in posters a partial response in the lung cancer KRAS mutant patient with monotherapy and a partial response in an non F1 loss function with monotherapy. I'm not -- unless I missed it, I haven't seen responses from other SHP2 inhibitors as monotherapy. So if you're comparing with that -- yes, one response, of course, doesn't change the world. But the point is not having responses as monotherapy with this particular target, which is so promiscuous and triggered by so many redundant pathways, yes, I think we're going to get used for the next years to see drugs that are not going to change the world as monotherapy. Because the standard of care is fortunately for patients so much better than when I entered my oncology fellowship in 2001, that now you need something really strong to make a difference. And that's the challenge for developers, especially in immuno-oncology, you need to invest in bigger testings and combinations to get it through. So not great activity in monotherapy. It's not -- I don't think it's the end of the world. As monotherapy, there's a lot of nice preclinical data showing the drug is active. And in terms of the signals that we have so far, I think, again, combination with KRAS, I think we have better chances. Will we have enough data to present this year? Possibly. The complication here in knowing when -- see, again, the most important thing to me, this is early development. And early development has to work to set the ground for a late-stage program. And the most important thing is to make the right decisions, a listed in this side of a company, then public disclosures will come. The decisions to -- about what to do next is going to be a little bit more complex here because it's going to come from a mix of data from 3 different studies, right? That could allow us to accelerate that decision. We're in a good position there. But of course, you're not going to present the poster with 3 different studies and 2 sponsors -- 3 sponsors, right? So to present the poster you need data from 1 study -- and yes, maybe I don't know if by the end of this year, we're going to have data from one study that allows -- what matters to me most is that I do think that we're going to -- the work that we're doing will enable us to have data for internal planning, which is solid and coming from multiple studies, multiple sponsors. So it's, again, data that we can trust.

And would it be fair, I think you mentioned earlier in your comments that is the PD-1 combo study has been going on for over a year. If we are going to see any data, is it most likely to be that data rather than the combo data with Amgen or Mirati?

Right. So that was -- so we started as a dose escalation. As you say, the FDA does like to see that your dose is well tolerated when you put it in combination. So that's why it's been going on -- well, we planned it over a year ago. The study didn't start over a year ago. So there's a -- we have to see. Again, I don't want to open the chest before we make our own decisions. But you're right, that study has the chance of giving a list data on the safety and tolerability of the combination earlier than others.

Got it. All right. So we're now 40 minutes in. Again, remember if you have any further questions, just keep them coming. I want to now move on to some of the platforms that have been acquired since 2019 and the strategy on , the Kiadis [indiscernible] NK cells, Tidal, in vivo cell therapy -- I mean obviously been a successful COVID developer with Pfizer, but it also seems to great science and collaborations with a number of companies, including Sanofi. But at the same time, I realize the platforms are exciting, but we haven't really got any sort of huge amounts of data. So perhaps you could just talk about -- I mean, are you equally excited about all 3 of those platforms or just give us a run-through how deploying those technologies and platforms, your level of excitement. And again, when we might see what are the plans to harness these technologies when might we see data from any of these 3 platforms his Kiadis, the NK cell therapy, Tidal in vivo mRNA and the BioNTech, cytokine RNA programs as well?

Sorry, you say Tidal, Kiadis and the third one?

BioNTech. The BioNTech.

BioNTech.

BioNTech. Pardon my accent. Sorry.

Yes. No, I also have a static accent. So Kiadis -- so BioNTech is, of course, great science, and I think we're all grateful. The entire board is grateful to them a Moderna for maybe a good part to do this great to them and Moderna for what they've done. For oncology, mRNA, it's an interesting way to do things. And of course, Tidal is another type of approach. With -- that our partnership with BioNTech is focused on intra-tumor injection of mRNA. So it's a local approach. And we've done a dose escalation and then combination with PD-1, cemiplimab and we're now in an expansion phase. So we'll see how that works. There was a SITC session dedicated to local regional therapies at the end of last year, which was very relevant, I think, for all these things. And I think the classical way -- you can't apply to original approach, the same philosophy that you apply to systemic approach. So I think there's geographical and logistical considerations there, but of course, the mRNA approach is something really interesting. The Tidal 1, in fact, is -- well, it's the Tidal 1, by the way, it's still early. So not yet coming to the clinic this moment. That gives a lot of hope, the possibility of modifying cells by injecting mRNA into a body, a patient, makes it so much easier and most likely less traumatic, less toxic than a CAR-T approach where you have to get the cells out and in. So that's -- very promising. The NK cells from Kiadis is, I think, getting there in a different way. And we've integrated a good number of people from Kiadis, the really nice colleagues to work with, and they've done quite some nice work, which now our focus is on expanding that and getting it to friction. What they've managed to do is to make it possible to do a cell therapy and do it off the shelf. So you not only don't have the logistical complications of having to extract cells from patients, not define and put them back. You can store them and then ship them wherever. But also it keeps -- it should give more efficacy than autologous cells. These cells are taken from healthy adult donors. They're not taken from cohort, unlike other type of NK cells, and they're preconditioned basically. So they're going to be -- because the cells have matured in an individual for 30 years or more of their life, when you put them in, in a patient, they're going to be really active. You know that the response rate expected in a relapsed/refractory ML patient is between 15% and 20% with a flag regimen chemo, and Kiadis was able to pass the 55%, 60% response rate with their previous generation of cells in 2 investigator-sponsored studies. The cells that we're going to -- we're about to test in patients now are an evolution of that because they're no longer grown with feeder cells. They've grown with particles, and they're off the shelf. So that could make a difference, and I'm really looking forward to being able to expand on what Kiadis started. But I think what's really exciting for me, again, today, we're not looking at a single drug at Sanofi. We're looking at themes, groups of drugs. I've showed you, we have a number of drugs that can work in the NK space, right? So besides having a really interesting way of giving NK cell therapies, we're -- we just brought to the clinic an NK cell engager for AML. We have interleukin-2, which expands NK cells. We have a collaboration and in license with Beyond Biologics with an ILT2, which is also expressed. It's a novel checkpoint inhibitor, which not only is expressed on T cells and macrophage but it's also expressed on NK cells. So this allows us, once -- as I was saying before, once we have a dose with all these drugs, we're going to be in quite a unique position in the NK space to possibly combine. So that's -- that becomes another level of excitement besides the excitement related to the specific platform or drug.

And part of my grants, when you talk about the next generation of these NK cells, you said they are using particles rather than feeder cells, pardon my language, what does actually bring to the table by this -- what you mean by that? What does that bring to the table?

So that was a technology patent by Kiadis, a way to expand these cells. You don't risk -- so when you use feeder cells, there's always some risk of infecting the cells that you're then giving to the patient. By using particles, you have no live cell that feeds your cell. And so you have much registers of viruses coming with the cells that you use. So that's -- yes, that's a good advantage. But apart from that, if you're targeting an acute disease like AML, having cells that are off the shelf and you can give rapidly and not having to wait the extraction, the modification and putting them back, that's a week for those patient matters.

And forgive me, you -- I was going to ask it, but it's come from a couple of investors, given that you've been talking broadly about your excitement on all 3 of these programs, the obvious question from the investors is, what are the broad time lines for data releases on these platforms? I mean, I know Tidal is very early, but you did the upfront that you paid, obviously, raised eyebrows given it's preclinical, but -- is there anything going into the clinic or any readouts that are on the horizon, be it in 2022 or '23? I realize you can't be massively specific, but any sketching you can do would be appreciated.

Yes. So the NK cells from Kiadis, we're collaborating with 2 groups. And soon, we hope to be able -- AML patients are delicate, and in this case, they are preconditioned with chemo regimen. So you understand how you screen a patient, and then unfortunately, not always they're in shape to get cellular treatment after. So that's holding us -- of course, we have to have the right patients to test the first in human. But we are collaborating with 2 institutions -- big institutions in the U.S. -- actually 3, so that we hope to bring them very, very soon. Well, more than bring them, we hope to initiate patient treatment very soon with the cells. In terms of BioNTech collaboration, that study has been ongoing. We already presented a couple of times on safety and tolerability, it's very well tolerated, we presented how we had some initial sign of activity in lock regional areas. So of course, as we complete cohorts, we'll start giving updates on that combination. And as you say, Tidal is a bit too early to present something.

All right. Separate question and jumping topics. We've seen a lot of the ongoing of TGF-beta, but obviously, we've seen a lot more dispute. I mean, is TGF-beta on your mind now finished? Or is -- I mean, I know you've terminated your asset, but is that a target now that you think it's just no longer worth interrogating -- or do you still harbor hopes to be able to establish something here.

Yes. So TGF-beta, I think we have already made -- and it's also on clinical trial, the study has been closed, so that tells you. I think in today's development world and in today's Sanofi, the ability to make tough decisions and being confident in the decision you made, I think it has to be celebrated. And many companies have many -- many investigators have been interested in the TGF beta space. It was a very hot target. Any academic investigator, we presented our pipeline at least in 2019, where we only had 5, TGF-beta was the most interesting of them. So many people have asked us to give them TGF-beta for their studies. So and many -- a number of companies have run Phase III studies and some companies have been just acquired just maybe less -- or over a year ago for their TGF-beta drug. So the target makes absolute sense. What we -- once I started applying since 2019, with support, of course, from our leadership, a rigorous statistical approach even to early development, even to Phase I studies. Once we started putting independently -- statistically independent cohorts on so that we don't do a Phase I study with all comers and see what comes and goes to a large Phase II study in one indication based on random efficacy, but we really check -- statistically each cohort. Then the potential of this drug became much clearer. We opened 5 independent cohorts in combination with cemiplimab, some in post PD-1, some in PD-1 lung cancer melanoma, bladder, liver. We had responses, and we will present at a conference. I want to present as soon as possible at the conference so that the scientific community can benefit off this. We had responses. But in our views, with the competitive landscape today in IO, you need to have important and durable responses. And I don't think that's what we had with the combination of TGF beta. And as I think has been made public before, well, and everybody knows, when you inhibit systemically TGF beta, you go into some coagulation issues, right? So this drug is very potent. We -- the top dose that we've tested in efficacy cohort is 22.5. And as we presented, I think, 2 years ago at ASH when the biomarker poster, we eliminate circulating TGF-beta as low as 0.5 mg. So the drug was given at a much higher dose than the dose that in TGF beta because it was well tolerated. And yet, -- once you statistically check homogeneous patient populations, it's not something that I want to keep giving patients. I think patients have better options today. So that's why we decided -- we made a tough decision, but very well thought through. And I do want to make this story and this data available to scientific community as soon as possible.

So clear. Okay. We are literally in the last few minutes. So Giovanni, maybe you -- is there any -- well, there are a couple of assets, I just wanted to just kick tires with your trispecific CD3, CD20, CD38, ICOS, and you've also got a HER2 triagonist. Basically, is there any other compounds, if you had to single out anything in the early stage oncology pipeline that you think is particularly interesting or where we might see some incremental data sets this year, please flag them? Otherwise, if you just want to make a comment on those assets I called out where we are and what are the next steps are? That would be a great way, I think, to end this session.

Yes. So these are all first in human studies. So as you know, it takes multiple dose escalation cohorts to get to a dose, and you can argue in dose escalation no news is good news. It means that the drug is well tolerated and you can keep going up. I would keep an eye on the ILT2, as I mentioned, it's different from ILT-4. There's ILT-4 in the clinic, but ILT-4 is most respected on macrophage. ILT2 is expressed on NK and T cells, and this is the first in class. And it's not so often that you find a true first-in-class drug. The other one, as you mentioned, the HER2 trispecific, it's interesting. It activates T cells once they come together and they come together when multiple antibodies get on the target cell. With dose escalation process is -- again, no news is good news. And preclinical data show which we already disclosed -- preclinical data show how this drug -- in preclinical, it works in HER2 low and cells, which, of course, doesn't happen with the approved HER2 drugs because it's a different mechanism, totally different mechanism than other HER2 drugs, it's supposed to work even in HER2 . So I would keep an eye on that. But again, I'm very excited about the NKp46 NK cell engagers. That's an NKp46 CD16. It's in dose escalation. We had a T-cell engager for CD123. And we shut it down for the same rigorous reasons we shut down the TGF beta project similar. In that case, flotetuzumab was further ahead. And flotetuzumab had shown 37% overall response rate and 27% complete response rate in refractory AML. So it's a -- so the target CD123 works. Flotetuzumab only got accelerated approval based on, I think, 88 patients or so. And at that point, with a drug that was already showing efficacy, and we also had a T-cell engager for CD123, it didn't make sense to continue rather to switch to an NK cell engager. Now we do have both the T cell and the NK cell engager for the same target that when you put them in monkeys, T cell gives you IL-6 and CRS, NK cell engager doesn't. So if you look at the flotetuzumab papers, it works, most patients get some level of CRS and they have to dose reduce, give pauses to the drug, dose again, our hope is that with this drug, you can go without major toxicity and hit a target that works and then we can combine with our NK cells and then with the IL-2. So I think that makes me really excited. I wouldn't want people to not look at that one. But in general, what I would say is, I'm interviewing lots of people because we have positions open. I presented our pipeline to a number of large academic institutions. People are normally impressed when they see what's our early development pipeline today. And that's not what they remember of Sanofi. So I think my key message is Sanofi today is not what you remember of Sanofi. This is a company that has done a lot of work on the people, on the culture, on the processes, on the leadership. It's a company that is uniquely positioned in today's IO world to be a good player, both in the T cell and the NK cell space and this is a great foundation for innovation that is sustainable and not just for the short term.

I can feel the excitement here from London. I'll be watching closely the development. But once again, Giovanni on behalf of everyone on Citi, I mention point the investors on the call. Thanks for your time. We'll be following the story closely, and enjoy the rest of the day. Thank you very much.

Thank you. Bye-bye.

Thank you.