So good morning. Thank you for joining us here in New York. For the next couple of hours, really looking forward to sharing with you the progress that we've been making with our pipeline and also with our R&D transformation overall. You may remember that in summer 2022, we highlighted up to 30 early to mid-stage readouts we were looking for in the next 18 months. Now we're here today in the heart of the world's financial center, home to our second listing. We're going through a number of those results, and more importantly, what they mean for us, what opportunities they can create for us in the future. So, yeah. Also, welcome to those that are joining us on the webcast today. You may be looking at a large slide and at a small picture. You may or may not know that you can actually adjust the view individually. That's good. For you to potentially play with that now, we're gonna start a small video. Could we have the video, please? When there's a great scientific discovery, it's not one moment that defied possibility or one point that changed everything. It's many. A miraculous breakthrough only comes by risking failure over and over. Increasing our potential to improve patients' lives means we never settle. Transforming the practice of medicine demands going all in on artificial intelligence. Every day, our team rises to the challenge to pursue what once seemed impossible, to lead innovation in clinical trials, and to break down barriers for those who need it most. These moments may seem small, but to our patients and their families, these moments are immeasurable. So as usual, I would like to remind you that information presented in this call contain forward-looking statements that involve known and unknown risks, uncertainties, and other factors that may cause actual results to differ materially. I refer you to our Form 20-F document on file with the SEC and also our document, for a description of these risk factors. So now I just would like to have a quick look at the agenda and use that for some housekeeping. So as you can see, we have grouped this morning's session into three larger sessions. Each is going to be followed by a short Q&A. We're probably going to take the questions in these first two Q&A sessions from the room, and then we have the large Q&A session in the end. We're also going to see if we can take some questions from the webcast. These Q&A sessions are going to be followed by some short breaks. They are really just for a stretch a leg, get another coffee, maybe 15, maybe 10 minutes, depending how we're doing on time. So if I could ask you to really make your way back quickly and so we can stay in time. For those that are actually following us on the webcast, please stay on the same link. We will get back to you on the same link. We plan to conclude the webcast and the meeting here at around 12:45, so quarter to one P.M. local time. But here in New York, we will actually continue over lunch, and we also will have some further scientific sessions in the afternoon. And with this, I would like to welcome on stage Paul Hudson, Sanofi CEO. Thank you, Eva. Good morning, everybody. Good afternoon for those that joined. At some point, Eva will read the entire forward-looking statement. We have an informal bet when that will be, but she'll do it beautifully, I'm sure. Thanks, Eva, and thanks for all the work you and the team doing in terms of preparing for today. I've been looking forward to today for four years, effectively, almost four years, exactly since we launched the Play to Win strategy in 2019. It's been quite the journey as we have discreetly and relentlessly built out a pipeline. We're gonna share that with you today. We've done it as we've improved the efficiency and the productivity of the company. We have reached quite an important or a very important moment in the company's history, and we've never been more confident in what is ahead. The agenda today, at least, that I'm really focused on in terms of helping make sure we share with you exactly how we feel about the future of this company, is really these areas. You know, I think, already, what our pipeline and priorities will be. You're gonna get to see that. I think the deck is already live. We talked in October about increasing our R&D investment. Let's be clear from my point of view, we're going to invest additionally in 2024, around about EUR 700 million additional in R&D. Let's be clear again, it's in D. When you skipped ahead in the slides, you can see the weight of our pipeline. You've got a real sense for the fact that we can't miss the opportunities to do this. And we have two choices as a company, you know this. We could hedge, partner, out-license, go easy, not develop all indications, get through 2025, and then take stock about how we will drive through Dupixent LOE next decade. Or we can invest what we consider to be an appropriate amount of money with rigor and precision in drug development, not discovery now. And in the pursuit of doing that, we give ourselves the very best chance of getting enough assets, 3-5, with $2 billion-$5 billion potential in flight in the second half of the decade, to power us right through into the 2030s. That investment now is critical to make sure that we create an incredibly valuable healthcare company, and I feel like we will do it. Later today, you will also hear and understand about R&D productivity. We're well aware of the sentiment that hangs around industry, but particularly, somebody called it to me last night over dinner, old Sanofi. We'll spend a little bit of time helping you understand how rigorous and transparent we are about how we're spending every dollar, how we're making the choices, how we're setting the key milestones for progress. We've no choice but to do this. Additional to that, you could call it table stakes. We'll share with you data of how good we are in drug development, drug development. On top of that, we'll roll AI in to give you a sense of what it means to actually be ahead of the rest of the industry in AI at scale. And I think we're gonna share with you some things that are really absolutely incredible, and we've shown more courage, and we'll get more benefit than almost anybody else. So look forward to Helen's presentation on that. Maybe just to focus the mind of who we are becoming, and we've worked tirelessly for four years to put ourselves in a situation where we can do incredible development-driven opportunities for patients. Our cadence has picked up. You see it in the science. We'll talk about it later. That will be tech-powered, and what do we mean by that? AI at scale, expert AI in discovery, development, portfolio optimization, and snackable AI in decision intelligence. The next generation of pharma companies has to real time, redeploy resources against opportunities immediately. It doesn't wait for a budget cycle. We can share with you how far we are ahead of everything else. As for serving patients, well, it's quite obvious. If we offer transformational medicines, which I believe we will, first in class, best in class, innovation is rewarded. It's our best protection for the long term of the company, and I think we do incredible things for those that need it most. Finally, accelerating growth. The launches are in flight. We've already communicated at Q3; we revised up our new revenue number from launches to greater than EUR 500 million, and we did that because we're very good at launching. I've been around a little while in this industry, and normally people say, "You don't have a pipeline." And when they finish saying, "Well, maybe you do have a pipeline," they say, "But we're not sure you can launch." And the reality is, we're showing you we can launch now. We'll share with you data on that too. That's sort of easy for us. We know how to do that. And just for good measure, we developed Dupixent at Sanofi, and we've done a really cracking job at developing a pipeline and a product. More examples of that to come. Well, let's see. Ooh. Hopefully, everybody is there. Great. This is my favorite slide from 2019. So I remember when we went through the vast Sanofi pipeline in 2019 to choose the winners we thought there would be. And the list was not much bigger than this list at the time. And people raised a few eyebrows. Some were still in phase 1. And let's just do a quick check on the report card. 2 approved and launched. 2 approved and launched successfully, ALTUVIIIO and Beyfortus. Very proud of that. 2 on track. For Fitusiran, you'll hear more about that at a congress. Exciting updates with the FDA. Real progress made. That's next year. Tolebrutinib, if you skipped ahead in the slide, you already know that we're, I would say, back in the game. We shouldn't miss the opportunity with our expert, with Erik, Tom, the team, in understanding how we position ourselves in the BTKI space and why we believe we still have the winner if we can manage the profile successfully. Two stopped, Amcenestrant and Venglustat, but not stopped late, which was an old habit, stopped immediately and quickly. You could argue there was still some activity with those medicines. We stopped them. We have better things to do with the resource. So that was 19, and this, this slide for me, this, out of all the things that we'll show, for me, this has been four years' work with the team. This slide is, I think, without comparison with other big immunology players. This slide has multiple shots on goal, multiple mechanisms, multiple approaches, advanced orals, IVs, subcutaneous, longer interval, shorter interval. We really have made sure that in all of the key fast-growing, under-penetrated, biologic-eligible patient populations, that we will be first or second choice. Mostly first. We've really set ourselves up here. Nobody can compete with this. Nobody. Very few are taking multiple assets on the same target in the same disease, and you know this, and we'll share with you the analog on psoriasis, how quickly you can penetrate and how all boats can rise. How can you have nine biologic blockbusters in psoriasis? What does it mean for us? Often those that observe us declare winners and losers. This is better than that. These are heterogeneous patient populations. We will win with all of these. Not all will make it, but those that do get to market, they will be game changers. We're particularly excited about the OX40 ligand, Amlitelimab, the oral TNFR1, and of course, the CD40 ligand, frexalimab. So that's great, right? That's the plan, but let's not forget, 2023 was an outstanding year for news. So if you were like, "Sanofi, R&D, blah, blah," you know, the drumbeat has picked up all the way through to Dupixent COPD. So you may refute, you may be hesitant, you may be thinking to yourself, "Do we believe that this company can really show the agility and reflexes to get it done?" You can't refute the news flow... the pipeline build, the cadence, the obsession over making sure that we win and become a leading immunology powerhouse. Let's put some numbers on that, because we're often asked: "Who's your favorite child? What is it gonna mean? How big can this be? How do we model that?" We took a lot of advice from people who told us how we should be doing these sorts of things, and we put that to one side, and we just tried to help everybody understand that in actuality, we're gonna have some very large medicines in the $5 billion+ box. We'll demonstrate to you why we believe that today, and some in the $2-$5 billion box. That's supposed to help you understand our priorities, is to help you understand that they can coexist, that they can be co-positioned, and that this company knows how to do it and do it very well. This really is the pick list. Let's assume only half of these medicines make it. It'll be 6, EUR 2 billion-EUR 5 billion drugs launched between now and the end of the decade. That is more than enough to power the company, even through a potential LOE of Dupixent, and of course, 100% owned by Sanofi. Think about that for a moment. First time, we'll have our entire future in our pipeline in our hands. Really important moment for us. So back to the... I'm sure if you have a pipeline, I'm not sure you can launch. I think we need to get over ourselves on that. We've had a lot of launches since 2020, since 2019. We don't talk much about rare. We quietly get on with our job, helping hundreds of patients, if not thousands. We've launched Enjaymo, Xenpozyme, Nexviazyme, even Rezurock in graft versus host, all successfully. On top of that, you've seen Beyfortus, ALTUVIIIO, and even Tzield, which will take significant work to educate a market. But when that job is done and biomarkers are identified and everybody understand who is going to lose beta cell mass, frexalimab will arrive. When the market fully understands what we're doing, we'll make a big success out of Tzield, and frexalimab will walk into a marketplace that is absolutely tuned to perfection to receive it. So we're also asked a lot about, "Well, can you tell us a little bit about the future? Can you tell us, as you've changed the guidance, what it actually means?" And we think this is about as simple as we can explain everything to people. We've communicated before that greater than EUR 10 billion of sales for vaccines by 2030. We had a vaccine R&D Day in May. It was well-received. The slides are available for those that need it. We're not missing it out today. We just don't think we need to repeat ourselves. We can do, if you need us to, in the Q&A. At the heart of what we're going to do is Dupixent, and while, you know, I hesitated personally, I was teased relentlessly over dinner last night, will there be another way point for Dupixent? The reality is, it's not really a great benefit for us to keep giving you a new number. But I think it's important in the context with what we're doing in this great company, that you understand why it's a cornerstone, why it matters, why it keeps moving. We chose CAGR, because, as you know, growth rates will fluctuate over time. If we gave you a fixed point, you draw a line, and then you hold us to that. We'll do this. That's not a problem. That's quite obvious on what that means for us, which is why the piece on the left is so essential, because we need to get to a place where we own 100% of the EUR 10 billion that we're throwing back into the mix at Sanofi, which will be launch, full launch mode, full launch mode as Dupixent's expiry approaches. This is what we do. We have to run the left and the center and the right fast, and then the left and the right have to run faster than Dupixent at the end. Just for clarity and for our great friends at Regeneron, Dupixent will grow, and it will be a priority right until its last day, and you know why that is. It does it every time. Okay, so getting to the end. We've come a long way. We have a pipeline. It's not scattered, it's focused. It's focused on areas we know how to do. Once you get over the can Sanofi do R&D, at least accept we can do D, certainly in immunology. The deck is stacked in our favor. We know what we're doing. We know how to do it. We got feedback after Q3. We understand what people are expecting from us, and I have to tell you that waiting is not my strong suit, but we now know where we're heading and why and what it looks like, and we fully understand that we have to earn the credibility for R&D. Doing less projects with less money in hope that somebody at some point will say, "Oh, you finally cracked it," will not be enough. Creating long-term value is absolutely the goal. We'll keep delivering a cadence on the quarters. We'll do everything as expected, but depriving ourselves of investing in this pipeline at this point would have cost an absolute fortune to recover 2026 and 2027 to offset the next round of questions that would come. "But Paul, what about Dupixent LOE? You should have spent more in 2024 and 2025." It's a great jobs you all have, that you can do two things at once. For me, I've got to make sure we deliver a great financial performance, that we invest in the pipeline 'cause it's fantastic, that we have rigor and candor, and we call it out early. You know where we're heading, you know what we're gonna get done. To empower that, to enable that, we have the great privilege today of having, for his coming out party, Houman Ashrafian, our new head of R&D. Why Houman? A lot of people said to me at the meeting last evening, "We don't know him. He's an unknown quantity. We don't know him at all. Why didn't you go for a very stable number two from a big pharma who wanted the title as head of R&D somewhere else?" Absolutely not. At our company, we want somebody agnostic to TA with clinician reflexes, with scientific reflexes, and importantly, and I believe it's going to become the new fashion in heads of R&D, capital allocation reflexes. There is somebody that's been a clinician, an academic, and of course, in venture. That gives us a unique blend of skills, and it gives us a real opportunity. He has been across every single scientific site since he arrived. He has been tireless, occasionally shoeless, and wearing a T-shirt, today dressed to impress with a three-piece suit. He has stood in front of scientists on every single project in the company. He's been working with us as an external advisor since February. He is knee-deep in the detail and is happy to duke it out with any of our scientists who've felt their game raising after his intervention. I'm very proud that he joined us. I'm delighted in the impact he's having already. He is fearless, but is as desired to deliver value creation as I am, and I welcome Houman Ashrafian. Thanks, Paul. Pretty hard act to follow. Good morning, ladies and gentlemen. I have the good fortune this morning, on my coming out parade, of losing my voice. So the two things I'd hope is that it lasts till the end of the day, and forgive me for the quality of my voice. Okay, so let's just get going. I've been at Sanofi since September, and it's been a really hectic and productive time. As Paul has said, what I've done is visited the majority of our major R&D sites. I've met our excellent people, and I've had a really deep dive into our science. And I've got a piece of news for you. Sanofi R&D engine is humming. I have no doubt that we have a pipeline that is going to sustain Sanofi for the future. So a few words about me. I'm a physician scientist. I have a background in R&D at UCB. I was practicing clinical medicine until recently, and I have had the privilege of investing in excellent science as a venture capitalist at SV Health Investors. I was a managing partner there, and that's a pretty well-known venture firm. And I founded a bunch of companies, and I built them. What's fascinating for me is coming to Sanofi. Those of you that know me will now have two North Stars. One is value for shareholders, and one is value for patients. And everything I will do during my time in Sanofi will be permeated by these two principles. So what's interesting fundamentally about venture is we're used to managing large portfolios and maximizing value. And I believe, following on from what Paul said, that we are at that point in Sanofi's life cycle. Being able to bring venture discipline to our amazing portfolio is what's going to transform our future, and we're poised to do it. What I hope to bring is a balanced, fresh, really deeply scientific perspective to our portfolio and to generate value as we move through our journey to becoming an immunology powerhouse. I'm incredibly privileged to be sharing the podium with these people. These are great leaders. Each and every one of them is a world authority in their own right, but the whole is far greater than the sum of the parts. What I hope to do today is to marshal compelling arguments for you guys to believe that we have real momentum, and that momentum is already delivered, but it will continue to deliver best-in-class medicines. Before we really get going, let me just share some candid views with you. I'll start with the good. I think what's true without a shadow of a doubt is Sanofi, Sanofi R&D is extraordinary. We have a fantastic pipeline, both our internal leading-edge technologies, but also our external activities, to which we, you know, in terms of innovation, which we're unrelentingly committed to, has generated real value. I, I have to say, I really believe that we have an exciting pipeline with first and best-in-class late-stage assets. And what's really important about these late-stage assets is, is what I'm gonna talk about a little later. We're gonna double down on. Paul's already commented about our D, and I think we're gonna double down on D, and that is the growth engine for the future of Sanofi. But not everything is perfect, right? Not everything at Sanofi was perfect when I arrived. I think what was really interesting at Sanofi was that we had a really interesting set of people and pipeline and activities, but where we could improve was on portfolio strategy, on productivity, and of course, that lends itself to my background. So what I did when I arrived for the first 60 days is we did a deep dive. We went through the portfolio, through the TAs, one by one. And the best analogy I can give you is that of a bonsai tree. Imagine pruning a bonsai tree. You know, inherent within that tree, this ungroomed tree, there's aesthetic value. But in order to draw out that aesthetic value and achieve perfection, what you need to do is prune that tree while keeping the roots, the trunk, and the branches strong. I feel that's what we've been doing, and I think we're getting there. Listen, there are some quick wins, and there are things that will take a lot longer to fix, but we're on it. The plan isn't just to, as Paul has said, match industry benchmarks. That's not what we're here to do. We're here to beat industry benchmarks. We are going to be the best, in my view, in my aspiration, biopharma company in the world.... But to do that, what we need to do is have hawkish portfolio scrutiny, and the watchword that you'll hear a lot today is dynamic capital reallocation. If there's anything we'll do, is we'll dynamically reallocate capital with the help of AI. One of the things I really need to do is to say that, look, I don't - what I don't want this to appear is to say we've not done well, because I think Sanofi's done very well, but we're going to do much better. Outside those, I think that we remain very committed to research. Paul's talked about development. We remain committed to research. We have a number of leading-edge platforms. We have innovative small molecules, biologics, mRNA and genomic medicines. Frank Nestle will talk about those a little bit later. The other thing that we'll do is really focus down on development. Now, what's been really interesting is I've traveled through the various Sanofi sites and spoke the various languages, and I apologize to all of you listening for my linguistic blunders. I've noticed people's commitment to urgent delivery of drugs to patients. This really is bringing the miracles of science to patients. And what I think we can rightfully contend is that we are the best immunology powerhouse in terms of development. So I've heard at dinner and even on calls during the day, we are the best immunology powerhouse in development. And I think Dietmar Berger, my friend and colleague, will share numerical criteria statistics to prove that we're the best immunology powerhouse, but also that we're patient-centric and that we're committed to diversity in our clinical trials, and that's really very important to us. And last but not least, we've said AI a few times. What's pleased me most from my time in Sanofi, and thank you, Helen, is our commitment to advanced analytics, AI, and advanced statistics in R&D. Across the arc of R&D, in research, in CMC, we almost never call out CMC. It's really important to understand that our groups that are bringing drugs to patients are using digital twinning and other technologies to advance CMC. In terms of faster, better data-driven decision making, in terms of clinical trial execution, and in terms of regulatory streamlining. AI is here to stay. AI is a really important part of what we do, and I think we, we seek and strive to lead the industry in that regard. So let me change gears and get to why immunology? We're uniquely positioned to win in the, immunology information market. Amongst our many competitive strengths and differentiators, primus inter pares, immunology is our strength. We have a deep provenance in immunology now, and it's self-fulfilling prophecy that as we get more deep immunology experience, we'll be better at developing immunology drugs and also doing research in immunology. The second reason is, apart from our provenance in this area, is that the immunology market is growing. As you can see, it's one of the most productive markets, with a 9% CAGR between 2023 and 2028. Molecules that come out in immunology are often blockbusters, have a greater propensity to be blockbusters. And perhaps most importantly, and Paul's already said it, I want to pause to say it one more time: biologic penetration in immunology is low. Even in ulcerative colitis, where drugs have been available for decades, advanced drugs have been available for decades, current biologic penetration in patients who are eligible is about 28%. The beauty of the immunology market is new entrants don't cannibalize incumbents. They grow the pie, and that's why we're very interested in immunology. Later, Shaju will talk about this in a much more eloquent, in a way. Okay, so the other reason is that we really do have the provenance to win in immunology. I'm pleased to say that we are either in the first position or a leading position in almost every aspect of the immunology market, whether that's total assets, asset indication density, or first-in-class assets. Again, what I don't want to do is to argue that we are we have a natural place to win, and so we should be complacent. Quite the opposite. I can guarantee you that we're hungry and we're not going to drop the ball. So why are we all in on immunology? The answer is because I've held a long-term conviction. You can call it a bias, that immunology underpins many of the major diseases we care about. And listen, this isn't something that we cooked up today. My academic, my pharma, and my venture experience all attest to the fact that I think immunology underlies all sorts of diseases that we haven't been thinking about today. So while our commitment to conventional immunology and vaccines remains unabated, what's really clear is that we're going to carry on driving into the near adjacencies, which include neuroinflammation, transplantation, type 1 diabetes, and immunology as applied to oncology. Felix very nicely calls this my signature slide, and I think this is going to be the way we think about immunology going forward. Two other facts to think about. That doesn't mean we're excluding other areas in which we have great provenance. So we love our rare disease franchise, and I can announce today that Fitusiran has achieved breakthrough designation. The FDA have been extremely kind to us and given us a breakthrough designation. Well done, team Fitusiran, for hemophilia B with inhibitors. We continue to drive on our rare franchise, and we'll continue to keep our eye open for immune-mediated diseases in our, in the periphery of what we do. But I want to remind you, and I'm going to say it three or four times today, we will do it all the way through good portfolio management and capital discipline. Shareholder value and patient value is at the core of everything. Okay, changing gear for the last time. What I really want to do is give you a granular and concrete sense of areas that we are changing R&D. I'm going to use this slide to signpost, and then I'll pack this, unpack this on slides to come.... The first thing we're going to talk about is peak investment. I've already said to you a couple of times, we're going to double down on R&D, Paul, on D. Paul's spoken about it, and I'll explain to you how we're going to do our phase three acceleration in the next couple of years. Second thing is, we've got to earn the right to do that, and I'm going to talk about how we're going to deliver portfolio focus across our breadth of platform sites and TAs. Finally, I'm going to talk about the importance of pipeline sustainability, particularly with respect to research over the next five to 10 years. Moving straight into it, what we've said to you, very clearly, is through a dispassionate, data-driven process, looking at the data around the phase two molecules that we have, we've decided to invest in our phase three pipeline. The reason we've done it is we regard that phase three pipeline as the pipeline that's going to lead to the growth of Sanofi in the next few years. Concretely, what are we going to do? We're going to increase the number of phase three trials that we do by 50% over 2024 and 2025, from 2023 to greater than 35 clinical trials. You can see what they are. This is at the essence of the Play to Win strategy, and I am shamelessly plagiarizing Paul's moniker here. You know, we need to increase investment in these long-term opportunities in order for us to drive real growth and value for our shareholders, and we do it in a disciplined but unashamed way. But you know, we can't do that without earning the right to do that by thinking about dynamic capital allocation, reallocation for other places. And one example of where we're dynamically reallocating capital is oncology. We continue to have the right to win in oncology, but in a focused way. Oncology is a massive market and a source of unmet medical need. Our view about oncology, my view about oncology, is the history of oncology has been dominated either by people who have deep domain expertise, deep therapeutic area expertise or differentiated platforms, and we will follow those two rules. So in the case of the first one, we will double down on myeloma, where we feel we have the right to win. And that results from our molecule, Sarclisa. So absolutely hot off the press, I can inform you that Sarclisa, in the IMROZ study, comfortably passed its second interim and had a, what I regard, a very impressive PFS hazard ratio. It confirms my bias that Sarclisa is likely to be the best-in-class CD38 monoclonal antibody, and I'll be even more excited about my bias when we have the subcutaneous molecule launched. Sarclisa is a really important molecule, and we remain interested in it. Alternatively, in terms of differentiated therapeutic platforms, in oncology, we have, I think we have the right to say that we are the world authority on NK-cell engagers, and that's a really important area. Technology's really good, and we have our CD123 and NKp46 molecule that we've showcased in ASCO and ESMO and will showcase further in ASH with promising phase 1 data. Last but not least, I'm delighted to announce that our CCAM one-- CEACAM5 Topo I molecule has dosed its first patient, and we continue to keep a toe hold in, ADCs. But don't be fooled. I'm going to take a moment to pause and say, please don't be fooled. What we're not doing is splashing the cash, right? We've taken real careful, dynamic capital allocation decisions, and we've been really decisive. So what do I mean by that? We've internally, dynamically reallocated EUR 700 million of capital within R&D from some TAs into development in order to be able to fund our future development pipeline. Disciplined capital allocation will define everything we do. The final component of this trivium is sustainable pipeline fuel by in-house research. Listen, we've made some really good choices in terms of internal platforms. I'm very happy with our internal platforms, and that's been really extraordinary. Frank Nestle will talk more about that. We're excited by what we're doing internally. But we also remain committed to our external innovation. You know, my background as an entrepreneur will mean that we drive and continue to look at what's the best of the external world. We use our venture arm and various tools we have to sample the external world, and we will interact with the external world as appropriate. We've had a great track record of doing that. Three launch molecules, Tzield, ALTUVIIIO, and Rezurock are all external molecules. So we remain really interested in doing both internal and external stuff. I'm proud to say, being a French European company with an international footprint, including in this magnificent United States, means we've had the opportunity to create really good strategic partnerships, multiple academic networks, and we'll continue leveraging those for success. But at the risk of sounding like a broken record, everything will be done through the lens of: how do we allocate every single dollar in the very best way? My belt remains tight. Okay, for the last slide. Listen, over the next two years, we, we're going to have significant pipeline momentum, and as Paul has said, we're going to have a great deal of readouts. Paul has already said we don't have any favored children, but I'm going to call out a number of molecules today just to give you a sort of heads-up of where we're going. So the first molecule I'll call out is tolebrutinib, our BTK inhibitor for MS, which is currently being trialed in MS. What's really fascinating is that I think we have a differentiated molecule. I think it's differentiated in biophysical terms. I think it's differentiated in terms of disposition, and I think it's differentiated in terms of its current clinical data. This is a molecule to watch. And while we remain incredibly cautious, we have an abundance of caution. Erik is going to share some great news with you from interactions with the regulator. I believe that if we take the right path, this will bring real value to patients with progressive multiple sclerosis and far beyond. More about that from Erik later. Second, molecule I will talk to you about is Dupixent. I'd be remiss if I stood up here today and didn't thank the BOREAS and NOTUS team. Manuela is going to say more about that later, for bringing value to patients with COPD, with type 2 inflammation. But we shouldn't forget that in itepekimab, we have an IL-33 molecule that will bring value to other patients, particularly former smokers with COPD, and I think that's really critically important. While we're on pulmonology, Dr. MeiLan, wherever you are, I think what we're also going to do is talk a bit later about our broad range of molecules, both rilzabrutinib and lunsekimig, our IL-13 TSLP molecule, which will increase the palette of anti-asthmatic drugs for pulmonologists treating patients of all shapes, from early to late in disease. And I think Naimish and others will talk about that. And last but not least, I just want to address the small molecule, oral TNFR1 signaling inhibitor. Over dinner, like Paul, I was ribbed about this molecule. And I just want to be clear about this. I've lived the journey of this molecule from its very first inception all the way to where it is today. So this molecule isn't an oral Humira. What this molecule is, is it's a TNFR1 blocker with all the excellent pharmacology that comes with that, which may relate to safety, it may relate to other factors, it may relate to potency. And I really think that we're moving into an era of clean, oral, advanced molecules that will begin to sit alongside biologics in the immunology marketplace. My prediction, if we handle this molecule right, and Brian will handle this molecule right, is that this will be foundational as both monotherapy, but also as foundational element in combination therapy in a multitude of inflammatory disorders. So listen, I think you can tell, I couldn't be more excited about being here at Sanofi. We're doing great things. We'll deal with capital discipline, and we are going to drive this engine into the future of biopharma. With that excitement, I have great pleasure in handing the mic over to, Naimish, who will tell you more about our immunology. Thank you, Houman. I have the distinct pleasure today of discussing our core immunology portfolio. Now, I've been fortunate enough to be a part of investor events for immunology for a number of years, and each time we've been building up to this moment, we're declaring that we have the intention to be the leader in immunology. I think there's three key components to getting there: having the right set of assets, the right strategies for these assets, and the right people, the right leaders, and the right talent to deliver these assets. I hope I'm able to convince you today that we certainly have all three of these things. The next 30 minutes or so, I am going to discuss with you six, yes, six, potentially mostly blockbuster, multi-indication blockbuster assets. In terms of the strategy around these assets, this is something that we're well-versed in. We have created a multi-indication blockbuster before, and we've developed a blueprint on how to do that. But I think we've even optimized this blueprint even further to do it better and faster than we ever have before, and I'll get into those details with each asset. So what is our approach? So we take a central, key core immune pathway that has the potential relevance to multiple diseases, and we develop a molecule to target that pathway from a variety of platforms. We pick a disease for which to first get our evidence that we can hit this pathway and make a difference in disease, and we learn from that initial study on where else we can take this molecule, and then we take it to multiple indications that are sometimes adjacent and sometimes in different therapeutic areas where we think the biology will really fit what this molecule is gonna deliver. In priority, we tend to choose diseases in dermatology, respiratory, gastroenterology, and autoimmunity or rheumatology. And what are we trying to deliver in these diseases? One is to raise efficacy ceilings. So even today, there are still diseases where doctors are using the same therapies that they used 20 years ago, 30 years ago, the same set of immunosuppressants. And these are areas where we can really make an impact with a new molecule. When you think of what Dupixent has done, four of the five indications where Dupixent is indicated today, it was the first advanced therapy, and COPD will be the next one. This is a place we can make major impact, and you'll see that theme play out in the next half hour. Another place where we're making a real concerted approach is taking some diseases like asthma, where we have a number of different MOAs. They all deliver a level of efficacy, but we're beginning to plateau on how well or how much we can make a difference to these patients. What if we actually combine two validated pathways that we know work in asthma to get something that's even better than we have before? I'll give you an example of that as well in our portfolio today. Another place we've made a concerted effort is in disease modification. We have specifically chosen targets that have the potential to change the course of disease. And we know, for example, hidradenitis suppurativa is a great example, a dermatologic disease that in part can lead to chronic scarring and incredible impacts on quality of life. Patients respond initially to a therapy, and they tend to lose response over the long term. Well, we want to create a molecule that can target a pathway that will lead to durable disease control, disease modification, and you'll see several examples of that in our portfolio. And finally, where I think is maybe the most exciting part is, and where the future of immunology lies, is early disease. So right now, most of the advanced therapies we have developed all tend to target advanced disease, severe disease, and usually patients in this category tend to have irreversible organ damage and limited reversibility of what we can do at that stage. Or can we intervene earlier in patients at risk to change the course of disease? This is much more, much way more efficient way of actually intervening in a disease to prevent patients from ever getting that sick. And you can imagine small molecules, safe orals, are, are a great way to approach this problem, and we have several examples of doing that. And so I want to start today with Amlitelimab, number one of six, of what I'll review to- with you today. Amlitelimab targets the OX40 ligand pathway, and this is a very central step in the, the activation of an immune response. It's really where the immune response gets programmed, and you can imagine once you put in a program, usually that program sticks, and you don't need to change very much. In the same way, if we can reprogram, rebalance immune response, the way we dose a drug could be very infrequent. We don't need to constantly reprogram. And that's the ambition for this molecule, something that delivers durable disease control with very infrequent dosing. And the one added benefit is of this molecule and this pathway, is that it targets a broader set of immune responses, both type 2 and non-type 2. And so there's going to be a unique set of indications where we're going to target this pathway, and I'll get into what indications we're going to start at pace. So there's two ways to target the OX40 ligand, OX40 pathway. One is to target the ligand, the other is the receptor. We think the ligand is a superior way of targeting this pathway. Why is that? Well, for one, the ligand is inducibly expressed at sites of inflammation. So what that means is when we give somebody a drug, it only blocks inflammation of where it's occurring, for example, the skin in atopic dermatitis, and it reduces the chances of off-target effects that might cause immunosuppression. In contrast, something that targets the receptor potentially can target T cells that are far away from the sites of inflammation. That might be important for other reasons. And specifically, some of the competitors that target OX40 receptors are depleting antibodies. What that means, they'll actually get rid of T cells that may be far away from the site of inflammation that might be important to fight infection or cancers or other needed processes that the immune system governs. Moreover, there's a certain important set of cells, T reg cells, that express OX40 receptor, and if we block the interaction with the ligand, we could activate T regulatory cells, and this, once again, lends credence to that long-term disease modification and immuno-rebalancing. The drugs that target the receptor will also deplete T cells that are T regulatory cells. So we think the ligand is a strategy for not only better safety, but also potentially better long-term efficacy. So we presented the results of our Phase 2b trial in atopic dermatitis recently this fall at a dermatology conference, EADV. This study was a study in moderate to severe atopic dermatitis patients, a 24-week study with a primary endpoint of EASI change, EASI score. I'll share with you today, again, the results from this study, but there's also a part B to this study, where we did a randomized withdrawal design, and the results of that part will probably be available in the first half of the coming year. So first, I'll share with you the top line results. So I want to direct your attention first to the highest dose, 250 milligrams with loading dose, and the number, 73.1% decrease in EASI score. This is as good as efficacy you'll see in atopic dermatitis at week 24. So fantastic efficacy. But if you drill down on these data, another interesting aspect to this was, if you look at the gray bars, that's week 16, and if you look at the light purple bars, that's week 24. Generally, across these doses, there was an improvement from 16 to 24, which suggests efficacy is still getting better, and we haven't plateaued. So further dosing likely will produce even better efficacy, and it goes very well with this mechanism I told you about, about reprogramming the immune response in a durable fashion. And finally, the other thing you might notice is that across all the doses, there's efficacy even at the lowest dose. Why is this relevant? Well, this gave us the first clue that-... Even the highest dose, which dosed infrequently, if we produce exposure that's equivalent to that lower dose, we could actually fairly infrequently dose this drug and still get a high level of efficacy and more to come on that. How was the safety in this study? Well, great, great, to announce that it was generally, Amlitelimab was generally well-tolerated across all doses, and in general, the rate of adverse events was equivalent in the dosing arms versus the placebo arm. There are no reports of serious infections, no reports of severe injection site reactions. Most notably, however, if you looked at those side effects that are often associated with cell depletion, such as fevers, chills, pyrexia, and influenza-like illness with dosing, we didn't see any of that with Amlitelimab. Moreover, aphthous ulcers, which might be a sign of T-cell depletion that has been noted with some of the competitors, was not noted with this drug either. So very encouraging about differentiated safety by targeting the ligand. Now, I want to focus your attention on the results for the highest dose, the 250 milligrams with loading dose, and the two endpoints, IGA 0/1 and EASI-75, which are the endpoints accepted by regulators for atopic dermatitis. As you can see, once again, that number, 49.4% IGA 0/1 and 61% for EASI-75. These are as good as numbers you'll see for a biologic at week 24. And once again, you can see from the gray bar to the light purple bar, we had a steep improvement from 16 to 24, and we expect that to actually continue beyond week 24. So this is the best dose, best efficacy we saw across all doses, and this will be one of the doses we use in our phase three program. So how about the biomarkers? Really interesting data here. One, Amlitelimab, as you'd expect, had a potent effect on the key biomarkers in atopic dermatitis. And the profile here was really fascinating. So we had a deep and durable effect, a potent effect on type 2 biomarkers, blood eosinophils, IL-13, and TARC. This is expected finding if you have a drug that's delivering the level of efficacy we saw with Amlitelimab, 'cause atopic dermatitis, most patients have some element of type 2 inflammation. What was really interesting here, however, was the non-type 2 biomarkers, IL-17A and IL-22. Both of those were also potently decreased with Amlitelimab compared to placebo. Why is that important? Two things: one, atopic dermatitis itself is a fairly heterogeneous disease, probably much more so than psoriasis. There's a large percentage, a large proportion of patients who have this mixed phenotype, both elements of type 2 inflammation and non-type 2 inflammation. And these patients are probably not best served by a, a drug that only targets type 2 inflammation. And so there's a potential here for Amlitelimab to address a distinct population of patients that might not be responsive to other mechanisms. Moreover, beyond atopic dermatitis, the fa... and I've said, mentioned this before, targeting both type 2 and non-type 2 pathways, there's probably a unique set of diseases we could potentially target with Amlitelimab that's different from what we've done before in terms of type 2 agents and what type 2 diseases we should go to. And I'll get into this a little bit more as well in the next few slides. So this is a really important slide. I wanted to direct your attention to this. So we took the data that we had from the phase 2 study, and we built a model for exposure versus response and in this model, we compared 2 dosing regimens, the Q12 dosing regimen with the highest dose versus the Q4 dosing regimen. You see on the bottom, the arrows, the brown arrows, represent dosing every 3, every 12 weeks, and the green arrow is dosing monthly. That green line in between shows you improvement in efficacy over time. You see, actually, you only don't see a brown line initially, just see one green line. That's because the two lines are superimposed. This means that Q12 dosing will give equal efficacy to that highest dose plus loading dose, dose Q4w. Best in disease dosing. Imagine getting just 4 injections a year for atopic dermatitis, having the best, best in disease efficacy with 4 injections. Furthermore, if you look beyond when we, when we stopped the dosing in this model, the line actually continues. Durable disease control, even post-dosing, so that disease modification piece that I, that I talked a little bit about. Eventually, you do see the lines, go back up. You lose response maybe after six or seven months on this graph. The, the brown line, goes up first and then the, the blue line is a little bit more durable, as you'd expect. But the key point here is both four shots a year dosing, and we're gonna include that as, as a dose in our phase three program from the beginning, and durable disease control. Here is the robust phase three program that we have initiated for Amlitelimab. Originally, we, we said that we were projecting Q1 to start the phase three program, well, we have started it already. First patient has already been dosed in the COAST 1 monotherapy trial. One thing we hadn't discussed before is that we actually started the OLE earlier this year, and we have already started enrolling patients within the OLE. Why is that important? Well, we thought it was really important to have a very comprehensive safety data package with the initiation of this trial. And by starting patients in an OLE upfront, we're going to have five years of safety data at launch, better than any actually molecule in this space. In addition to the classic monotherapy trials, two monotherapy trials and a TCS background trial, we're also planning to initiate a Bio-IR study, so patients who are inadequate responders to either a biologic or a JAK inhibitor. And we think Amlitelimab, because of its unique mechanism, has the potential to make a huge impact even on these patients who are failing other therapies. So unprecedented Q12W dosing, bio or JAK IR patients, inclusion of adolescents in the phase III program upfront, so we'll have that at launch, extensive biomarker plan, and five-year safety data. So let me summarize Amlitelimab, and there's a lot of new things actually in my summary to talk about here already. So comprehensive atopic dermatitis, phase III program that has initiated already going at pace. An asthma program that's going to read out in the coming year. Hidradenitis suppurativa. So I mentioned the issues with HS and how patients often lose response. Amlitelimab and the mechanism is well tailored to try to attack this disease, and we have already started a phase II program, first patient already in for this study. And today, I'd also like to announce three additional programs: alopecia areata, celiac disease, and systemic sclerosis. All three of these diseases, the current standard of care is poor, and we need to raise the efficacy ceiling. And so a couple of themes I talked about, durable disease control, raising efficacy ceilings, and now six indications before we've launched the first one at pace. Multi-indication blockbuster, better than we've ever done before. It's really exciting stuff for Amlitelimab. Next, I'd like to talk about lunsekimig. This is actually a really novel molecule in terms of multispecific targeting in asthma. It has never been done before. This is a molecule, a nanobody, that combines IL-13 and TSLP, bispecific targeting. Now, our team in research, Frank's team, a number of years ago, identified the potential for targeting both TSLP and IL-13 together. TSLP is a very upstream initiator of inflammation, and IL-13 is a downstream cytokine that's responsible for much of the tissue organ damage we see in airways diseases. And what Frank's team found in preclinical research is that if you combine and hit both these targets, you get actually synergy and an effect on type 2 inflammation that's much more potent than either alone. So we're talking about synergy, not one plus one equals two, but one plus one equals three. And so we're very excited. This is potentially going to deliver something that's best in disease and asthma, and a range of other respiratory diseases. And as I mentioned, we always want to develop that initial proof of concept to prove in the clinic, in patients, that we're seeing the same response. And so we, what we did, is we designed a phase 1 study in mild to moderate asthmatics and gave them a dose of lunsekimig and measured FeNO as a primary endpoint. Why FeNO? Well, FeNO is a biomarker, fractional exhaled nitric oxide, that's used clinically in asthma treatment by clinicians today. And there's a host of literature saying that if you affect FeNO well, it correlates very well in the long term with better asthma control, improved lung function, and fewer exacerbations. So if we're going to prove that this drug impacts FeNO, it will correlate with efficacy in longer-term asthma trials. And so we presented the results of this trial at ATS. The first time I saw this, I said, "Wow," this level of improvement in FeNO had not been seen really with any biologic. So after a single dose of Lunsekimig, 40 parts per billion reduction in FeNO in asthmatics. On the right side, you can see a comparison to give you context on what this means. In trials of anti-TSLP alone, you get a reduction in FeNO of about 10-15. In trials of anti-IL-13 alone, you get reduction about 10 or 50, 10-15 as well. This is 40, so maybe 3x, maybe almost 4x. We're talking about one plus one equals almost four. And so you could imagine what this could do long term in asthma patients delivering best-in-disease efficacy. And so we have started at pace, the phase IIB program in lunsekimig, with our first patient in already enrolled. This is a study with the primary endpoint of reduction exacerbations with four dosing regimens plus a matching placebo. And because we're so confident in, in the potential for this, we've designed this trial as a pivotal trial. So this will potentially be one of the pivotal trials, and we only have to do one more phase III after this because of the confidence we have from the data we've generated today. Beyond asthma, we think there's huge potential for this elsewhere. I should say, beyond moderate to severe asthma first, because it's been well noted in the literature. So those two type two biomarkers I talked about, high FeNO and also high eosinophils. If patients who have mild to moderate asthma have elevated levels of these, these are the patients who are going to progress and end up into that moderate severe category in the future. So we're thinking, can we change the asthma paradigm to now intervene at an earlier stage in asthma, so we can prevent these patients from progressing? So those two other concepts I talked about, disease modification and intervening in early disease. Huge opportunity in asthma and changing a paradigm. And the, the epidemiology out here is 1.9 million. That's the number for today's moderate to severe asthma population that get biologics. But if you add this other population of early—high risk, early asthma, it's much larger. In addition to asthma, we're going to start another program in CRS with NP, nasal polyposis, also in the coming year. On top of that, a program in COPD to come soon after that. And finally, are we going to see the synergy, or will we see the synergy beyond respiratory disease? It's a, it's actually a very valid scientific question, given the prevalence of TSLP in the skin, and so we're going to start a phase IIb program in the coming year in atopic dermatitis as well. So that's 7 million patients eligible for this program alone, so a lot of excitement around this program. Okay, number three, our anti-TL1A. So we had our eye on this pathway for a number of years because TL1A is an important cytokine that blocks both inflammation and fibrosis. A very unique combination of things, very relevant to inflammatory bowel disease, especially Crohn's disease. There's a deep genetic linkage between IBD and this target as well, and a number of our competitors have tested an anti-TL1A in ulcerative colitis, and it's shown efficacy to be better than any other biologic therapy. We're really excited about this collaboration with Teva and TV-46574, 'cause we believe this molecule has the potential to be best in class among all of these. So why do we believe this could be best in class? So I'll direct you to 2 pieces of data, 1 preclinical and 1 in the clinic, that's brand new, hasn't been shown before. So here we look at a preclinical study comparing TV-46574 to one of the anti-TL1A competitors, and we see about an 80 times improved potency compared to one of the competitors. Then on the right side, we look at the specificity of binding. So what's been noted by the scientists at Teva is that TV-46574 binds to TL1A and prevents the interaction with the DR3 receptor, which is the receptor for TL1A that promotes inflammation and fibrosis. However, it doesn't seem to prevent the interaction between TL1A and the decoy receptor, DCR3. Now, why is that important? So it seems that the decoy receptor is actually a natural autoregulatory mechanism. It clears TL1A as a natural sink to temper inflammation, and we can actually take advantage of that to actually improve potency even further of a molecule by keeping this interaction intact. So in other words, not only do we get the anti-inflammatory effect of blocking the DR3 receptor, we preserve the natural regulatory effect of the decoy receptor. I'll show you for the first time some clinical data that that's a proof point of this. So in the multiple ascending dose study of this molecule, TV-46574, patients were dosed with three different doses of the TV-46574 molecule or a placebo for three doses and followed over about 12 weeks. What you can see here with the first dose of the TV-46574 molecule, at even the lowest dose, you see profound reduction in free TL1A levels. This is exactly how this molecule is supposed to work. The decoy receptor will clear TL1A, so this is evidence of potent target engagement demonstrated in a patient study. This, the multiple ascending dose study was actually in patients with mild asthma. So this shows clear target engagement of the target, and we know already it's more potent than the competitor. So we think this has a clear possibility to be potentially more potent and more effective than the other TL1As, and also with a very competitive dosing regimen. We have a study in a phase IIb study in both UC and Crohn's already ongoing that our Teva colleagues are running. The interesting thing here is that none of the competitors have done a Crohn's disease study yet in phase IIb. None of them have done a dose-ranging study. So we could potentially be first to market in Crohn's disease with this molecule, in addition to being best in class. So really excited about this program. IBD alone represents an opportunity of 2.3 million eligible patients. But I don't think we're done with IBD with this molecule either. Now that we're in a partnership, we'll run through Frank's very interesting engine that he'll talk about on how we pick indications for novel molecules, and I can see certainly in the future a number of additional indications with this target to come behind this IBD program. So another potential multi-indication blockbuster. Okay, so I think I'm on number 4. So I'm going to shift gears a little bit to the oral portfolio and oral drugs in our portfolio. So I mentioned where we are positioning these molecules, so early disease. So small molecules in particular are amenable because patients are willing to take, more willing to take small molecules, even if they don't have as severe disease. These three programs, the rilzabrutinib, the covalent BTK- covalently reversible BTK inhibitor, Kymera's SAR656 or KT-474, the IRAK4 degrader, and oral TNFR1 signaling inhibitor, SAR566, program. Three very exciting programs targeted for early disease in a number of different indications. I'll start with rilzabrutinib. So this, this is a really interesting BTKI that came to us with the Principia acquisition, and what differentiated this molecule is the reversible covalency. So the way this molecule binds to its target, BTKI, it has two different binding domains that provide it more specificity, so a lower risk of off-target effects that might impact safety. And also, but it's reversible covalent binding, so you don't need a high level of systemic exposure to keep the drug onto its target. What does that mean? So higher specificity and less need for high exposure. Both of those things can translate to better safety. And so we think the main differentiation point for this molecule is the potential for better safety than other BTKIs. And given that profile, we are really excited to explore a set of diseases that are different, where, from where other BTK has been explored, moving away from the B cell-mediated diseases to the diseases that might be mediated by mast cell, basophil, and eosinophil activation, atopic dermatitis, chronic spontaneous urticaria, and asthma. And today, for the first time, I'm going to share with you the data from all three of these trials. So we started all three of these with multiple doses, at pace, shortly after we made the acquisition. So first, chronic spontaneous urticaria. We saw a statistically significant improvement in the primary endpoint of UAS7, which is the regulatory accepted endpoint for CSU. 7.5-point reduction, which is on par with what we've seen with the competitors. If you also looked at the itch score, the ISS7, which is a FDA-approved primary endpoint, we also saw a significant competitive reduction in the ISS7, so significant improvement in itch. I highlight that specifically because in the AD trial, we did not—we saw trends for improvement in lesions, but we did not see a statistically significant improvement in the EASI score or lesions. But what we did see was really interesting. If you looked at the itch data, there was a clinically significant, clinically meaningful reduction in itch that was rapid and progressive over the time for this study, which was a 16-week study. There are a number of dermatologic indications that are driven primarily by itch. One is prurigo nodularis, one is CPUO, chronic pruritus of unknown origin. We think that this mechanism might have real impact in both of these diseases, where, for example, prurigo, even the lesions are largely driven by itch. But I think the most exciting piece of data that we got from this set of studies is in asthma. So this was another wow moment for me when I saw this data. So we did a study, which is an ICS withdrawal design that we've done previously with a couple of biologics. This study is, you take moderate patients, patients with moderate asthma, optimize them on their inhaled therapy, ICS and LABA, and then you have an optimization period for four weeks, and then you withdraw, first the LABA and then the ICS. When you do that, the patients generally lose asthma control, and these patients, before withdrawal, are started on either the drug, rilzabrutinib or placebo, and we see whether the drug is able to prevent loss of asthma control. And indeed, rilzabrutinib did show a trend at the lower dose, in a 25% reduction in asthma control. I should also mention, these are just the results of the low dose. The high-dose cohort is going to read out in the coming year. But what was really exciting was the effect on asthma symptoms, the ACQ-5. Here you can see a rapid and significant reduction in asthma symptoms even before we did ICS withdrawal or LABA withdrawal. You can see it was fairly persistent. ICS LABA withdrawal began at four weeks and ICS at six. The effect even stayed despite withdrawal of the inhaled agents. This is potentially transformational for asthma. There's a huge swath of patients with asthma today in the moderate category and even in the mild category, not having frequent exacerbations, but are extremely symptomatic despite ICS LABA. The profile of these patients is a little bit different. A lot of them actually have non-Type 2 asthma, and that's in part why they don't respond to ICS and as you get milder in asthma severity, the Type 2 population actually is much larger. So this is a large, potentially addressable population who has severe asthma symptoms, poor quality of life. They probably don't qualify for a biologic today because they're not having frequent exacerbations, but clearly, there's a high unmet need for these patients. And we can change potentially the asthma treatment paradigm, having a brand new oral that can treat this huge segment of patients for which there's no therapy today... potentially treatment paradigm shifting in asthma, getting into a new age of now intervening early in asthma. And this is a distinct population for rilzabrutinib from the one other one I talked about for Lunsekimig. That was a type two high population. This is actually potentially type two low and symptomatic. So making clear inroads into asthma, into earlier disease with different mechanisms. So rilzabrutinib, in summary, so we're really excited in the coming year to have the additional phase two data from the higher dose cohort, reading out in the first half of the year. The EPI, again today, has 1.9 million there for the moderate severe patient. If you add this other population of patients, it'll be much larger. We're also announcing today we're gonna start phase three programs in the coming year in both pyoderma gangrenosum and chronic spontaneous urticaria. We have the IgG4-related disease trial going. We'll have a readout for that in the second half of this year. We also have our rare blood indications, both ITP and warm autoimmune hemolytic anemia, to read out in the coming year. For ITP in particular, at the ASH conference this weekend, we're gonna have further data from our phase 2 trial, showing further data on it, both efficacy and patient quality of life in patients with ITP. So altogether, over 3 million patients eligible across indications for this multi-indication blockbuster. Okay, number 5, our IRAK4 protein degrader. So I think this is probably the most innovative project we have in the portfolio today, because it's the most advanced protein degrader in immunology. This has never been done before in immunology. And why is this program so interesting is because...in part, because of the target, IRAK4. IRAK4 is an important signaling protein downstream of toll-like receptors and IL-1 family, that have broad potential to treat diseases across the therapeutic areas I mentioned. But it's a difficult to drug target. Why is that? Because it has two, two functions. One is an enzymatic function, as a kinase, that most proteins, and classically, we develop kinase inhibitors that inhibit protein function. But it seems if you use a kinase inhibitor against this, protein, you don't get very potent anti-inflammatory effect. That's probably because there's another function that IRAK4 has, which is a scaffolding function. It binds to MyD88 and forms a cluster of proteins that develop a signal to, to activate inflammation. And that process, the scaffolding process, is not inhibited by a kinase inhibitor. You need something different to target that, target that, and a protein de- degrader is so well suited now to hit this specific target. The preclinical data that our colleagues at Kymera generated show that this molecule was just much more potent at inhibiting inflammation than other kinase inhibitors that have been in the clinic before that. Then we had very exciting phase 1b data. Our colleagues at Kymera did a 28-day study in patients with atopic dermatitis or hidradenitis suppurativa, and this was really just designed to be a proof of mechanism, and we established that in terms of we could degrade IRAK4 in the skin of these patients. We had good penetration of the compound, and IRAK4 levels went down. But really, interestingly, we did measure the clinical efficacy, and we saw improvement in lesions in atopic dermatitis and itch in atopic dermatitis, as well as lesion improvement in lesions in HS, which is fairly hard to do in a 4-week trial. So this, this generated, on our part, a huge excitement for the potential for KT-474 / SAR-656 in these two diseases, atopic dermatitis and HS. As HS in particular, is one of those diseases where we want to intervene early. Patients who have late stage HS tend to develop scarring of their skin and irreversible damage that can be disfiguring. We want to intervene earlier in that disease, and this is a potentially outstanding way to do that. So we've started two programs in phase 2 in atopic dermatitis and hidradenitis suppurativa, and first patient in has already occurred for both of these indications. So we're moving at pace, and we look forward to a readout for both of these studies in 2025. Beyond these two indications, which represent about 3.4 million patients, we think there's potential for this pathway beyond just dermatologic diseases. There's probably other derm diseases we can think about, but even beyond in other therapeutic areas, in respiratory and, and potentially even GI. So the potential for another multi-indication blockbuster. Finally, I'll end with number six, which is last, but absolutely not least, our oral TNF receptor 1 signaling inhibitor. Now, this molecule took years to create because it was very difficult to develop, but we have a molecule that does exactly what it's supposed to do. And what that is, is this molecule binds to soluble TNF trimers and inhibits the binding of soluble TNF trimers to TNFR1. And that's a receptor that generally signals the inflammatory component of TNF signaling. But it leaves intact the interaction between membrane TNF and TNFR2. Why is that significant? One, TNFR2 probably serves as a protective mechanism against infection. And we were actually able to demonstrate, Frank's team was able to demonstrate that in preclinical studies in a bacterial infection model, where a biologic TNF caused high levels of mortality in this mouse model. But using oral TNFR1 was protective, much lower severe infections in that model. And so that's potential safety benefit over a biologic TNF. Then the second aspect is TNFR2 also activates T regulatory cells, so the natural autoimmune, natural, excuse me, brake on preventing out-of-control inflammation. And that goes back to that disease modification motif that I talked about. One of the key issues with TNF biologics is that many of them lose response over time in the indications they are today. One of the reasons it's thought that this happens is anti-drug antibodies, and potentially it could be 'cause we're not getting effects on Tregs, 'cause they probably block TNFr2. So in summary, we're talking about a drug that, in the short term, can be as efficacious as TNF, but in the long term, provide the disease modification that TNF biologics could never provide. And on top of that, improve safety, so patients can safely feel safe about taking this long term. That's the vision for this product. And if you think about it, TNF-mediated diseases are the largest set of diseases in immunology, hands down. The potential for this is not an oral Humira or another oral TNF. This is TNF blocker 2.0, an upgraded version, improved efficacy and improved safety. As we have with all the other programs, proof of mechanism to establish what we're saying in terms of the mechanism. We did a 28-day study in mild to moderate psoriasis, looking at efficacy in terms of PASI score, which is a global assessment of psoriasis and also TLS, which is an individual lesion score. On both of these parameters, we saw significant improvement in patients dosed on oral TNFR1 SI, compared to placebo. That level of efficacy is on par with what we've seen in biologics at that very early time point, four weeks. We also saw a significant improvement in the biomarkers downstream of TNF activity, so indeed, this drug does block TNF as we expect it to. Now, the safety differentiation piece is something we'll have to show with much longer-term data, of course, but this gives us good confidence that, yes, we are blocking TNF. And so once again, with this data, we're starting at pace multiple indications. We've started both a phase IIb study in psoriasis. Patients are already being screened and recruited in that study, and also a rheumatoid arthritis phase IIb program, where patients are also already being screened. We'd also like to announce today an IBD program will start in the coming year, and a psoriatic arthritis program straight to phase III in subsequent years. So once again, starting at pace because we've gained the clinical belief in this molecule that we needed, and over 8 million patients eligible for this mechanism. So I hope I've shown you that we see a very clear path to leadership in immunology. We have the assets, and we have the strategy to deliver, and this afternoon and today, you'll have a chance to meet the people. The leaders for all these individual programs will be available for discussion in the afternoon session. There's, of course, a lot more talented people on the program, and one of those most talented people, I'd like to invite to the stage right now, Shaju Backer, who's the franchise leader for immunology, and he's going to show you how all these assets are actually going to expand the market across the diseases. Thank you very much. Okay, thank you, Naimish. Good morning, good afternoon. I know there are a lot of people who have joined us online as well. My name is Shaju Backer. I'm the global head of the immunology franchise at Sanofi. I joined Sanofi 2 years ago, but I'm not new to immunology. I've been in immunology for 20 years, with the origins, launching infliximab Remicade in its, all its early indications. Prior to joining Sanofi, I was the global general manager for Humira franchise across all 16 indications. I was also responsible for Skyrizi and Rinvoq in the gastroenterology development programs in UC and CD. I joined Sanofi 2 years ago as the global franchise head for Dupixent in respiratory gastroenterology, responsible for the launch of EoE, relaunch of nasal polyps, and really focusing our asthma program post-COVID, whilst preparing for the launch of COPD as well. I'm thrilled to be here, to taking on this role as of July 1 this year. In the next few minutes, I'm going to walk you through the why there is a significant opportunity in immunology, how multiple MOAs new drugs can coexist by growing the market and go on to become blockbusters. I'm gonna take you through a couple of case studies. So for the first point, these are all the diseases you heard Naimish talk through a few minutes ago. And look at the advanced therapy penetration. And what I mean by that, across US and EU5, there are over 100 million patients diagnosed just across these diseases. Of those, 20 million patients are eligible for a biologic or an advanced therapy, small molecule. Yet, less than 4 million patients are on an advanced therapy today. Looking on the right side, our lead indications are where Sanofi we lead today. AD, only one out of 10 patients end up on an advanced therapy. In asthma, which in many ways is a severe disease, only two out of 10 end up on an advanced therapy today. COPD, obviously 0, AT penetration, as there are no approved biologics, but we're gonna change that, and you'll hear more about that in a few minutes this afternoon. But I do want to highlight asthma here. The 1.7 million, what Naimish touched on, that is just the moderate to severe patient population. You heard two additional assets we're going to take into asthma, not into this patient segment, a completely new patient segment, the mild to moderate, uncontrolled, high-risk patient population. An expression I learned recently, "We're going to skate where the puck is going." I didn't know what that meant. I did look that up. That is what we are going to do. We have the ability to change clinical practice. We've done this. We have the track record. We've done this in AD. We've done this in nasal polyps. We've done this in EoE, and we're about to do this again in COPD. We have the ability to take the science and the drugs into completely new patient population, meet the high unmet need. Now, the case study I was referring to, I'm going to use the psoriasis market evolution as my case study to explain to you why multiple MOAs can coexist. Not only just coexist, grow this market. I was there at the origin. As I mentioned, I was involved in launching infliximab in psoriasis in the early days, and it was tough. The dermatologists were worried about PML. That's all they knew. Biologics, they were scared, like: What does this mean? They were not used to monitoring patients. They had the safe, the topicals and managed their patients. They never had a late night call-out, and then the industry endured with the biologics. Yet look at that. For five years, they only had TNF as an option, which came with black box warning. It still grew the market threefold from 30,000 to 100,000 patients during that period. They got comfortable. The science led the way. Now, on the left side, you have what each MOA can bring to the market, potentially. It could be efficacy, safety, or convenience. At year 5, you saw the entry of the first IL-12/23, with no black box warning, so elevating from a safety standpoint, but also bringing the Q12 weekly convenience dosing. A similar analog I'm going to pull with dupilumab, that Naimish covered, the our ability, potential, opportunity to go into this Q12 dosing in AD. Now, let's stay with psoriasis. Year 10, the first oral, PDE4, came into the market, and it brought in a whole new patient population onto advanced therapy treatment. The dermatologists had a safe option, pre-biologic option. And again, pulling our analog here, you heard about three orals in different diseases we are developing today, in AD, in asthma, and TNFR1 across multiple diseases. Now, after 10 years with the number of entry, you would think the market, you know, would be saturated. No, that was the time when the IL-17s and the first IL-23 entered the market, raising the efficacy to from PASI 75 to PASI 90. And meanwhile, the label and warnings, they were cleaning up as well. So each of these mechanisms were bringing a new differentiation to the table. Now, by year 15, you would think all the, you know, unmet needs, you know, that's not a term you could use in psoriasis. And you saw the entry of the IL-23 that raised the efficacy once more to PASI 100 absolute clearance and broadened risankizumab, the efficacy, sorry, durable efficacy. And that expert term you heard Naimish use with Amlitelimab, durable efficacy. And during this 15-year journey, you've seen the market grow from 30,000 patients at the origins to 100,000 when the second MOA opened up the market, all the way to over 300,000 patients, and the market still continues to grow. What does this mean for AD? I would like to make one more point in psoriasis. Each of these MOAs, as they entered the market, they grew the market, and in revenue terms, it went from $3 billion to $24 billion. And seven of those molecules or seven of those products went on to become blockbusters with more than $1.5 billion. So if there is any doubt that multiple MOAs can coexist and become blockbusters, here's your proof point. Here's your case study. Now let's look at AD. AD is in its infancy in many ways. Six years in, it's technically only four products. Lebrikizumab is only just approved in Europe recently. So if I look at 2022, the market size, $7.5 billion, comes from essentially four products. Just three MOAs and only one blockbuster, which happens to be ours. We know this market. Look at the journey ahead. Oh, by the way, 2022, the market growth in AD was 45%. This market is about to explode, and we have three assets, you heard a few minutes ago, in AD we want to bring to really drive this market growth and grow with this market and become blockbusters. How can they coexist? And I'm going to walk you through just the AD, just to give you an example. As I mentioned, the market we anticipate will grow by fourfold from $7.5 billion in 2022 to 2035. That's our estimate. Amlitelimab, using the psoriasis analog, best-in-class, durable efficacy, very differentiated efficacy with a patient-friendly Q12 convenient dosing. It will... Very heterogeneous disease, as you heard earlier. It has the ability to bring in a completely new patient segment or reach a new patient segment. The IRAK4 degrader, pre-biologic option, an oral option, safe oral, to get patients onto advanced therapy, becoming the gateway drug before they go on, move on to a biologic. The exciting nanobody, Lunsekimig, IL-13 TSLP. You heard about the 1 + 1 math. You know, it started with 1 + 1, 2.6. I've heard 3, and I even heard 4 now. So the number, the 1 + 1 effect seems to be going up, and I'll leave that to the scientists. But the point is, we have an asset that can really raise the efficacy ceiling and lead our leadership in AD well and truly into the next decade. We have the asset that can raise the efficacy ceiling, as you've seen in the psoriasis example with risankizumab. Now, switching gears, a true pipeline in a molecule asset, the TNFR1 signaling inhibitor, and you've heard this said again and again, and I will repeat it again. This is not an oral TNF. This is a differentiated mechanism. It's a selective R1 signaling inhibitor, sparing the R, R2 pathway. With that comes differentiated safety, efficacy, and durable efficacy. That's where this molecule will be differentiated. Now, look at the rheumatoid arthritis segment. This asset, we plan not to compete just on the old generation TNF biologic segment. We want to take this into the newly evolving oral segment. Recently, Morgan Stanley, the article that just came out, there is truly an oral play in immunology today, and we have multiple assets, and this being one of them. So 70% of rheumatoid arthritis are today made up of the old generation TNF mAbs and the orals 22, 70%, and we have the asset to compete in that segment. And just as a reminder, of the $38 billion TNF market today, 40% of that is in rheumatoid arthritis, and the only oral option is a JAK, comes with a safety baggage, and we have the differentiated asset to compete in that oral segment. In IBD and UC, 50% of the responders today on all the available medication within 52 weeks, end of year one, lose efficacy, half of them. Frank calls it the mean drug survival is 1-2 years. They're cycling through to the next treatment option. There is a big need for a safe, pre-biologic options. Again, today, there are JAKs and S1Ps. They both come from safety baggage- with safety baggages. So we have the ability to bring in and position as a pre-biologic, safe and efficacious oral option. Psoriasis, very fragmented market, as you see. Even there, when we talk to the dermatologists, they still say there is a need for a safe and efficacious pre-biologic options. PDE4 came in as the first orals, but the efficacy was not quite there. The JAKs have come in, they sit somewhere between the PDE4 and biologics for efficacy. So there is still a need for truly differentiated oral for safety and efficacious oral, I mean, in psoriasis. Once we understand the mechanism of this asset, we have then an additional opportunity to be the backbone for combination therapies. As you know, in IBD, for example, the TNF IL-23 combinations have already been studied in the biologic form. What if we can do that with the orals? There is a tremendous opportunity for this asset to be the backbone for combination therapies in the future as well. So to wrap up, I want to leave you with few messages. There is still a significant unmet need in immunology. Let me remind you or put it in a different context. When we were preparing for this meeting, we did some analysis. By 2022, we have created the third largest immunology company in the industry, with very little overlap with the number one and number two company, Janssen and AbbVie. Because we have gone after the undruggable diseases, the high unmet need diseases, and we know how to do that. That's how we build the third largest immunology franchise in the industry today. And now we have a phenomenal pipeline, and we have the conviction and the capability to go beyond and be a premier immunology company. We have the innovative science, breakthrough differentiated therapies. We have multiple multi-indication assets with blockbuster potential. We have aggressive parallel development plans. You heard number of studies that Naimish mentioned, going straight to phase 2B or phase 3 directly. We have the confidence, conviction, and the know-how. And above all, we have a world-class team, experienced in development and commercialization of these assets. So with that, we'll pause for a short break, a Q&A, and after that, we will continue with our leadership in immunology story. Eva? Thank you very much. So please stay, please stay. We're going to get some, some chairs, four chairs, because I also would like to welcome back Naimish, Paul, and Houman. So we have Alizé, who I hope many of you and my team know. She's here ready with the mic. And we would like you to ask really the questions that are focused on this session. Obviously, we have more Q&A sessions later. Can we have a clock, please? 20 minutes. So who wants... I said four. We need a first question. So we start with Florent. Thank you. Thank you very much, Florent Cespedes from Société Générale. Thanks for the presentations. When we see on the slide 10, next year, we will have BTK inhibitor phase 3 results, then in 2025, the IL-33, and then the next set of phase 3 results will be in 2027 and beyond. So my question is, would you consider to maybe acquire some products, do some BD activity to kind of bridge the gap between the short-term phase 3 readout and the 2027 and beyond? And if yes, would you consider, let's say, which areas, as in immunoinflammation, you already have a pretty broad portfolio, and could it be on adjacent areas or in other sectors? Thank you. Okay, thank you for the question. I think the readouts we have on tolebrutinib on, there'll be other interim readouts. There is the high-dose asthma readout with the Lunsekimig, and of course, there's IL-33. They're pretty important readouts. So first of all, that's exciting. Secondly, I think we've shown that we've got good discipline, so if we want to add, we picked up Tzield, inflammation, in inflammation, and off to a good start with the launch. We picked up, you could argue, in inflammation, graft versus host, Rezurock, and we're off to a great start with that as well. I think we've shown that we'll pick up the pieces that add to the shape of our business, but only if scientifically it has some credibility and if the marginal cost to deploy is lower. There's no point in us picking things up to deploy huge commercial footprints in the areas that are not overlapping. There's just absolutely no point. We're perfectly balanced now between investment in R&D and commercialization effort. Things that can go in the bag, to use the old phrase, things that can add, and we can deploy with our expertise for incremental value, very interesting for us. So we just stay open-minded to that. David? What a hand. David Risinger. Thanks very much. Dave Risinger from Leerink Partners. So I have two questions, please, one for Paul. Could you comment on the potential for Dupixent patents to protect Dupixent beyond the early 2030s? And then second, for Shaju, just interested in how you're thinking about positioning Amlitelimab relative to Dupixent. Thank you. Okay. So I've clearly been asked the question a few times before, and the first thing to say to everybody is that before I joined, we had brought over a lot of senior executive expertise from the Humira IP team to join Sanofi. Our new general counsel of a couple of years ago, one of the first things he did was kick the tires on the IP on Dupixent, because he knew how important it was, and said that this was one of the most impressive strategies he'd ever seen, and he's quite good. The third thing is, you know, that we go, I think, to March, roughly March 2031 in the U.S. and September 2032 in Europe. But while we don't share much beyond that normally, we have a strong series of innovation patents that range from 2034 to 2040. So more news to come on those, but you would assume a company of our size and quality, who knows how to do this, to have those innovation patents ahead of us are very important opportunities for us and for the brand. As for you and your brilliant answers, Sharon? It's, we don't think of it as co-positioning. I mean, I, as I walked you through the psoriasis example, we believe the new MOAs coming in will really grow the market. And as I mentioned, the AD market grew by 45% just last year alone. The projection is similar trajectory, and the heterogeneity of the disease, I'll let Naimish talk about that a little bit. So if you look at the profile, it is completely different. The durable efficacy, the convenient dosing, it differentiates completely from all available treatment options for AD today. So for us, our hope is to bring a whole new patient segment and really drive the market growth, capitalize on that. And as for as how the mechanisms will work differently, I'll let Naimish talk about the heterogeneity of the disease. Yeah, absolutely. It's well recognized that atopic dermatitis is a fairly heterogeneous disease, that patients have been characterized as intrinsic versus extrinsic, and then some have a type 2, pure type 2 profile, others have this mixed phenotype. And it depends a little bit on actually things like racial background, geography, other factors. So clearly, there's segments of the population are gonna respond to one better than the other. And plus, the big differentiator with rilza as well is the infrequent dosing. And patients want choice, doctors want choice, and depending on who the patient is that's sitting in front of them, now we're offering them different choices on what's the best drug for their patient. And I- I'm sorry. Go ahead. The psoriasis example, as you saw, with the new MOAs entering the market, it didn't stop the existing drugs to grow. They all continued to grow, and the expression that rising tides lifts all ships, and that's exactly what we expect to see in the AD market. When Sharjun and I worked on Remicade a lifetime ago, there was a Swedish biologics registry. And it said the average number of biologics a patient had had was 5, and there were only 3 approved. And we know that as patients do very well on a biologic, they get this efficacy they've wanted all their lives. And then when they drop from, say, in this psoriasis example, from PASI 100 to PASI 90, they're not happy. So they go back to the doctor and try something new. And this churn in a vast penetrating market just means there's so many new patients presenting. And I'm well aware that particularly skilled observers of the industry like yourselves, they like to declare winners and losers. You're better. This data, side by side, says, you win on this, you lose on that, and like to declare a cannibalization impact on the loser. We spent some time preparing that one slide on slide 60 to help people understand, and I think you said it really eloquently, you have multiple biologics in the space because they will all go on to be mega blockbusters for the reasons outlined. It is not winners and losers. Dupixent will grow, and we support it to grow until its very last day, and it still means everything else will go on to be a blockbuster next to it. As long as it has efficacy, safety, fair enough, as long as it's approved. But if you get there, you win, and it's a question of how many we win with, which is the most interesting for us. It looks like Seamus really wants to ask a question, so if we pass him the mic. Tariq, can you get through? Hi, Seamus Fernandez from Guggenheim. So, my question's on the oral TNF, and I just wanted to, you know, drill down on this a little bit more. In four or five years from now, we're gonna see probably 10 or 15, you know, biologics available. I think you make a pretty compelling case for, the science behind the product, but really proving that this becomes a, you know, sort of core alternative, can come from a number of different directions. It can come on price, it can come on, you know, differentiation on safety, or it can come from your conviction that you can pursue additional oral therapies targeting IL-23 and other mechanisms, that are combinable. So really interested to just get a sense of how you're thinking about those three separate, opportunities for oral TNF. Then maybe, just as an add-on, how druggable orally do you think IL-23 is, versus some of the other potential options? Thanks. Hey, Seamus, thank you. Thank you for that question. My voice is just about- You're getting emotional. Yeah, I'm getting emotional. I'm about to cry. Every time I talk about that molecule. You've positioned it beautifully, right? The reality is, that this will be a gateway molecule. If it's safe, if it's efficacious, it's a gateway molecule. It's absolutely... Excuse me. Thank you, Eva. There's no cold chain. You don't need an injection. If you're gonna have another biologic on top, you don't need to take two. So the reality of this is the three, three vectors you chose were perfectly correct. I just want everyone to be super clear. This isn't an oral Humira. It'll have a different profile, a different risk profile. It'll be used in a different population. It may well be applicable to primary care. So I, I think in terms of its commercial positioning, its clinical positioning, its combination positioning, all of those things will make it differentiate. And then I think, just to add a little bit, there's a lot of chatter around what will the biosimilar marketplace be like by then? It's just a complete misdirection, because this is an advanced oral therapy with a different safety and efficacy profile. So let's just get that straight.... And if you forecast it as an advanced biologic, then you start to understand what it can do. It is most likely going to be used in combination, may even be used on top of many of the standards of care. You know, this is a new battleground. And you, you know, you, you ask about the 23, you know, the more the merrier, because we know what happens to the market. The necessity to go advanced therapy orals with new efficacy or tolerability into mild to moderate populations, to take penetrations from what? 30, 40-60, 70. This is a whole new ball game. A whole new ball game, and you have to have a different profile to go earlier. Much like taking rilzabrutinib, and the only advanced oral into mild to moderate asthma patients. You know, this is just a different game. It's almost different diseases. There's so much opportunity if we get the profiles right. We're not, by the way, you know, the same disclaimer, you know, we don't know how these things will play out play through phase 2 and 3, but if we get this right, these are literally game change. You know that. I mean, that's, that's how it's going to be. Specifically, some 23, maybe 17, those have a narrower indication set. If we get an oral TNF correct, we can go across all the indications. One of the reasons why we wanted to create some bandwidth in the R&D budget to decide, particularly with the IRA ahead of us, to say: You know what? Should we really leave indications on the table or should we move? Because you get one chance to have a drug like this. Well, I just want to add, we're respectful of time, but we've talked about mechanistic differentiation. Something that people never talk about is pharmacological differentiation. So while we love biologics, there is there's early data suggesting, published years ago, that antibodies get sequestered into joints, into tissue by the TNF. The beauty of small molecules, the different pharmacology, will give you a different pattern of efficacy. So while I think, I think it's a misnomer to have this biologic versus small molecule discussion, it's an orthogonal treatment option that will create a whole new therapeutic space. Okay, here we have Emily from Barclays. Hi, Emily Field from Barclays. Thanks for taking my questions, all of us, too. The first one is for Houman. In your prepared remarks, you mentioned, you know, when you were doing your deep dive into the, R&D portfolio, that there were some quick wins and some things that would take longer to fix. I was wondering if you could provide some color on the latter, and just, you know, an example of that, perhaps. And then on Amlitelimab, in your peak sales potential, I was wondering if you could get into how much your probability weighting the success of the Q 12-week dosing. You know, is that really going to be necessary in terms of reaching the upper end of, or getting above $5 billion? You know, how does that differentiate the commercial potential if perhaps it's only successful in every four weeks? I'll take that one first. Yeah. So we have built a profile, and you heard Naimish go through that. We have a high degree of conviction and confidence on that, first of all, and maybe Naimish can touch on that. But having said that, we have done the sensitivity. I don't think that will... It's a durable efficacy. That is the biggest differentiator, because one of the things we are going to really explore with this molecule is, for example, you know, can we get the patients into remission? And that's a terminology in asthma. Recently, guidelines came out on remission, and that is something we are really exploring in AD as well. So there is, you know, we're not over-indexing on the dosing alone. The durable efficacy is also a key differentiator with OX40 ligand mechanisms. But hopefully, Naimish can give more confidence on the Q 12 weekly dosing. Yeah, absolutely. If you think back, the phase 2 data for Amlitelimab, we showed and Kymera had originally showed that a set of patients, 70% of the patients who had an IGA 0-1 response by the end of that trial, it was a small trial. If we followed them out off drug over six months, 70% of them still had a deep, durable response off drug. This gives us a lot of confidence that we could dose infrequently. I mentioned the part B of our study that's going to read out in the second half. We're going to essentially try to recapitulate those findings in a much larger trial, and we have high confidence that we will there. And the third thing I'll add is that what I didn't mention in detail, the first dosing arm, 250+ loading dose Q4, that's only for 24 weeks, and even in that arm, we're going to go to Q12. So all roads lead to Q12 dosing. It's just when it'll happen. Okay, thanks for the question. At the risk of beating an analogy to death, I'm going back to my bonsai analogy. The near term is the simple organizational change, simple, which requires the pruning, and I've been really excited about how my leadership team and the rest of the R&D organization have responded to the capital allocation, discipline, and leadership. What's harder to do is to build those roots and to grow those roots. And so those roots for us are innovation. And over the next three to five years, the value that I bring, having come from outside the organization and had a real open vision on how we build innovation in this organization beyond the innovation immunology we've already got, is something that take a little bit longer. We've got a number of mechanisms we'll share in the next couple of years with you guys, but we are really, as we go forward, layering in scientific excellence and innovation as we go. I mean, as I said, we hope to be the most innovative biopharma company in the world. Okay. Steve? Thank you. Steve Scala from TD Cowen. It's been a great presentation, but analysts are supposed to be skeptical, so allow me to play the devil's advocate.... Going back to the very beginning, you're arguing that Sanofi is going to enter a new trajectory in multiple therapeutic areas, from a position of being a competitor to a position of leader. But when I think about this industry over a very long period of time, such ascensions are rare, and I would note that most CEOs tell us that they have the best pipeline and they're on a new path. We've heard that two or three times in the last two weeks. So why is it different at Sanofi now? And what does Sanofi have that others don't? I think industry leadership needs to be more than lots of compounds and being number one in a crowded therapy or immunology market, or are you saying that that's sufficient for industry leadership? Thank you. Yeah, it's been a few R&D days. I think, I think the difference is quite fundamental, which is in 2019, we picked a list of assets because we didn't really have a choice. We knew that we knew how to do immunology. We knew that actually it's very hard now, particularly with FTC and everything else, to accumulate the mechanisms that we have in immunology, right? And we started this in 2019. We started accumulating. And, you know, there's very... I can't see anybody structurally getting as many shots on goal by disease as we have been able to. So sensitivities have increased, you know that. Secondly, we're very good at immunology. You know, I tried to say it earlier, you may give us a D-minus on some discovery, but, you know, we've developed Dupixent to be what, you know, there needs to be a new category of super brand. You know, we boldly went after COPD. We know exactly what we're doing. We know where to take risks. We know investigators, hospitals, regulators, geographies, reimbursement, HTA. So, all we're doing, the reason we doubled down immunology, partly the science, fast-growing market, could argue more durable in oncology over the longer term. But we stacked the deck, right? We know that we know how to do these diseases, so we're not surprised. We know exactly what we're looking for. And it's very hard. If I turned around to you and stood up here and said, "I'm gonna have a new NASH drug, then I'm gonna have a new drug in something else." And you're like, "Okay, not sure. More white space," you know? No. The reason why we feel... I feel confident saying how we're gonna do this, is because we've gone to where we're strong. We've built something that's hard to replicate. We know exactly how to do it. We will get failures. We'll get - not everything will work or come out at the... But 12 shots to get 5 mega blockbusters in an area we know, particularly with biologics that have a high POS, you know, all we've done is put the odds in our favor. I would argue maybe other CEOs say that. I'm not sure that they, that they can argue the same collection of variables that can get us there. So I know you're only playing devil's advocate. I know it's not your own view. But, but I'm, I'm excited that, we spent time on trying to help you understand how you can coexist at scale. And I have to tell you, most of my conversations with observers, they like I said, it's winners and losers. We spent time on psoriasis just to help remind you that there is a phenomena about to happen in under-penetrated markets that has really not been seen before. Maybe asthma in the early nineties, maybe type two diabetes in the last decade. You know, there are very few markets where you can actually do this, and we are absolutely unique, so it's an easy bet for us. Okay, I have to close the first Q&A session. We're running a little bit over time. Hello. Didn't have that problem with the vaccine colleagues in June. Just to keep the internal competition going. But since we have a really intense program also in the second session, I would actually like to keep a 10-minute break. And I'm really excited about the next session because next to our speakers on NS and respiratory, we also have two- Yeah ... external speakers joining us. Yeah. So just to give you the energy to go through another really intense and fruitful session, if you just get 10 minutes, you stretch your legs, get another coffee, and we get back in. And the same for you on the webcast. See you at 10:40. Thank you. Pete, we're here for a question. Oh, yeah. Oh. Very sorry to interrupt all this discussion. Could I just please ask you, take, take your seats again so that we can continue with the main session... in, in a minute or so? So are we good? Doors closed? Okay. So welcome back. So our next session is going to focus on neuroinflammation, as well as our late-stage portfolio in respiratory diseases. And for this session, we've also invited two external speakers to share their perspective, and they will also stay for our following Q&A session. For MS, for example, a dozen treatments are available today, but we continue to explore potential new treatments as we believe-... Significant unmet need remains, but we really want you to hear this from an external voice. So for this, I would like to welcome on stage Dr. Sharon Stoll, to introduce herself and to share her perspective. Thank you so much for that introduction. Hi, everyone. I'm Dr. Stoll, as you just heard. I have over 10 years experience in treating MS patients as well as other neurologic diseases. Most of that time I've spent at Yale University in Connecticut, and I also want to thank Sanofi for bringing me here to speak on behalf of my patients. One of the first questions that I get when meeting a new patient is, unfortunately, "Dr. Stoll, when will I end up in a wheelchair?" And even with all of the MS medications that we currently have on the market, and we have over 20, all of those medications are geared towards new relapses, new lesions, new disease activity. And we still have a bit of ways to go when it comes to disability progression. What that means is, patients that are not only having new relapses, but even after those relapses they've recovered from those relapses, they still continue to progress over time. What that means is, basically, somebody that goes from being able to, let's say, run across the stage in four-inch heels without tripping, like I just did almost, to eventually needing a cane and then a walker and then a wheelchair. You can see here that this study was done not too long ago, back in 2015, and at that time, we still had a number of new novel MS medications that were in the market. 70% of patients were still concerned about disease progression, and over 50% of those patients reported worsening physical function since diagnosis. Since diagnosis usually means since they started new medication. To the left of the slide, you can see the top two bars. That's the natural history of the disease. So when I first started treating MS patients over 10 years ago, the scene was very, very different. When patients came in after their first or second relapse, even with the medications that were on the market, and we had a few, we had about 4 or 5, the chances of them going from relapsing or remitting MS, which is the overwhelming majority of the disease, so about 80% of patients with MS have that type. After 10 or 15 years of the disease, they developed that secondary progression. So that's even patients without medication and the patients that were on those initial MS medications that were introduced back in the 1990s. This study shows that the treated cohort, so that blue line at the bottom, blue, purple, the color of my jacket, and the color of Sanofi, even those patients continue to progress despite being on medication. So this is still an issue. And then to the right of the slide, you can see that in this cohort, over 1,000 patients were looked at, and of those patients, it was broken down into two groups, the patients that had relapsing, worsening disease, so that means brand-new symptoms, whether it be numbness or tingling in a part of the body or blurred vision in one eye or difficulty walking, and then having worsening from that, versus patients that continue to progress even without relapses. And that makes up over two-thirds of those patients. So two-thirds of those patients continue to progress. Unfortunately, the market is very, very, very slim when it comes to medications that we have to treat progression. Some might ask, "Well, how many medications are there? How many FDA-approved MS medications are there to treat secondary progressive multiple sclerosis without relapses?" The answer to that is zero. We have zero medications that are approved to treat secondary progressive MS without relapses, and we only have one medication to treat primary progressive. So that makes up over 10% of the MS population, those primary progressive patients. Our basic understanding of MS is evolving. It's constantly evolving. It's one of the reasons I love neurology, and I love this field because I consider myself a forever student. I love learning. I love it when my kids ask me, "Mommy, how long do I have to be in school? My gosh, this is forever." And I'm like, "Forever. You're gonna be in school forever." They love that answer. They stopped asking me that question. So to the left of the slide, we have acute neuroinflammation, and this is generally where we are with MS or where we were literally until a year ago. Everyone in the field, we believe that this is where the disease is. It's acute inflammation. If we can control new lesions, we can control new relapses, we have the disease covered. We're done. We finished our jobs. Congratulations, we can all go home. Sanofi, stop spending your money. You don't have to. Everyone here can just leave. Unfortunately, though, now we have a consensus. It's not just new relapses and new lesions. Unfortunately, our patients are still progressing. If you look at the right side, so this is the current understanding of the disease, that there's this smoldering, I don't want to say fire, that fire is really those new lesions, those new relapses. That smoldering disease is kind of, you put the fire out and, oh, my gosh, what's left is fantastic, right? After you put a fire out in a house, you could just move back in. No!... Right? There's smoke damage, everything is charred, and that's kind of what's going on in the brain underneath. Unfortunately, that's not just happening after a big fire, but that charred, burnt brain, if I can call it that, I hate calling it that, and I would never say this to a patient, happens in the beginning of the disease. It's not just two processes, A and then B, or the chicken and then the egg. It's really happening at the same time from disease onset. And what that translates to a patient is somebody that comes in, and they tell me that they haven't had a new relapse, they haven't had a new lesion in 15 years. They're stable. Their neurologist, their general neurologist told them, "There's nothing to do. Fantastic. You're walking into my office. You're not in a wheelchair. Congratulations, we cured your MS." So why is the patient coming to see me? Why are they seeing an MS specialist now, 15 years after? They're told that their MRIs haven't changed, there's no new lesions. They're coming in because they're still complaining of a number of different symptoms: chronic fatigue, word-finding difficulty, brain fog. A lot of these symptoms we've heard about with COVID pandemic over the past few years, that this long COVID, long-haul COVID, something that I'm very familiar with because, unfortunately, a lot of my MS patients complain of the same symptoms. For anybody here that has had long COVID knows it's hard to get out of bed in the morning when you have debilitating fatigue, and it's very difficult to be functional at work when you can't remember the name of your boss, or you can't remember the name of your students, even though it's three months into the school year and you've never had an issue before. They come in, and they want answers. They want to know, "Why is this happening, Dr. Stoll?" Well, one of the reasons it's happening is because they have significant brain atrophy. So you can see this normal brain density in a 20-year-old, those slit-like black spaces in the brain. That's what a great 20-year-old brain looks like. This patient has MS. You can see the little white dots on that slide next to the ventricles, and now you have a severe atrophy in a 55-year-old MS patient. So one of the reasons that we frequently say that dementia is more common as we get older, right? Those word-finding difficulties, senior moments. Nobody calls them young moments. They're called senior moments for a reason, because the normal history of the brain is it shrinks over time. It happens to everybody. There's no amount of Botox that you can inject in your brain to make it stay young-looking forever. Although that would be great. If anyone wants to develop something like that, I'm on board. I could be a test dummy. But this should not. The brain should not look this bad in a 55-year-old. Period, end of story. All I have to do is basically show the patient their brain, and they understand why they can't remember the names of the students three months into the year. And there's nothing on the market that does a good job. We have things that do an okay job at preventing atrophy, so we're definitely not where we were 10 years ago, 20 years ago, but we could be doing a lot better. Here's another one of my patients. Again, patient told their brain is stable, there's nothing new. And you can see over time, so this is over the span of 4 years, the brain is literally shrinking before our eyes. So again, I measure the ventricle space, so if you could see it's 25 millimeters, then 26, then 28, and this is over a matter of four years. This is somebody that is currently on MS medication, an appropriate MS medication. They're not having new lesions; they're not having new relapses. This is considered a good therapy. This is, this is great standard of care medicine. But if I showed anyone in this room, this is what's happening to your brain, I don't know if you would be happy with those results. So when I treat my multiple sclerosis, the first question that I usually get from a new patient is: When will I end up in a wheelchair? And we've made good headway when it comes to that, when it comes to new relapses and new lesions. In terms of disability progression, there's still a long way to go. One of the last questions that I get from patients that are established, that have been following with a neurologist for years, following with me for years, is, "Dr. Stoll, when will there be something new on the market? When can I try something new?" and fortunately, because of companies like Sanofi, I can say soon. Soon. Hopefully, the next time I see you, I'll have more data for you. Hopefully, in a year, we'll have something new on the market that will, that will reduce that cognitive haze, that, that word-finding difficulty that you have, that severe debilitating daytime fatigue that's so crushing that, you need 10 cups of coffee just to get through the morning. One of the other diseases that I treat as a neurologist, and this, this is a disease that, I was actually very surprised to learn that there's only 30,000 patients in the U.S. that, that have this disease. I feel like I, I treat so many of them that it's not rare, but I guess it's considered rare. It's CIDP, otherwise known as chronic inflammatory demyelinating polyneuropathy. Try saying that 10 times fast. It's actually pretty easy. Just kidding. But for this disease, there's one medication, and that medication is not specific at all. It's known as IVIG, which is IV, so, intravenous, IG, immunoglobulins. Basically, anybody here that's donated blood? They separate the red cells, the white cells, those white cells, there's some immunoglobulins, and they put the good immunoglobulins into somebody with bad immunoglobulins. That's basically it. So not a specific medication. Thankfully, close to 70% of patients respond to this, so it's a good medication. 30% do not at all respond to not just IVIG, but steroids or plasmapheresis. All those medications are extremely, extremely time-consuming and burdensome. And it's not a really good response because patients often have a significant worsening as it gets close to their next treatment. And you might wonder, well, how long are the treatments? Five minutes, an hour, once every six months? No. It's four to five days, multiple hours, every single month. So I don't know how understanding your bosses are, but imagine going to your boss and saying, "Hey, I'm gonna need one month—one week off every single month for the rest of my life." Right? I'm sure they would say, "Here's the door. Don't let it hit you on the way out." So you can imagine a lot of patients are on disability, not because of the disease, but just because of the medication. So here, there's a long way to go when it comes to treatment for this disease. So anything would be better than this. Not to mention all of the other risks of these medications, which I won't go into just 'cause of time constraints. But if anybody has any questions after, I'm happy to answer them. So before I introduce my colleague, I just want to say that, again, thank you for having me. Thank you for listening. And hopefully, my accountant will let me take my jacket as a tax deduction because I didn't realize I would match the screen. I just want to thank Sanofi for investing in my patients, so that when I go back to work tomorrow, I can say, "Yes, there will be something new. There will be something to help with your symptoms, and hopefully, you won't end up in a wheelchair, and you'll be able to walk in those five-inch platforms for the rest of your life." So thank you, and just want to call Erik up, wherever he is. There we go. Thank you very much, Dr. Stoll. It's a little bit disturbing to see that picture of a 55-year-old brain on the screen. I will not tell you why. So first, the slide, just to give a little bit of quantification of what Dr. Stoll talked about in terms of the unmet needs. So we have a couple of different parts of this display. So one is the relapsing MS patients and where that is going, what type of growth are we seeing there? And it's really only one part of the treatment. And it's really only one mode of action there. It's the CD20, and you see the numbers from 2017 to 2022, and you see the prediction from 2028, that this is, this is the segment that is currently growing, and, and that's where we need the new treatments that, that can raise the bar, okay? That is a segment of, of RMS. Then we talked about progressive MS, and you can see the quantification of those patients that actually have primary progressive MS or non-relapsing SPMS. But Dr. Stoll also told you about the mechanism driving, disease and, and that they actually occur quite early in, in the disease. You have this concept, smoldering MS, which is sort of a combination of things. So the middle panel, if that shows you the late patients, actually, many of those mechanisms are there in other types of MS across the MS spectrum. And many MS physicians now are moving away from this classification, progressive, relapsing, and this watertight doors, and really are looking for new options to treat the disability progression. That's where we have the unmet need. So what are we doing about it? Well... The first one, so I will talk about two MS treatments, and then I will talk about CIDP. So first, tolebrutinib, and here, of course, many of you, I think probably all of you heard the news about ibrutinib and sort of and think that that raises doubts about this class. Can it really do something in MS? I want to remind you that we have talked quite some time now about differentiation of these BTK inhibitors, and it's not, it's not restricted to this particular class of medications. Not all medications look exactly the same. I'll show you some actual data. This is the first set of data. I think first you have to look at the phase 2 data with the limitations of sort of comparing across studies. Here you see a quite pronounced suppression of lesions. If you look at different compounds, the two to look at, I would say look at the evobrutinib phase 2 data, suppression of 56% or 70%. If you look, New England Journal of Medicine, Montalban, look at that paper, not a very high number. If you look at another agent, ponesimod, that actually did beat teriflunomide in a head-to-head trial, lesion suppression of around 80%. So just a little bit of data to back up that there is differentiation between these compounds. And then look at the right side, talking about having enough of the compound in the brain and having enough potent compound to do something in the brain. And here I'll actually show you some. First, I'll show you some old data, and then I will show you some new data. So the old data is this one. And actually, we showed this in February 2022. It's a study we did in an independent laboratory. We compared tolebrutinib, evobrutinib, and fenebrutinib side by side. If you don't believe me, have a look in the slide deck from February 2022. This is taken exactly from there. You can see here. Based on this comparison, we do predict that tolebrutinib is the one that has the best chance of actually getting into the brain and doing something in the brain. But you may think, "Well, that's all fine, and that's pharmacological data." But what actually happens in patients? Well, in patients, we do have some new data for you, actually, and it's kind of comes in two part, one without tolebrutinib and one with tolebrutinib. First, on the left side, Amit Bar-Or and colleagues looking at patients treated with, again, CD20. And there's a lot of focus on CD20 because that really sets a bar for us, and I think our agents really targeting patients in the segment where we have- where we do need high efficacy. Which is a large fraction of MS patients. But anyway, if you look at this figure, these are patients treated with an anti-CD20, in this case, ocrelizumab, for 48 weeks. At week 48, where you have more than enough time to have maximal effect of this compound, you measure a factor in the blood called neurofilament light chain. It's a measure of neuronal damage, and you can... Perhaps not very surprisingly, you can see that the patients that still have higher levels of neurofilaments, they have more disability progression events over time. I think what's interesting is even patients that actually have low neurofilament, they still progress. So I think that's a data point actually illustrating what Dr. Stoll said in her talk, that there is still unmet need. We need these new mechanisms to tackle this unmet need. And what about tolebrutinib? Well, here we have a study from Dr. Danny Reich at NIH, and he took patients that had been on an anti-CD20 treatment for approximately 2-3 years, and then switching some of them to tolebrutinib. And what we can see there is a little bit of trend already at week 12, but at week 48, it's quite clear that the protein in the CSF did a proteomic analysis, analyzed several different factors in the CSF and saw that that's actually different in this patient. And particularly, again, neurofilament light chain in the CSF was significantly reduced. And if you put that data together with the data from Dr. Bar-Or and his colleagues on disability progression, I think you have something that goes beyond just the clinical pharmacology findings and a concrete piece of data to support that actually, these compounds may be different, and tolebrutinib has a very interesting potential. And so what about safety? So we heard again, the week before this week, we heard another update from fenebrutinib and Roche, again, a clinical hold. We have been working with the FDA for a while now, including having a meeting where we actually talk about the progress we made in identifying mechanisms. We go through details of the cases, and most importantly, we go through the mitigation measures. What can we do to overcome this risk of drug-induced liver injury, which is low, but it is there. And we do think, based on all the current data we have from these ongoing trials, that the best way to approach this is very close liver monitoring in the beginning, especially month two and three. That is the period where we need close liver monitoring. FDA, taking the unmet need into account, so they have prioritized, at this time, progressive MS, but they have told us, "Yes, with the data you have, with the mitigation you have, we are going to allow you to treat patients with tolebrutinib that progress in the progressive trials and to treat patients that go out from the phase three trials, to be offered tolebrutinib open label," and also in the only trial that is still recruiting, the PERSEUS trial in PPMS, to start recruiting that trial again. And the next slide. Looking at the program. So I just want to remind you that we do have the broadest program in the industry for this for a BTK inhibitor. So we not only have RMS, we also have non-relapsing SPMS and PPMS. The update today is that these trials are running towards its end. We will have the data from both relapsing MS and non-relapsing SPMS in the mid of next year, around the same time. The PERSEUS trial, we expect that it will be fully recruited towards the summer this year, and then we'll have the readout 2025. What is new today as well, and new information, is that we did a pre-planned futility analysis of the SPMS trial, that the trial passed. So, blinded from us, DMC looking at efficacy, saying, "Yes, it meets the predefined criterion, and the trial should continue to its end." What does this mean? Well, population size here, you see, but again, I would really emphasize that this is getting a little bit old-fashioned to see these different segments. It's still important, especially for regulators, but we know that the mechanisms go across MS, and we know that we need new medications to tackle these mechanisms that the current drugs don't really tackle. And that's why I want to, want to switch gears and actually move to, to another program with a very, very different mechanism. So that is frexalimab, and, and it's... So it's not OX40 ligand, so you are not- I didn't steal naming slides. CD40 ligand, okay? This is a, this... But it's also, it's also a co-stimulatory molecule. And why is it interesting for MS and-... autoimmune diseases beyond MS. Well, it's interesting because first, it's not a lymphocyte depleting therapy, okay? It doesn't take out 90% of your B cells, and that is important for MS patients that may-- that need treatment year after year. MS starts typically in the late twenties. So that's an important aspect. Another important aspect is that it's not just B cells, it's interaction of T and B cells. It's interaction of T cells with the innate immune system. And exactly as Naimish already talked about, there is potential for this reset of the immune system. One word for that could be peripheral tolerance. One classical— If you look in immunological textbooks, one... What happens typically is that if you have autoreactive cells and not have co-stimulation present, you get deletion or anergy of these cells. And that's something that we will continue to see if that could happen with this type of treatment. So what about the actual data we have to back that up? Well, this is the trial design. So we explored higher intravenous dose and a lower subcutaneous dose in a phase 2 MS trial, and it turned out it was the higher intravenous dose that was the best dose. And I'll show you that data. We are not giving up on subcutaneous. Subcutaneous was well-tolerated, and we are now actually increasing the dose to match the intravenous dose with the subcutaneous application. So we will take the higher intravenous dose into the phase 3, and in parallel, develop the subcutaneous dosing form. This is the data. This is the top-line data. So again, you can see you're starting to recognize now this new gadolinium-enhancing lesions. And here you see very early, already week 12, you see quite pronounced suppression. And then, as I said, especially of the higher, of the higher dose. And also interestingly, if you look at the—just the higher dose and you look over time, so week 8, week 12, week 20, and week 24, you can see that the effect doesn't seem really maximal at week 12. And it's quite typical. It may take a little bit longer, but week 12 is typically a really, really good indication whether you have something that is actually really potent or not. Then week 24, you have a very high fraction of patients without disease activity. But I would want to remind you, think about the mechanism. This is not the same. This is the first-in-class agent. This is the first real full MS data we have with an anti-CD40 ligand antibody therapy. And this type of therapy has potential to have effect beyond the B cells. It's B and T cells and innate cells. So where are we taking this? Where are we taking this drug? We are taking this drug into RMS. We are taking this drug into SPMS. So it's a, it's a comprehensive program. In terms of trial conduct, to be certain that we have enough power of this analysis, because we know that over time in MS trials, the disease activity is going down. We have event-driven trials. We have also optimized the way we measure disabilities. Instead of only have measuring disability with EDSS, we have added two more components. So the Timed 25-Foot Walk and 9-Hole Peg Test, these are tests of walking and test of arm function, upper limb function. These are very well known to, to MS physicians and, and well accepted by, by MS physicians. And if we look beyond, we have the phase 2 data. We have the strong phase 2 data from the MS trial. But if we look beyond what can be done with this drug, I think one of the most interesting, and actually, Paul talked about this. We are accumulating experience and knowledge in type 1 diabetes with our T cell, and this is potentially a very suitable mechanism for type 1 diabetes. You see some mouse model data. You see one way of summarizing human genetic data. And that trial, the phase 2 for type 1 diabetes is starting up, and we expect to recruit the first patient in the first half of next year. If we put all of that together, so MS, type 1 diabetes is what we have on the, on the upper part here. Sjögren's syndrome, SLE, these are also ongoing studies, and we've put that all together and potentially even more indications. This is a very, very promising product. I didn't tell you so much about safety. So of course, many of you know that this has been engineered to take away this. We call it second generation because it has been engineered to take away the thromboembolic risk that stopped the first generation compounds. And what about infections and sort of immunosuppression? Of course, we have to see, we have to accumulate, but the experience is growing with this class of compounds and the MS data. Please have a look at the MS data. It looks really, really clean so far. Of course, we have always to be careful, and we will keep a very close eye on those aspects, but it does look very promising. And one more, actually one more first-in-class, okay? So one more first-in-class agent. Now we're going to a complement inhibitor, and this complement inhibitor is not a C3 or C5. It's again, we go for first-in-class differentiated molecule. This is a really Probody. It is an antibody, despite the name, you know, the new naming convention. So it targets activated C1s. It's part of the classical complement pathway, the part of the pathway that is associated with autoimmune conditions and does not touch either alternative or the lectin pathway, which we think can be an advantage in the long run. This is also a compound with long half-life and active anti-C1s is not that abundance. You don't need that much of drug to be effective. And then unmet need, Dr. Stoll has already talked about that. High burden for patients on IVIG, and there are the patients that don't respond. So what did we do? We unlike some of our competitors, we didn't sort of go to patients that already respond to treatment as the first step. And I'm thinking, of course, about efgartigimod, that actually specifically made sure that the patients were treatment responsive before they put them in a randomized withdrawal design trial. We actually went to patients and prioritized patients who are refractory to standard of care. And this is what it looks like. So as a background, in CIDP, it's uncommon for patients to spontaneously improve, unfortunately. There was a recent meta-analysis looking at CIDP and they find that around 11% you would expect to respond spontaneously. Not specifically in refractory, probably even more rare there, but across CIDP in general. And we said: Well, we wanna see at least 35% response in refractory patients to think that this drug has potential. We did see 50% response in patients that were quite advanced with CIDP, quite refractory. And we did it with a classical endpoint called INCAT, Neurological Rating Scale, with some similarities to EDSS for MS, but obviously not the same. What you can see here is that most patients, already in the first 12-week, actually had a response, one-point decrease in the INCAT score. You can see that that response was maintained over time. We looked in the patient that responded and looked at other endpoints just to see, is this isolated to this particular score, or... Well, what about the other secondary endpoints? We looked at I-RODS, another neurological rating scale, so we have a very good response there. We looked at MRC sum score, which is muscle strength. We looked at grip strength in the dominant hand, and all of them were consistent. We also had some early neurofilament data that is also trending in the right direction. For this compound, we also had data with CAD, cold agglutinin disease, further sort of strengthening the case that this is actually a really nice antibody that really does its job well. And you have a dotted line here with another abbreviation. So you learned already one, CIDP, chronic inflammatory demyelinating polyneuropathy. But what is MCID? So MCID is a minimally clinically important difference. And you can see that in this patient responding, actually, on all the secondary endpoints, the response is well beyond what is considered minimally clinically important difference. So it's not only the number of patients, it is also the magnitude of the response. We also have data in IVIG-treated patients actually transitioning, showing stability, and showing that a significant number of those patients actually improved, which was a surprise because they already are responsive. They improved further when they switched to rilzabrutinib. And that's why we are having the phase 3 program the way we have designed it. So again, to make sure that this drug is playing to win and actually has a good solid place in the future CIDP market, where there may be at least one more advanced therapy as well. But this is a very different stage of phase 3 program. You have one trial, specifically going for refractory patients, trying to replicate what we saw in phase 2, in the phase 3 setting. And then we have another trial, which is another novelty in the CIDP field, where we actually try rilzabrutinib against the standard of care, the IVIG. There, we are going for showing improvement, or at least with the non-inferiority design, showing that the compound is non-inferior, and we have stability in these patients. We think that this program, if successful, will give a really, really, strong profile for a compound in CIDP. And we have the phase 2 data to back up both parts of this program. That's just finish off here with the neural inflammation part. So I think neural inflammation is an area where we really have background in the company, and it fits really well with our immunology pipeline. So this is an area where we really wanna maximize the assets. We are gonna be build the evidence stepwise, and we're going to indications with high unmet need, where it really makes sense. So I'll stop there, and I will hand over to Manuela, who will talk about the Dupixent and then talk more broadly about COPD, another area with very high unmet needs. So please, Manuela. Thank you very much, Erik, and hello, everyone. I have the pleasure to share the continued success of Dupixent and also share some groundbreaking new data in COPD that will allow us to expand our leadership in respiratory. If you recall, in CMD at Capital Markets Day in 2019, we laid out our ambition with Dupixent to be the foundation of our immunology pipeline, and also for Dupixent to be the key growth driver, a key growth driver of Sanofi. I'm very proud to say that we are delivering against that ambition, and that we're exceeding it. As you can see on the slide, we already have 9 approved indications with Dupixent, and with the potential to treat more than 7 million eligible patients in major markets across indications. We're currently already treating more than 750,000 patients around the world, in more than 50 countries, and patients as young as 6 months of age. As you can see on the graphs on the left, we are leading in NBRX share, both with dermatologists and with pulmonologists, and we also hold firm number one positions in NBRX share in the U.S., with in all indications actually, whether that's atopic dermatitis, asthma, CRS with NP, EoE, or PN. That is a testimony to excellence in execution, not just in bringing first-in-class and best-in-class assets to market, but also in launching and competing effectively in the spaces where we play in. Having said that, and knowing that Dupixent is already a top performer, and Charlotte mentioned this earlier, there's still a lot of opportunity for growth in the indications where we already are approved. And if you only look at atopic dermatitis and asthma, for example, in AD, only 9% of patients in the US and EU5 are currently on a biologic. In asthma, only 17% of all eligible asthma patients are on an advanced therapy. So there is a lot of room for growth in those two important indications, but also in all other indications that we have approved. Yet we're equally excited about the opportunity to launch new indications, at least six new indications for Dupixent in the future. And those indications will again bring the opportunity for us to be first-in-class or best-in-class, either in that therapy area or a subpopulation. As you can see from the slide, just those new indications combined will have the opportunity to add 1 million more patients in the U.S. alone, and of course many more in other markets around the world. And the one indication that we're most excited about, of course, is COPD. Why? Because it is a huge burden for society. It's the third leading cause of death worldwide. In the U.S. alone, 150,000 people die from COPD every year, and it also is a significant healthcare cost burden. $50 billion are spent every year on COPD alone. And if you look at the 23 million people that are living with COPD currently in the U.S., EU5, and Japan, 1.7 million of those are uncontrolled and continue to exacerbate despite the fact that they are maxed on maximum standard of care. This is where we come in, because we don't only have one shot on goal, we have two shots on goal with Dupixent and itepekimab with a phenotype-driven approach. Of course, we're really excited about the data that we have recently shared already, and for the first time, we're sharing it live with all of you around the NOTUS trial, confirming our landmark BOREAS trial which we have published earlier this year. In terms of the results in COPD, the NOTUS trial showed a significant reduction in exacerbations of 34%, and it confirmed the significant improvement in lung function that the BOREAS trial was showing. At the same time, it proved that the same known safety profile that you know of Dupixent was validated here as well. So we can't wait to take this data and file it with the FDA before the end of this year, and to bring Dupixent to COPD patients as soon as possible, and we're also in conversations with other health authorities around the world. But as I said earlier, we don't just have one shot on goal with COPD, we have two, and the second one is itepekimab. It's an IL-33 inhibitor, as you know, and it also has the potential to be best-in-class and first-in-class in COPD. If you remember, in 2021, we published phase IIa results for itepekimab, and while the results weren't statistically significant in all patients, in the subpopulation of former smokers, it actually showed an impressive higher than 40% reduction in exacerbations. And while being generally well-tolerated, and having an acceptable safety profile. If we take a closer look at those two, phase IIa results with itepekimab, you can see on the left-hand side of this slide, that the reduction exacerbation wasn't just happening in high EOS patients, but also in low EOS patients, so working on Type 2 as well as non-Type 2, COPD. Interestingly, it also showed a sustained efficacy 20 weeks post-treatment, meaning that there is an opportunity for a long half-life and bioavailability of the drug. Based on those results, we then initiated, the phase III study, and as you can see here, this is the design of the study. We focused it, of course, mostly on former smokers, but at the same time, we included a population of current smokers, because we didn't want to leave any stone unturned for that part of the population either. We're happy to report that earlier this year, we passed futility for itepekimab, and we also received fast track designation by the FDA. So again, two shots on goal, and the most important thing to remember, they're highly complementary. As you can see from the graph on the left-hand side, the table actually, you can see that Dupixent is gonna be focused on type 2 COPD patients, COPD GOLD E patients, to be exact, irrespective of former smoker status. So it's gonna be focused on current smokers as well as former smokers. While itepekimab is going to be focused on former smokers, but irrespective of their EOS level. So considering both, low EOS and high EOS patients. And together, they will be able to cover more than 80% of the GOLD E COPD patient population, which is approximately 2 million patients across the G7 markets by 2035. So highly complementary, two shots on goal. We're really excited about it, and most importantly, I'm sure you're very interested in that number. We believe that this will allow us to exceed, to have a peak sales potential across both of those assets, exceeding EUR 5 billion in sales. So I'm gonna leave you with three things. Dupixent is gonna it still has a lot of opportunity for growth, both in existing indications and in new indications. We're far from done. Secondly, we know how to execute, we know how to launch, and we know how to compete, and we'll be able to do the same with future assets as well. And thirdly, we can't wait to bring those two assets to market for COPD patients. Meaningful innovation that really will make a difference for the patients that need it the most. And talking about COPD patients, I have the privilege to hand it over to a panel with Brian, Liz, and Dr. Han, who will talk more about the physician's perspective in COPD. Thank you very much. We've beaten the chairs up here. That's quite a feat. Please. Thank you, Manuela. Really excellent, excellent job, Erik, Professor Stoll. You know, this particular session, we're a little bit biased. We prefer this session over all the other sessions because as I think, and I'll, I'll steal one of the lines from Houman, is that I think one of the things that you share with the organization is that your two North Stars, you talked about, one of those key critical ones for us is patient value. And as we think about this session, we started it with a KOL, and we're gonna end it with a KOL as well, because who better than a KOL, an expert, to really help you understand the patient populations that we're talking about here? And these are patient populations where we're hoping to bring... They're difficult to treat today, but we're hoping to bring really innovative medicines in the next few years to really change the way that we treat that patient population, those patient populations, I should say. So, my colleague, Liz, and, and I are extremely privileged and honored to be able to spend some time up here with Dr. Han. I will start with the introduction. I'll let you, because you'll do a much better job of yourself, but, Dr. Han is a professor and chief of pulmonary medicine and critical care at the University of Michigan. She's also not only treating patients on a day-to-day basis, but she's extremely actively involved in clinical trials. So she has knowledge, maybe you will try and get it away from her today, of everything that's likely going on in this space for COPD patients, but that makes her really an expert for us for this particular time, together with all of you. And then I think finally, as I've gotten to know her a little bit better, she spends a great deal of time with a whole host of organizations to help advance the care of COPD patients. One of those organizations is the GOLD Committee, and this is an internationally recognized organization that sets guidelines for not only the diagnosis, but the treatment of COPD patients. So truly an expert in this space, and so we're really honored to have you here with us today. So, I'll have you do a little bit better job or a lot better job than me of introducing yourself. And really, if you could, start off with your time in COPD and you know, how did you get into this space, your dedication to this space, how you've grown in your career there, and then also take us into the patient population, if you don't mind. Help us understand a bit of the burden that these patients suffer with every single day with COPD. Thank you so much, Brian. It's a real pleasure to be here today. And I really wanna thank all of you for being here, which probably sounds a little weird coming from me, but I really do wanna thank you for being here. The needs in COPD are so great that we need investment in COPD desperately, and that's really the message that I wanted to get across to all of you today, and honestly, why I'm here. So I've been doing pulmonary medicine, actually at the University of Michigan, for about 20 years. I actually recently stepped up as chief of pulmonary and critical care during the pandemic, so I've been a little busy lately. But I started out in COPD, and at the time when I first started, we had three drugs, really, that we could treat patients with, inhaled steroids, and some bronchodilators. It has been 20 years, and I still have three drugs to treat this disease. Think about that. I started out wanting to care for patients with COPD because, to be honest, I didn't see a lot of other people around the room wanting to do it. There's a lot of stigma associated with the disease, and to be honest, it really wasn't all that sexy for my colleagues. We didn't really have great, great drugs. So I saw a huge need, and honestly, I really, really wanted to see if I could help. So I spent the last 20 years- ... trying to help patients in the office and also trying to advance the field with respect to clinical trials. I can tell you, I work at a tertiary care center, so that means most patients have probably seen a primary care doctor, maybe one or two pulmonologists before they finally get to my office. The one thing that they always say to me is: "Is there anything else you have to offer me? Because what I'm on right now isn't enough." I cannot tell you how heartbreaking it has been for the last 20 years to not be able to say that I have something more. Often I can offer clinical trials, and I, I try, but honestly, there's just a really narrow subsegment of the patient population that's been eligible, and even the clinical trials that we have had are often just me-too. So more of the same in different formulations, but not something truly, truly new. So it's really, really been my desire to try to offer something new to these patients. And I think, to be honest, I think it might help you a little bit to try to just kinda get your head around the need for this patient population. And by me telling you a little bit more about the kind of patients that walk into my office, and there's really two driving things that patients will come to me. One of them might be severe shortness of breath. And I want to paint for you a mental picture of what that's like for just a moment. So imagine a house and imagine a driveway, and at the end of that driveway, a mailbox. And next to the mailbox, a chair. And that chair exists because my patient cannot get to the mailbox to get their mail and get all the way back without sitting down to rest. And believe it or not, I have heard that story from more than one patient. Now, the other story I hear, is just the sheer frustration and exhaustion patients have from having frequent flare-ups of the disease. We call those exacerbations. And, I want you to think for me, again, for a moment... I'm gonna guess most people in this room have had COVID by now. and so think about just how crummy or maybe many of you felt crummy when you were in the middle, you were in the thick of it, but you had hope in the back of your mind because you're thinking, "Okay, this is only almost a week or two, and, you know, in a month, I will be back on my feet, and I can go on to live my normal life." But imagine having an event like that, and then just as you're starting to feel back to yourself, just as you're thinking, "I can get back to life, I can see the grandkids, I can go and go back to work," whatever that is that's meaningful to you, and then you get it again. And then you get it again. You can't even predict when that next, next event is going to occur. I recently had a patient call me, and she said, "You know, Dr. Han, we really need to talk. I'd like you to put me in hospice." And, let's just call her Mary. I said, "Mary, I don't understand. Your lung function isn't that bad. Why are we even having this conversation?" And she said, "Well, you know, with the shortness of breath and how many times I've been in the hospital this year, I can't do this anymore." And I was heartbroken, absolutely heartbroken, and that is not the first time I've had to do this. I have had patients in hospice for years, which isn't really even supposed to happen, but the disease kills so slowly, it will rob your soul before it steals your final breath. So that is why I am so excited. That is why I am here today to be having these conversations about finally being able to change this conversation and have something new to offer these patients. Wow! Amazing. Well, Dr. Han, thank you for being here, of course. You talk about this debilitating disease and high unmet need, difficult to function daily, you know, and you talk about being in for the last 20 years with only your 3 therapies. Talk a little bit about what you think the challenges of developing sort of drugs for this really high unmet need segment are. Yeah. So there are a lot of things about COPD that make it really challenging to study. If you think about it, it's honestly the perfect storm of a disease. There is a graveyard of therapies for COPD that I've seen in the last 20 years, and it is not for the faint of heart. You can't just dip a toe into COPD. It is slowly progressive, but that also means it's hard to show in a reasonable timeframe that you can move the needle. It's also very heterogeneous, and I think we have not really understood the key mechanisms or inflammatory pathways that are truly relevant in the disease. Fortunately, we've had a lot of headway in the last 20 years to try to better understand that, and I think we're finally being able to see that if you can target the patients correctly and you have the right molecule and the right pathway, we really can make headway in this disease, but it has been incredibly challenging. You know, not for the faint of heart, graveyard of indications. This sounds like the perfect place that Dr. Liz Laws likes to spend her time. She thought she was gonna be up here and just ask questions. She's gonna get a few questions, actually, because it does make us excited about where we are in the development of COPD for Dupixent, and Liz has been leading that program now for many years. So maybe, Liz, talk to us about how you overcame some of the challenges of the development of such an asset in this particular area. Yeah. Well, certainly, we recognize the heterogeneous nature of COPD. And, you know, our approach, we thought, as you mentioned, that the one-size-fits-all approach was perhaps what was sort of leading to all the development challenges that have been faced by the last 20 years of development. I would say that we followed the playbook that we had with that Naimish outlined this morning, asset, strategy, people. You know, with asset, we followed the science. And with the strategy, we follow the first-in-class strategy, and then, of course, the people with the follow-through execution. I think in the case of Dupixent, we went after the type two patient population, which, of course, was well-credentialed with our successes in the other type two inflammatory diseases. There was a signal for success within the type 2 population, so we went after that. We went directly to phase 3. We made a bold move with no phase 2 data to guide us. In order to inform that, we did actually go thoughtfully into a phase 3. We sized for first-in-class efficacy, and we gated that investment with an interim analysis to make sure that we were, we were right in the scientific, thought leadership that we had. I would say then following on that, you know, it's the people. I mean, I think we, we started the program, we got the program approved in 2018. The program got started in 2019. Both studies recruited through the time of COVID, and, you know, sort of heads down, we just kind of enrolled through and executed through, to enroll, both patient, both studies. You know, and I'm happy to report, of course, last week we had notice, notice readout, the team is rapidly on course to, finish a filing by year-end. So, I mean, in less than a month, basically. So, really, really impressive, collection of people. You know, I think someone asked a question about, you know, is it the asset? It's the asset, it's the people, it's also the all-in winning mentality, that we go in, or Ted Lasso's believe mentality that we're gonna actually make it, so. I think that's a reference everybody can follow, for sure. And that's quite... I think let that sink in for a second. So it was last week, 'cause sometimes we think it was multiple weeks ago. It was last week, and you're gonna have filed by the end of the year. I mean, that's... Someone was asking me last night at dinner: "Okay, what's different about Sanofi now? What's different?" I mean, this is a living example where hopefully you see what's different about Sanofi. We would have never, the old Sanofi, I've been here for six years, the old Sanofi would have never gone directly into a phase three for a disease state, as you nicely described, a graveyard, you know, not for the faint of heart. We would have been very, very, very measured. I think we're very strategic about how we did it. We followed the science, as Liz, you said, but that was a change of Sanofi. That was an important, I think, moment for Sanofi. But, Liz, I'm not gonna let you off the hook before I come back to Dr. Han. We have another program, 'cause I think Manuela mentioned something else in COPD. Maybe you can speak a little bit about how we're overcoming the challenges there in a different way. Oh, yeah, certainly. So happy we have another program, it's itepekimab. Together, Dupi and dupilumab and itepekimab will cover over 80% of the COPD patients, high unmet need. Again, we had such a fantastic signal in our phase 2a data, as Manuela mentioned, in the former smoker population, the pre-specified population. We went very strategically into a phase 3 focused on that. We are very excited for the readout in 2025. We also had a gating process of an IA, so we passed it earlier this year. So we're well on track to repeat the playbook, deliver the success, and really deliver options and therapies to this high unmet need population. Yeah, I mean, again, really exciting. And this is nice because when I started the beginning of this presentation, we've had this conversation, I was a bit depressed because, I mean, these patients really have nothing, as you said, they, you know, their life is debilitating. But as you can see, I think we're gonna end towards the end of this presentation with the excitement of what the future looks like. Maybe you can speak about that because you can feel your excitement when we talk to you about what the future looks like. So maybe you show your perspective- Yeah. Dr. Han, on the future. Sure. So, as you mentioned, I sit on the GOLD committee, which is the scientific advisory committee that helps to write the treatment and management strategies. I also write for UpToDate, which is, I think, probably the number one go-to resource for physicians. When they're not sure what to do, they go straight to UpToDate. And I cannot even tell you the amount of excitement among my colleagues within both groups about you know, changing the paradigm for how we treat COPD and really ushering in a new era of biologics. There's so much excitement among all of my colleagues. And I really think there's actually two things in the last few years that have really set us up for success in this area from sort of a practical perspective. I think the first thing is that, pulmonologists are now used to prescribing biologics for asthma. So whether it's you, yourself, or whether it's a colleague, I don't think there's a pulmonary practice in the U.S. at this point that doesn't have the capability of administering, biologics with respect to the nursing support with that. But the second thing is, I think with COPD specifically, we have had one new therapy for COPD. It's not a drug, it's valve therapy for severe COPD. But the key is that the indication for that is really around an FEV1 of about 50%. So lung function at, how much you can blow out in the first second at about 50%, which is really kind of a mid-range disease. And what that requires is, it requires patients to go in and get, you know, a CT scan and a bit more of a fancier workup. And a lot of times, primary care physicians don't really know if a patient's going to qualify or not. But because that treatment is out there now, primary care physicians no longer say to themselves: "Oh, I got this, there's no need to refer." They now know, "Oh, wait, there's something else maybe I need to refer this patient to." And so those referral pathways have now kind of been ingrained, where primary care knows they need to refer earlier and get them over to a specialty office. And so I think both of those things combined have will really set us up for, again, ushering in a new era for biologics in COPD. ... Extremely exciting times. Yeah, and I wanted to maybe follow up on your researches in imaging, and wanted to have you share, you know, where you think that next generation imaging is going to take us. Yeah. So I do a lot of research trying to understand how to subtype the disease with respect to imaging. I'm actually a member of the Fleischner Society, which is a thoracic imaging society, but it writes a lot of the guidelines about how to follow up on things like incidental findings. And, interestingly, I think again, here, we have two very interesting things converging, which will really allow us- really take us into the next century for treatment for COPD. The first is that a lot of patients with COPD are now getting lung cancer screening CT scans. And so we have a lot more imaging just available, sitting around in the system on both patients with COPD as well as those at risk for the disease. The second thing is the introduction of AI. The field is becoming increasingly ripe with techniques and technology to be able to go in and pick out patients who have emphysema or airways disease. I just got off a call with the head of the diagnostics for University of Michigan. They're looking at buying, you know, figuring out which software package they need to be. All big healthcare systems know they have to invest in software. We actually already have some at the University of Michigan that I was able to help develop. It's already becoming part of the workflow. I think as we, you know, move forward to the next phase and the next drug, and hopefully the one after that, our ability to subset and really highly target patients will really be easier. That's incredibly exciting. You know, so as we start to wrap up this session and give the audience a chance to ask Dr. Han some questions, you know, I'll take you back to, as we said before, the value of the patient, the value to patients. And I think you brilliantly described those patients today, where they really still have nothing today. Now, we're also excited to be sitting here and talking about some therapies that hopefully, in a very short period of time, they'll be in your hands, and you'll be able to say, "I have something for them." And hopefully, back to Manuela's point, those 150,000 lives that we lose each year in the U.S. alone because of COPD, hopefully, we can start to save some of those lives. And so speed is of the essence, and I think that's one of the other things that I'm incredibly proud of the organization that I work for, that we have tried to do everything possible to get it to these patients as quickly as possible. But this last part is what gets me really excited, because if you can identify those appropriate patients very quickly, that might be applicants for these types of advancements. I mean, the sky is the limit when we go back to those biologic penetration rates that we talked about in these patient populations. What could COPD, what should COPD be? It should be 100. It shouldn't be the best, what we see today in RA at 55, it should be 100. Maybe this imaging, maybe this identification of these patients and getting them to the right individuals like yourself, to take care of them with appropriate therapies, can really do something quite different in COPD. So we're, we're extremely excited about it. So thank you again, so much for being with us. Now we're gonna do a Q&A, and we're gonna allow the audience to ask some questions to Dr. Han and a whole host of others. Thank you. Thank you, Brian, Dr. Han, Liz. Yes, we're also going to ask Manuela, Erik, and also Dr. Stoll back on stage. So we have planned 15 minutes for this Q&A. And yeah, I'm actually also hoping you really have some questions for our experts, and you take advantage of that. But obviously also, I have my own internal experts here on stage as well. So if we start with Luisa from Berenberg. Okay, thank you. Luisa Hector from Berenberg. So thank you. That was a super interesting session. My questions are on MS. So for Dr. Stoll, the way you were describing the, the atrophy, and the issues that patients are now facing, I just wonder if ARR, relapse rates are the wrong endpoint. How, how can the phase three trials be run to kind of identify the improvements here, surrogate markers, and how could, you enrich for those patients into trials that you think, are most exposed there? And on frexalimab, is, is there evidence that can penetrate the CNS, and should we expect some of the benefits there as well on the atrophy? Excellent question. So I'll answer the first part. No, it's not the wrong endpoint because we still have to make sure that the medication works for relapses and new lesions, because that's still the primary crux of the disease. However, I think that in addition to the annualized relapse rate, an additional endpoint, and this has already been included in many trials, is brain atrophy, but also SDMT, which really looks at how that patient is doing cognitively over time. Yeah, and I could add there in terms of the endpoints, of course, the phase three endpoint that is mostly correlated is the disability endpoint. That's where we want to see the effects of these new agents. And in phase two, the field is still looking. You know, this is an active area of research. Is it the slowly evolving lesions? Is it the neurofilament? Is it the com- is it combination? The field is still looking, and there's nothing really as good as the enhancing lesion to the annualized relapse rate. But that's an important development, and I think there is progress. In terms of frexalimab, no, it's an antibody. It doesn't penetrate well to the CNS, but please remember, it is a complicated inflammation in MS with multiple components present in the central nervous system, and many of these components infiltrate in the central nervous system. So, I think we do need multiple ways to approach this, and. Just to give you a couple of more data points to amplify that. I mean, first, perhaps most obvious, the only treatment we have for primary progressive disease is actually an antibody. We know, for instance, with natalizumab, that we have indirect effect on microglia cells in PET studies. And many people still, actually, our own experience, many people still say, alemtuzumab Lemtrada, that has a remarkable effect on progression. And it's an agent that targets both the T and B cells, and it also doesn't penetrate the central nervous system. So, I think we need multiple ways. We need to investigate them and to really cover these aspects of MS that are not well treated today. Okay, so I have a question from Mark. Yeah, thank you very much. It's Mark Purcell from Morgan Stanley. Firstly, on the tolebrutinib, I hope you can help us understand the relevance of ALT elevations for both regulators and physicians. So physicians, there's all sorts of different safety concerns across the multiple therapies you've described. So how concerned are you by ALT elevations, and how do you manage that workflow? And from a regulatory perspective, it's great news that you've got progress now in terms of starting to redose patients. But do you have any mechanistic insights into what is causing these elevations? There's no BTK receptors in the liver. We've seen, you know, clean profiles in other diseases like CSU and rheumatoid arthritis. So is there a multiple sclerosis specific effect here? And then the second one is a shorter one, thank goodness. It's itepekimab and AERIFY-2. Could you help us understand what the futility analysis criteria were? Were they similar to Borealis? And as you think about sort of POS and what's considered a higher risk area for biologic drug treatment, how should we think about the POS of the program now, given the sort of this gating effect or this gating position as sort of move forward? Thank you. Start with Amos? Sure. So I guess I'll start with the elevated liver enzymes. As an MS neurologist, it's not concerning at all, because every MS medication that is currently on the market, we check LFTs. So it's also something that our patients somewhat expect monitoring in terms of the frequency of monitoring, because when the damage or when we start seeing the elevation, it's fairly early on in the disease course or in the treatment course. Telling a patient that, you know, you need to come back once a month or once a week for LFT monitoring is not only something that I think is they're used to, because it's something that we do with other medications like teriflunomide, but also because we know what we're looking for, we know what we're monitoring, we know what the risks are. As long as we can realize it and pick it up before it causes any damage, then really you nip the problem in the bud. When I talk to a patient about risks versus benefits, the real risks are things that could potentially happen years later down the line. Those are things that patients and physicians like myself are concerned about, things that randomly pop up, that we don't have good monitoring tools for, like cancer or PML or other kinds of infections, severe infections. But something that we know is going... or we know how to monitor, we know what we're looking for, and we know what to do. I mean, that's really not that much of a concern. Maybe I can add on the regulatory sort of perspective and mitigation. So, yes, I think, regulators, and rightly so, they care about the safety of the patients. They are very concerned. And what about mechanism? Mechanism, yes, there may be an increased risk in MS patients. It is likely related to a more immunological mechanism rather than direct cytotoxicity of these agents. And we are looking into how to even further optimize this, and we are looking at near patient testing, for instance. It is coming to make it simpler to do close liver monitoring. We are looking at artificial intelligence, machine learning to further improve selection of patients, further perhaps improve monitoring. It's actually interesting when you talk to the artificial intelligence machine learning people. They tell me: "Well, you have too few patients with these issues." I think we have too many, but it's sort of data-intense exercises to find this algorithm. But I think over time, it will become better, and hopefully, not too far away, we will have even better tools to make it simpler for patients to follow in this period, which is in the beginning for this particular compound, particularly in months 2 and 3, and of course, it's a chronic disease. Okay, then we had just quickly on itepekimab- Yeah, so- What we can share, and then I think we're going to go over to Erik. So, just on itepekimab, you know, following similar playbook as with BOREAS, we had a pre-specified set of criteria for independent data monitoring committee to review the data, to gate the continued investment. We are blinded to the data, so but it certainly, it we did pass just as we did in BOREAS. And we continued, and you see now with BOREAS notice, you know, the readout at the end. Yeah. Thank you. Eric Lebailly, Stifel. Two trial design questions. First, on BTK and Gemini 1 and 2, given what just happened with your German colleague, what is your expectation about the comparative arm in two Gemini 1 and 2 in terms of relapse rate? And what is required to reach statistical significance with the primary endpoint with your compound? And then in terms of frexalimab, given it's an injection, why not going comparative in RMS against a CD20 rather than teriflunomide? No, thank you for those trial design questions. So maybe I'll start with the second one. I think that teriflunomide is a very well-established comparator now. It and it's something that's very simple for patients to take. It's once daily, very well established, and we know how to conduct the trials. We know how to power the trials. And I'll expand a little bit on that because that will answer your second question as well. We have a couple of different trials now. We have, of course, the recent evobrutinib data, where we saw that the relapse rate for evobrutinib was similar to teriflunomide, okay? But we also have data from three other compounds with teriflunomide as a comparator, which really helps us to design trials. So those are ofatumumab and which obviously had a lower analyzed relapse rate. It's obinutuzumab, and it's ponesimod. And ponesimod, when you look at the MRI effect, it's around 80% suppression of lesions, which is higher than what we normally associate with teriflunomide. And it shows that you can beat it in a head-to-head trial. And also with obinutuzumab, because many people were surprised, "Oh, has the biology changed?" Not really. It's the population has become less active, but if you have the right compound, you can certainly show superiority over teriflunomide. Okay, Peter? Thank you. Thank you, Peter of Citi. Two questions, Professor Han, to you, to you, maybe we can tap into your clinical trial experience. Just, you know, you talked about the unmet need and the elephant's graveyard of drug development. Just your perspectives on the IL-5 and IL-13 sponsors going back to COPD, whether, you know, with their second bite of the cherry, can they be successful with better patient selection? I'd be interested in your thoughts there. And then, perhaps a little bit unfair, itepekimab is clearly great data, first in class, but there are also other IL-33s hot in pursuit. So any, from your perspective, differentiation amongst the class? Thank you. Ah, I think they want me to comment on your competitor. I thought that might happen. I thought that might happen. So I think it's difficult to say. I think what Sanofi has shown is that with really crisp trial design, they had much tighter inclusion criteria with respect to eosinophils, that they were able to, you know, show benefit. I think that the competitor studies are following the playbook and going back and doing something similar. So I think there's definitely potential. If you look at the data from, say, the MEPO studies that was already published, they were close. They were really close. And so I think it is possible that if they go ahead and, you know, again, follow a similar playbook, they may be able to get it over the finish line. From my perspective, I hope they do, because the more therapies that we have for patients, the better. The second question you had, sorry, was around- IL-33. IL-33. And what, sorry, what specifically was it? So it's interesting, if you look at the inclusion and exclusion criteria, data that Sanofi has versus some of the competitors, they're not identical. And it's based on subtle differences in the preliminary data that Sanofi had, compared to the competitor space. Differences, I think some subtle differences around things like smoking status, chronic bronchitis, et cetera. And to be honest, from my perspective, I'm not 100% sure whether that's related to just wobbliness in the data or whether that's because there's some true differences in those molecules. So for me, from my perspective, those are those subtle differences that right now I'm keying in on. But again, you know, the data that we're seeing coming out of the itepekimab program right now is super exciting. At least for this molecule today, they've seemed to be able to match drug to patient population, and are gonna be probably, hopefully, first out of the gate. So I don't know if the other companies have been on the right courses or not for their own molecules, but those are the things I'm watching. Can I? Sorry, I just want to. I know the question wasn't directed to the sponsor, but maybe just to comment on Dupixent versus IL-5s. You know, so certainly exacerbation reduction is 30%-34%. We also had improvement in lung function, which is definitely flat in both competitors, and I don't expect that to improve at all. We also had improvement in health quality of life, so SGRQ, and we also had E-RS improvement as well. In our high pheno populations, we also had great improvement in lung function as well as exacerbation. So I, you know, I think I know our data best, of course, and we've studied our competitor data. I don't expect their trials to have improvement in lung function or SGRQ as well. I think maybe just quickly to touch on IL-33. You know, I think we had also a large phase 2A readout with good, solid data. I think the other competitors don't have as much data. They went directly phase 3 with less lack of data, even. You know, I feel confident that we made a very informed decision on how we would set the inclusion, exclusion criteria, and really move forward the phase 3 program. Can I add a couple things to this, too? 'Cause I think we all agree that, and we've seen this throughout this presentation, the red thread, right, is that we're all excited about hopefully a host of therapies coming to these patients that you were just describing. Because as we've seen in immunology as well, you need them. They're gonna grow the marketplace. But I, there's a couple points I wanna make sure that people capture here with us. This is also a transformative moment for us in Sanofi. We used to copy others. Others are now copying us. So if you look at what we did with IL-33, we weren't the first IL-33 program. Matter of fact, we weren't really even the second IL-33 program, but we did something very different than others did, and many gave up on their IL-33s. You probably covered a lot of them. Many of them gave up on their IL-33s when the first company became negative. We didn't. We found something that was quite unique in our program. We followed the science, we ran the playbook, and so on and so forth. But that was also a proud moment, I think, for us as an organization, where Naimish talked about this, right? Where we should probably be receiving some form of royalties from a few of these companies because they started to copy us. But we took it as a sign of we are changing as an organization, which was really important for us. The last thing I would come back to is, I'd link it back to the question that we're getting on MS, is one of the things you should judge us on, is our ability to pick the targets, but not just the target, the class of the targets, but the specific ones in there. You see your question is about the differences of the IL-33s, but yet we're kind of casting a cloud on the whole BTKI category right now, and we believe we have picked the winner there. I mean, we've done a differentiated program that actually sets us up, that I think others have not done. And now we're not just best in class, we're likely first in class, or we are first in class. So again, I wanna link it to your question because it is an important one. They're not all created the same, and hopefully, we become better and better as an organization at picking the best one there and developing them. I mean, that's the goal. And you'll hear from Helen, maybe a little bit later, how we're doing that. Okay, thank you very much. Specifically, Dr. Han, Dr. Stoll, thank you so much for all that passion, you know, that you're also sharing, and that is really also helping us in our lives to really keep moving forward. So we're running a solid half hour late, which I'm not at all sad about. Really not. I just have to solve for it. So I'm gonna drop the second break. I don't think we need it. I wanna move straight into next and you can see Frank is ready, and the next session is really also going to be really interesting because we really wanna look closer on our R&D productivity across research as well as development. Obviously, if somebody of you absolutely has to, you know, go and see a restroom, please just sneak out quietly and come back in. I'm planning that we're probably going to finish around 1:00 P.M. local time. Still, you know, having a full hour for lunch. So thank you, and over to you, Frank. Thank you very much, Eva. Stretch your legs, take a sip of coffee. We're going now into the finishing stretch, into the third section of our R&D week. Now, I would like to discuss with you today how we are leading in immunology research, propelled by a combination of incredible scientific talents, a unique technology toolbox, and also transformative pipeline assets. Now, we've built a leading research organization over the last few years, generating differentiated first-in-best-in-class molecules. We established a strategic innovation engine focusing on immunology inflammation, and probably the best proof point has been what you've heard this morning from Naimish, from Sergio, from Erik, an incredible clinical pipeline moving towards patient impact. Also, we had 12 IND first in humans in just 3 years. This is unprecedented. Now, we are also focusing on precision medicine. This gives us our unique target and indication idea engines on genomic medicine, where we're propelling our in vivo immune cell programming programs forward. We are focusing on portfolio excellence, and just our fast-track projects are breaking cycle time ceilings. Now, we also build enablers such as next-generation biologics, and two-thirds of our portfolio is now in biologics. We also established an AI research factory, which is driving productivity gains. Finally, we know we cannot do this alone. We're partnering with the best in the industry, and yes, 25% of our projects are on what we call the external bench, working with partners. This completely revamped, agile research organization has doubled research productivity as measured by dollars spent per clinical candidates, but it also has doubled first-in-human entries. Now, what does leadership in immunology research look like? It looks like a clear ambition on a clinical breaking of efficacy ceilings, achieving clinical durable responses, and expanding in new indications. You heard examples about all of this this morning. We're focusing on pathway science to propel our multi-indication assets forward, and Naimish talked about this morning about how we are doing this. We're breaking new frontiers in technology innovation to unlock previously undruggable biology. Finally, we're using precision immunology and leveraging precision immunology to precisely tailor our pathway assets to patient unmet needs. Now, let's have a peek in our nugget toolbox of molecules. Transcription factors are very interesting target class, very difficult to drug. STAT6 is the central transcription factor for Type 2 inflammation. With our partner, Recludix, we are working on an oral small molecule, which blocks Type 2 IL-4 and IL-13 pathways. Now, this molecule is very specific and very potent in blocking Th2 cells, which are central to type 2 inflammation, but not Th1, Th17 cells, Th1 cells, or markers associated with hematological hemostasis like STAT5. This molecule has excellent oral bioavailability, and it also blocks, in a preclinical model, in vivo STAT6. Thus, this STAT6 inhibitor offers potential for antibody-like efficacy with oral convenience in type 2 diseases. Now, another exciting molecule and pathway inhibitor is our anti-IL-1/IL-33 SAR399 molecule. This is a multi-pathway-targeting antibody. It targets three cytokine pathways with one molecule for potent IL-1, IL-33, and IL-36 family inhibition. You can see this depicted in the middle panel with very potent inhibition of IL-1, IL-33, and IL-36. But most importantly, it's also a very potent antibody to block immune chemoattractant-induced skin inflammation in a preclinical model. This is a highly translationally relevant skin inflammation model. Now, all of this leads to a pipeline and a drug potential across multiple inflammatory indications, with an expected readout for phase one in 2024. Now, technology innovation is driving our immunology pipeline. It allows us to design medications which unlock previously undruggable biology, but also create completely new target product profiles. One excellent example is our multispecific nanobody technology platform. This type of platform allows you do, to do combination therapy in a single molecule. It can dial in perfect PK properties for extended dosing approaches, and it also has outstanding CMC properties. Now, this productivity flywheel of a nanobody platform has already produced three clinical assets, and there are 13 more assets coming in discovery. Another very exciting and emerging platform is our in vivo cell reprogramming platform. Here, we are delivering RNA, encapsulated in lipid nanoparticles, via nanobodies to immune cells of choice. Now, this has multiple exciting applications. One of the applications we are personally... I'm personally and, and we are excited, is in vivo CAR T-cell therapy. Now, in vivo CAR T-cell therapy has the benefit that potentially it is off the shelf, it is redosable, and most importantly, it doesn't require viral genomic integration, which is a big topic currently in the CAR T-cell therapy field. Now, we heard a lot about AI. Paul told us, Hooman told us we're all in with AI. We established an AI research factory empowering our drug discovery pipeline, and I just give you a few examples. Our AI-empowered target ID engine has discovered 19 novel targets, and most importantly, has advanced 7 targets into the research pipeline as we speak in just 1 year. Our AI-empowered single-cell genomic disease maps are now credentialing 90% of the targets we have in the pipeline. Most importantly, there's massive progress in AI-empowered drug invention, accelerating drug molecule design and optimization, impacting three-quarters of our small molecule discovery pipeline. We're going to hear about, from Dietmar, about our virtual patient engines, where we are driving in silico trials and comparisons of our molecules before they get into the clinic in terms of their phase 1 properties and in terms of competition to other molecules. Now, again, we are not doing this alone. We're partnering with some of the best in the industry, with Exscientia, Insilico Medicine, Atomwise, Aqemia in the small molecule space, with BioMap in the large molecule space, with CytoReason and Owki n in precision medicine. Now, here's an example how we use generative AI. Generative AI is a household name, driving chatbots such as ChatGPT and Bard, actually, Gemini now, Gemini now since yesterday. And you can see that our key AI models achieving more than 80% productivity. On the lower left, you can see in the panel that there's a very good correlation between predicted activity and experimental activity. We are also using advanced active learning approaches, improving AI model training, and actually requiring twofold less data to train our models. But most importantly, we're also pushing the borders of understanding how these AI algorithms work. We are applying what's called explainable AI and virtual reality to apply AI learnings and highlight key structural elements to guide design cycles. Now, moving to precision medicine and its role in the immunology research pipeline. Patients are at the center of immunology research, and patient unmet need and the underlying mechanisms are what's really driving the pipeline... We are designing and creating exciting molecular disease maps. We are then driving the understanding what the mechanisms of disease are. We are taking these targets then to our technology toolbox and matching them with the appropriate modality. We are then forward translating these molecules into patients, and ultimately, we are creating a virtuous precision immunology engine consisting of back translation and forward translation. Now, it's very difficult to discover novel first and best-in-class targets. At Sanofi, we have developed a target immune engine computing more than 100 million data points when we do the readouts. It includes Sanofi multimodal data, including genetics, bulk transcriptomics, single-cell genomics, network and pathway analysis, and we overlay it with safety, competition, and disease endotype data. You can see that we do an AI-driven prioritization exercise, and we have very quantitative target assessment scores. You can see the distribution of those scores, and our future targets in IBD are hidden in these high scores 3, 4, and 5. This is exactly where TL1A and where TNF alpha is. With these types of engine, we're creating more than 15-50 target hypotheses, and we already moved seven novel targets into the research pipeline in 2023. Now, moving on to single-cell genomics. Single-cell genomics has completely revolutionized how we understand the immune system and how we understand how immune cells infiltrate tissues to create immunopathology. We have analyzed asthma patient samples, and we made remarkable new discoveries. For example, the role of macrophages and monocytes related to the mechanism of action of our bispecific nanobody, lunsekimig, the anti-IL-13 TSLP nanobody. We are using single-cell genomics to analyze Lunsekimig patients before and after treatment, and we uncovered unique mechanisms of action relating to non-classical monocytes, to neutrophils, and to NK cells. Now, the most important slide is probably what the future will look like, and I'm very excited to say that we're aiming for 3 first-in-human entries in immunology over the next few years. We are also going to have, in the next 2 years, 4 phase 1 readouts and 4 proof of mechanism readouts. But what is probably most exciting to me, and truly unprecedented, is that we are going to have 15 clinical phase 2 readouts over the next 2 years in 11 different indications. And with that, I would like to close and hand over to Dietmar Berger, our Head of Development and Chief Medical Officer, to talk more about R&D, productivity, and AI. Thank you, Frank. Very good. Let's bring this home before the night falls, which is a bit of an inside joke. As you heard, my name is Dietmar Berger. I'm heading development, and I'm the Chief Medical Officer for the company. You've heard a lot at this point around, you know, the data on our portfolio, how we're developing our molecules. I was really encouraged to hear before, you know, on, on the panel, these statements around development science. It's actually not by chance that you get to these findings of we have an IL-33, and there's really unique data in the prior smoking population. You need to set up the studies for that. It's also not by chance that you go with rilzabrutinib, and you say, "Look, there's a unique finding in itch, and there's potentially a unique finding in asthma that we can utilize." There's development science behind that, and I want to speak a little more about how we are pursuing our pipeline, how we are advancing a productive and maturing development pipeline, and then how we have modernized development to bring treatment options to patients as quickly as possible. We have drastically stepped up our R&D productivity over recent years with the intention, you know, on our quest, basically, to improve patients' lives. We have increased the number of NMEs in our portfolio. We're now at 34 new molecular entities in phase 1 to phase 3. We have literally more than doubled the number of first-in-human NMEs that we're developing per year. Again, this year, we're right now at 7 first in humans that we've started this year. And we've quadrupled our pipeline value when you compare 2019 to 2023. We're using 3 key levers in order to drive this: a lean and fast development engine driven by leading-edge digital and AI capabilities, and then, of course, decisive portfolio management. I will speak a little more about the first two, and then Helen will take on the third one a little later. Talking about the lean and fast development engine, we have in development integrated all relevant capabilities that you basically need in order to drive a drug from research all the way then bringing it to patients, basically to a regulatory submission and an approval. development strategy, early clinical trials, translational sciences, then late-stage development and clinical operations. And that allowed us to really get to synergy and to seamless collaboration across the group. This, in my view, resulted in shortened timelines, increased efficiencies, and more transparent decision-making. But don't only take my word for it. What we've summarized on this slide is KMR data. KMR is an independent benchmarking organization that looks at R&D performance across the leading biopharmaceutical companies, basically the top 12-15 biopharmaceutical companies. It gets all those data, and then it compares, right? And Sanofi is playing in the top quartile across different of those parameters with regards to shorter cycle times, lower development spending per approval, and higher NME success rates. And that's not only apparent when you look at these external benchmarking data, when we look at KMR data. Also, when we look at our own metrics, we see the acceleration, especially over the recent five-year period. I want to get to the next slide, but somehow... There we go. You heard a lot about AI capabilities and how we are all in with regards to digital and AI capabilities, and that's also, and especially, a tool for development. We have implemented digital and AI capabilities across the R&D continuum, and you see some of that on this slide. We're trying to utilize all data sources and advanced analytics to really enable a faster, more targeted, and also highly efficient approach to development. And you see some concrete use cases here, all the way from indication finding to then dose selection and optimization to disease modeling and digital twins. I'll talk about that also on my next slide. Then clinical trial modeling and study design, Frank also referred to that. Patient and site identification, document writing using large language models, we're making progress on that, and then automated adverse event intake, signal detection, risk evaluation in pharmacovigilance. I'll just give you two data points to further highlight that. In those sites where we used, you know, digital tools to identify sites and patients from large databases, our recruitment goes up by a factor of 2, right, across the board. We've also been able to use a digital approach, for example, to data cleaning in our studies, which leads to a 30% decrease in monitoring and also leads to a 25% acceleration between basically last patient and then database log, which, you know, makes a difference, right? Every month that you save actually makes a difference in this environment. So in my view, we're in the midst of a digital and AI revolution in development, and we see this, we see the impact at Sanofi on a daily basis. I want to give you another example, which is really going back to Lunsekimig, which is our IL-13 TSLP nanobody, as you've heard, and you may realize that I'm actually standing in front of a ginormous nanobody right here in, in my background. That's the structure of the molecule. And you heard from Naimish and Xue and Frank about the phase one data, about the commercial potential, and also about how we used single-cell genomic analysis to further understand the mechanism of action. Here, what I'm showing you is a quantitative systems pharmacology model. So what we did is we took all the available data, mechanism of action, physiology, pathophysiology, pharmacology, and our understanding of the, you know, what drives asthma in, in type 2 inflammation. We put all that into a model, and this allowed us really to predict the biological efficacy before we even treated a single patient. Comparing then the phase 1 data with our model showed us, yeah, we've actually selected the right dose and schedule. We can even correctly predict biomarker changes like what you see here on the slide, FeNO, eosinophil counts, IgE, and we can even go further and predict efficacy for Lunsikimig, but also for competitor molecules. In discussions with regulatory authorities, we've been able to utilize this QSP model, this quantitative systems pharmacology model, to accelerate our phase 2b study start. Because we were able to discuss in a much better way what doses have we selected, why have we selected them, why should we not go to more, dose finding studies, why should we go to the phase 2B in a specific way, more quickly? It also gave us the confidence, and continues to give us the confidence, that we will be able to break efficacy ceilings in asthma with this molecule. Let me come to a topic that's really near and dear to my heart, and that's patient centricity and diversity, in development and in clinical trials. When we changed our organizational model, when we put the development, organization together roughly four years ago, we implemented a really strong focus on patient-informed research and development. Now, four years later, we are working with 80 patient advocacy group partners around the globe. All our late-stage trials are informed by patient insights and patient experts, and in some cases, this leads to real study simplification when it comes to patient access, when it comes to participation, or for example, when it comes to decentralized clinical trials, which are, of course, a real advantage for patients. We have formulated a patient charter, which clearly lays out the principles of our commitment to patients, and we communicate our metrics very transparently on an annual basis.... We firmly believe that our patient, site, and investigator communities have to be representative of the diverse populations that are most likely to benefit from our medicines. I'm proud to say that all our trials at this point have clear diversity targets and are designed to make a difference for patients around the globe. Let me get to some of the near-term milestones of our development pipeline. Frank showed you a similar slide for the early pipeline. This summarizes key news flow items in 2024 and 2025. This includes data for 14 different assets. Most target central inflammatory pathways, as you've heard earlier, have first in class or best in class potential, and provide large, multibillion-dollar opportunities. Overall, what you see here is we'll have 15 phase two and 10 phase three readouts with transformative potential for patients. I am firmly convinced that the increase in our development spend is very targeted, and it has the potential to yield high returns. On my last slide, really giving you a preview of upcoming key regulatory submissions, we expect to bring transformative therapies to market across all of our therapeutic areas. In 2024, I want to highlight, you know, these additional submissions for Dupixent COPD, and then for Sarclisa in newly diagnosed transplant-ineligible myeloma. You've seen the press release this morning of the IMROZ study, but there are also additional important opportunities across the portfolio. You heard about tolebrutinib for MS, itepekimab in COPD, Amlitelimab in atopic dermatitis, and obviously in additional indications, frexalimab in MS, type 1 diabetes, and of course, you see here also for our Vaccines portfolio. I'm looking forward to keeping you all updated on the progress of our exciting portfolio, and then how we are making a difference for patients and for all of our stakeholders. With that, I want to hand over to Helen Marianos, who will speak more to you about portfolio management and even more about AI. Thank you, Dietmar, and hello to everyone here in the room and on the Zoom. I feel like it's finally my turn. There have been so many references to this. Let me, by way of introduction, share a little bit about my background. I'm a scientist by training. After several years in management consulting, I spent 15 years in R&D at a peer group pharma company in various different roles, from commercial to portfolio management to project leadership. I joined Sanofi 2 years ago to lead a business transformation in portfolio management. What attracted me to Sanofi was the opportunity to have a business impact at a company level, and how aligned the senior leaders were about the need for the change. I've been in and out of the portfolio management space for, like, nearly 2 decades. In just two years at Sanofi, I am amazed at the amount of progress we've made in portfolio management and the capacity for change at Sanofi, leveraging AI as a key accelerator. I hope by the time we're done today, you are as excited as I am about the potential in this space. So let's get started. When I first arrived at Sanofi, I found that we were making very robust assessments and decisions on an individual project basis, but the portfolio perspective was missing. Today, we are taking each and every one of these decisions in the context of the portfolio end to end, from target through to commercialization. So you're probably wondering, but what is really different? Well, we have really shifted from what used to be an annual retrospective reporting capability to a dynamic, prospective decision intelligence approach, taken in the context of a portfolio strategy, which Houman outlined for you earlier. The business impact has been tremendous. We nearly quadrupled our pipeline value since 2019, according to an external source. Now, we're proactively guiding these decisions through three portfolio management lenses: R&D return on investment, time to market, and all remaining patient-focused. And Dietmar talked a little bit about our focus on patient centricity, and that applies here as well. In terms of progress on our transformation, we are where we want to be in terms of being quantitative and data-driven, with radical transparency. All of our decisions in R&D are data-driven, and those data are shared across Sanofi. We have increased our external focus. It is embedded in every decision, but there's more that we think we can do in terms of digitalizing our competitive intelligence capability and integrating it with our internal perspective. We are constantly ensuring that we're linking strategic choices with our operational decisions, but there's more that we can do to enhance the feedback loop. We have started to leverage AI for hidden insights, aggregating our internal and external data to make smarter and faster decisions. We're about 12 months in on this journey, and we think the opportunity here is massive, and you see that reflected on the slide in terms of progress. Now, I'd like to spend a couple of minutes talking about how we're leveraging AI to drive this transformation in portfolio management... We have co-developed a decision intelligence tool called Play, that aggregates greater than 1 billion data points across Sanofi. And those data are a wide variety of data: internal data like clinical trial data, commercial data, financial data, milestone data, and external data, competitor news flow, et cetera. There are four key elements that I'd like to highlight with respect to Play. Play delivers actionable insights and transforms them into recommendations from strategy to operations. I'm going to highlight a little bit more about this in a moment. We are leveraging AI for predictions for value drivers, so probability of success, timing, enrollment, R&D costs, and we're using it to challenge our internal thinking, and oftentimes it's generating strategic alternatives. Third, we have a 360-degree view across Sanofi and competitors, and this end-to-end portfolio view is leveraged and used by downstream functions like supply chain and commercial, to rely on the most accurate and up-to-date R&D data to make the best decisions for Sanofi. For example, someone who's planning launch resources in a market can go into the app and understand when the product is going to be approved in that particular market and plan resources accordingly. Fourth, we're doing what-if simulations at a portfolio level and operationally, and I'll share a little bit more about this in a moment. We really believe it's the combination of these four elements and our holistic approach that is truly differentiating here at Sanofi. Okay, now I'm going to share you how we're using this in our day-to-day work. So what you're seeing on the screen are real screenshots of the Play app. So the screenshots are real. The data in them are illustrative for the purposes of the presentation. We have launched the app about 12 months ago, and we already have 9,000 users across Sanofi using the app, and we're using it in our day-to-day meetings as a single source of truth. Now, I'd like to highlight a couple of specific examples of how this is working. On the left-hand side of the screen, you can see dynamic portfolio view with recommendations. The recommendations are there in the center of the screen. We're getting recommendations at a portfolio and an asset level. At a portfolio level, we're getting recommendations to stop lower-value projects at the first opportunity to maximize savings. On an asset level, these are investment decisions, that are milestone investment decisions, like no-go/go decisions for progression. These are based upon what you would expect, financial measures, like expected return on investment and expected net present value, but also strategic considerations like: Are we going to be first to market? Where do we stack up versus the competition? Not only does it give you a recommendation on whether or not to invest, it gives you a recommendation on whether or not you can accelerate and how to do it, how to do it, how much it costs, and what the impact is. My favorite feature, though, is you can pin this decision, and so the AI keeps track of all the investment as, assumptions that were known at the time that you made that decision. It keeps track of that as they dynamically change and alerts you at the earliest opportunity that you may want to reevaluate that decision because the parameters look different now. I love that. Lastly, on the right-hand side of the screen, you can see our what-if capabilities from a clinical trial operations perspective. So this is an enrollment of our product and a competitor product, and you can see the AI is predicting overlapping timelines, so neck and neck. My favorite feature here is I like to go to the next milestone, and I like to toggle that by a quarter or two, usually two, and then I click on the two recommended actions button, and it tells me exactly where to find sites, how to add patients, and how much that costs you, what it buys you, and then what the implications are. So what I want you to remember from this is Play is not a dynamic dashboard. It is interactive, that's capable of giving us recommendations to stop projects at the earliest opportunity to maximize savings, to make smarter investment decisions at an asset level and track those over time dynamically and accelerate our programs to beat the competition. Now, I'd like to take a step back from the AI-specific element here and give you a couple of examples of how our new portfolio management capabilities are really influencing decision-making at Sanofi. So we didn't really have the capability of doing longer-term strategic planning because we weren't modeling our pre-phase II assets. Now that we've built this modeling and simulation capability, we're able to do this, and the data and analytics have supported more aggressive asset strategies at the first sign of clinical efficacy. And you heard about several of these today from Naimish, the IL-13 TSLP nanobody is a great example, and the oral TNFR1. In addition to this, we have also made strategic portfolio trade-offs, and this is what you would expect, and other companies do this, too. It's the forced ranking, it's the periodic portfolio pruning. Of course, we do that, but we're also able to do more strategic and sophisticated trade-offs, thinking about opportunity costs as well. The example at the bottom of the screen here was a decision that we were making between funding incremental investment for Amlitelimab up for a more expansive, differentiated phase 3 program, versus a similar investment to pursue geographic expansion for a marketed product that was gonna require another phase 3 study. We decided to fund Amlitelimab to fortify the differentiation. We told the other project team: "You have to find another way to do your geographic expansion." They came back with a real-world evidence approach at minimal additional cost. So through our new capabilities, we were able to maximize both of the opportunities for the same investment amount. Most importantly, we were able to put the little bit of incremental risk in the right place in the portfolio. I hope that I've given you a window into how much progress we've made in portfolio management space in a very short period of time, and we're really just getting started on our AI part of the journey. There's so much more that we want to do, and I hope I'll get a chance to update you in due course. Now I'm going to turn it back over to Houman for some concluding remarks. So listen, the first thing I want to do is to thank all the members who've participated, the incredible work done by the IR team and my teams. I'm incredibly proud of everyone. The reason I make that point is because I've been sitting there wondering what we need to do to make you all believe that we've got it, right? I think what we've done... I think sitting here, the team have provided some interesting proof points to argue that we're leading in immunology with our key pipeline assets. We're going at speed, but not recklessly. As Dietmar said, the spend is being carefully applied to development to generate growth. We're stepping up R&D productivity. Helen's told you we measure it, we think about it, we distribute risk in the right way, and we really, really are going to be the first AI-powered R&D in biopharma. So as I sit here and I think, over the next little while, we're going to have greater than $10 billion of sales contribution from launches by 2030. We're going to have 12 NMEs, 3 of which are going to be really big NMEs. I sit here and think what... You know, and I do it with humility. I recognize that we need to give you proof points. I recognize that we're going to need to show how we take that small molecule, TNFR1 signaling inhibitor forward, et cetera. But my conclusion is, I think we've got it. I think we've got work to do. Not everything's milk and honey, but I really hope today's shown you that we've got excellent teams, excellent drugs, and an excellent machine to drive this forward. With that, I'm going to hand you back over to Eva. Thank you. Thank you. So as per program, I really want to give you another 20 minutes of Q&A. I really hope you have some, some good questions to Frank, Dietmar, Helen, obviously Houman, and, and since this is the last one, I also obviously still have Paul and Brian for some, for some more strategic questions. So if we, if we start with, with Holger. Thank you. Holger Blum, t Patinex Management. Two, two questions, or one question on the timelines that you have provided. They are really helpful, but to me, it seems maybe a little bit conservative, like the IRAK4 degrader, when you're already in phase two on a 16-week trial and you are so fast in analyzing the data, why should we expect the readout just in 2025 and not a bit earlier, potentially? So normally we'd answer that question empirically, but I'm going to hand over to Helen and Play. Oh, you don't have your phone with you? Wait. I think the question is really on the IRAK4 and the timelines and the readouts. I mean, those studies, we've just started those studies, right? So with those studies, we need to have a... We need to recruit the patients, we need to see the benefit, basically in the trials. We need to read out the trial. You have a treatment period. So 25, I think is adequate at this point. You know, the... When we think about acceleration on the development side, there are two phases I generally think about. One is how do we accelerate through the studies themselves, right? Can we have smart study designs? Can we have fast study designs? But you absolutely need to give it the time. For example, in a disease like hidradenitis suppurativa, to really see the clinical benefit. So in many cases, you see then that people try to do like 12-week, 12-week readouts, when actually the 24-week is much better and much more impactful. So you need to give the trials the time to read out. But what really will lead to acceleration is how do you reduce the white space, right? And how do you think about innovative study design concepts, right? How do you think about multi-cohort studies? How do you think about Bayesian approaches, et cetera, et cetera. And for the IRAK4 program specifically, we've driven that quite fast I think, actually. We've minimized the time between the phase one and the phase two, and we've immediately gone into two indications, which are indicative, right? One is basically AD, the other one is HS, indicative of different levels of impact that you want to have from a biological perspective. I hope that answers the question. If not, I can ask Naimish to give you more detail. Okay, thank you. Just a quick follow-up on the industry-leading benchmark that you have shown. Are these that like shorter trial duration, is it adjusted for the indications? A cardiovascular trial would take much more time. ... than an autoimmune trial. Yeah, it's a very good point, right? Portfolio mix does play a role in these types of benchmarks. There's some recognition of that. There's some adjustment in that as people are looking at these different portfolios. That's why I mentioned actually, it's not only when you look across the industry that we see that we're actually positioned very well, that we're performing in the top quartile. It's also when we look at performance year over year over year. That's what's important to me, right? Because I can show, when we look at, for example, phase one timelines or timelines, when a molecule comes out of research and how quickly can we bring it into first in human, we have real acceleration there, right? We really see ourselves in our metrics that, for example, we brought that time down by more than 3 months over recent years, and we brought down the time... To go back to the other point, we brought down the time of the white space between, for example, phase 2 readout and phase 3 start considerably, where we're now at, you know, literally usually like 6 months or less. Next question from Peter over there. Tariq. You guys, you have to get out of your phone. Thank you. Hi, it's Peter Welford at Jefferies. Two questions, quite broad. First one, just on trial design, I guess more generally in terms of, you've talked a lot about terminating programs early and also best-in-class potential. I guess curious why in studies like, for example, the oral TNF, you don't consider using a Humira comparator, or not necessarily statistically, but at least as a comparison. And equally in, for example, the Amlitelimab studies, you know, why not put both from the point of view of payers, but also from the point of view of differentiation, a Dupi arm, even if with placebo as well, you know, a Dupi arm in those studies, so you can show the difference potentially between these therapies? And then the second one is again, more broadly, you... I appreciate tonight it's your message about immunology and it's, you know, taken on board. But I guess this is an R&D day. So beyond that, I guess when we look at things like rare diseases, where you've got a huge commercial presence, a lot of sales, we've heard very little about rare diseases, and I guess, you know, oncology is still pretty early stage, to be honest. Could you just talk a little bit about, I guess, from an R&D perspective, your commitment to those areas? Because, you know, they seem both areas where we've heard relatively little, today, during the course of the day. So, Peter. Thank you for the question. I'll try to answer both of them and with alacrity. The first one is we remain both committed to rare disease and to oncology. I described sarcoidosis for you today. We've got further sarcoidosis studies coming, including sarcoidosis extension for the subcutaneous formulation. We remain extremely committed to rare disease. As you say, we've got great provenance. For the sake of clarity and simplicity, we chose immunology today. It's an area that we have doubled down on becoming a powerhouse, but I don't want anyone to go away from here thinking that we've neglected the other two therapeutic areas and indeed, vaccines, which are critical to our future. The second question. The first question was about, if I boil it down, clinical trial design and having an active comparator head-to-head with existing standard of care, et cetera. That is something we may at some point consider. At this stage, we're driving, as the previous questioner asked, our molecules at the hardest timelines to be able to generate value for patients as quickly as possible. To do that, running these randomized controlled trials is a sensible thing to do. We may consider that at some point. Maybe I can add a couple of things. There's really no regulatory requirement at this point to do head-to-head for these molecules. They're different MOAs, and as Houman said, we're trying to get them at pace back to patients. So with Amlitelimab, we are doing the biologic inadequate responder trial that will answer some of those questions that you're asking about patient selection and which patients might do better on the other one. And the same with oral TNF. I think it's a different profile than Humira, so we don't feel the need to compare to Humira in an early phase trial. Remember, long-term efficacy and safety is a differentiating factor for that molecule, so it doesn't make sense to do a head-to-head in a relatively short dose range finding. Actually, I'm going to see Naimish and match him and raise him. The other thing is, we're becoming an AI-powered pharmaceutical company. We are not that far away from doing digital twinning and structured comparator arms, even to be able to compare across trials, and that has been done in the industry. So rather than putting patients at risk or taking excess time, we can twin those studies. So I think the days will come when we do that digitally. We're gonna try and take a question from the webcast. Do we have Graham Parry? Yeah, great. Can you hear me okay? Yes, we do. Perfect. Thanks for taking the question. So firstly on frexalimab, there's a quarterly IV. Just wondering, you know, how you'd expect to differentiate versus anti-CD20, where, you know, the IV dosing there would be six monthly, given MRI lesion reduction so far looks quite similar. I think before you've discussed a biomarker population, you might be able to target this. Is that something that's still in development? Similar question from the Amlitelimab. So again, you've talked again about, you know, TH17/22 broader population. So is there a biomarker strategy that you might be able to follow further down the line to select, patients for frontline rather than just Dupi or JAK failures there for that asset? And then just a question for Paul, really on aspiration, really. You've highlighted here, you know, $10 billion from launches, $33 billion peak sales potential, $21 billion for Dupixent, and consensus is modeling mid-single digits growth in revenues the back half of the decade. So is it Sanofi's aspiration to do better than that? And a similar question with the margins. You abandoned a 32% 2025 margin target, but the products you're investing in are mainly wholly owned. ... So what aspirational margins do you think Sanofi can achieve with wholly owned products rather than something you're paying over half the profits away? Thank you. So as always, you're pushing it. So let's start with MS. Several questions. So with frexalimab, yeah, we're taking the IV into phase 3. There is a subgroup of MS patients that seem to prefer IV. Natalizumab is still around, but we know that subq is also popular, and we are developing subq in parallel to phase 3 to have that available as an option. And then Amitay Mak. Thanks. Thanks, Graham, for all the questions. With regards to biomarker strategy, that's definitely an approach we're interested in looking at in detail. As you know, there aren't a whole lot of examples in immunology of precision-guided biomarker approaches. However, I think I mentioned a couple of things that we could think about short of that, which is some of these characteristics of the non type two profile actually track back to demographic characteristics of patients. Younger age, certain ethnic backgrounds, such as Asians and African Americans, tend to have that profile. So these are other things that we could think about, taking the biomarker and then taking demographic profile to map a more clinically useful strategy for identifying responsive patients. Maybe I can briefly add to that. I think the biomarker questions are important, and as Naresh mentions, right, there's no biomarker selected, you know, treatment in immunology, maybe with the exception actually of type two and eosinophils, right? As a clinical biomarker. Yeah. Right. But, the important piece is that we're actually doing the work, right? And I think that differentiate us- differentiates us. We're really trying to understand the science in the clinical trials. All clinical trials are accompanied by a broad biomarker program. So we can do the analysis, we can react to it, we can learn from the science, and that really helps everybody to move forward. And maybe if I can comment on the biomarker question, there's like a different perspective on biomarkers. There are co-diagnostics, which are moving with a drug into an approval phase. But there's also the whole biomarker space, and I hope I could convince you about back translating and understanding endotypes of disease and then getting us ready for the next targets, for the next subsets. And that's all in the works. So it's like different views on biomarkers. We're doubling and tripling down on understanding disease mechanisms, patient subsets, and bringing forward new targets and also stratified patient approaches. Okay, and then Paul and JB on top line and bottom line ambitions. Well, thank you, Graham. I think talking of biomarker, our initial targets we set up with Paul in December 2019, of 32%, was also expressing the fact that we had a very great asset, but partnered. And as you summarized it, going all in this pipeline of fully own asset is part of this desire to break this ceiling of margin and reach best-in-class profitability in the industry. So that's where we want to go. That's why we took such a difficult step to double down in R&D, go through the LOE of Dupixent with the capacity to keep growing our EPS, because, as you know, it's enough to replace Dupixent with $2 of Dupixent with $1 of a fully owned asset to go on growing our EPS all through this period of time. So that's where we are now. That's what we aspire to. It will, it will show up progressively. You've seen our top-line aspirations, so pretty clear. Thank you. So who else? So I'm gonna go to Mark again. Thank you. That's kind. It's Mark Purcell from Morgan Stanley. On the topic of rise of orals in immunology, I'd be fascinated to understand what the PLAI modeling is showing. I guess at the moment, we've got penetration rates of orals between 12% in COPD to, like, 45% in ulcerative colitis. But there's compromises along the way. You know, the JAKs are in refractory patients, the lack of activity within psoriasis and those first-line options compromises those as well. So when it comes to combinations of clean, effective oral immunology drugs, how high can oral penetration rise to? So this is one of my favorite questions. Thanks for the question. I remember. I think logistics really matters. So I want to start with answering a different question, which is, some people will continue to prefer injections, especially if they're at long intervals, right? There will be a bunch of people who don't want to take tablets every day, whatever. If you just think about not just our world, but the broader world, the absence of a cold chain, the ability not to have to have an injection, possibly delivered in primary care, not having to wait for a delivery. The reality, and I don't know if any of you know people on biologics, which are brilliant, is there are logistical challenges. The ability to have a small molecule that you take as a foundational therapy, so a pill in a bottle without a cold chain, without any hassle, is really powerful. And when you look at molecules that worked in that space, statins, whatever, penetration is actually quite high. The real, the real issue for me, though, is one step greater than that, which is in the future of immunology therapy, like in cancer therapy, it's gonna be combinations. And it's gonna be a lot easier to combine a small molecule with a biologic or a small molecule with a small molecule, rather than taking three or four biologics. So, so the short answer to your question is, I think the ease of use of those molecules, as long as they're safe- ... will lead to great penetration. Brian Foard? Sorry, yeah, just to add to Houman's point. Mark, a lot of it will depend on what patient type you're going after as well, right? So we talked about in asthma, the two programs that we went through with the two assets. We, I mean, lenzacabeg not being the oral, the TNFR1, and also we talked about the rilzabrutinib, for example. I'll use that as the analog. We're going after the moderate to severe patients population, but as well as the mild to moderate uncontrolled. Now, we do assume different biopenetration in the different patient types because you have for the milder the population, there is a higher hurdle from a clinical practice change standpoint as well as from a payer standpoint. So we tend to differentiate the different patient types and apply different biopenetration. Just pass it to Luisa. Thank you. Thank you. Luisa Hector at Berenberg. JB may correct me, but I think since launching Play to Win, Sanofi has spent around EUR 25 billion on R&D and around EUR 18 billion on external business development, M&A, and we've absolutely seen the results of that today. So Houman, I wanted to understand a little bit more your perspective on internal versus external allocation for the coming years, maybe how that ratio might move, but also how you evolve internally with Sanofi, within Sanofi, interactions between BD, R&D, Helen, with the app, Play app. Does that encompass that sort of external proposition as well? So how does it all come together as you move forward from here? It's an excellent question, Luisa, as we expected. Just, just to start with a very simple point, our strategy since 2019 has not changed, right? We remain thoughtful about the external ecosystem. We will do BD M&A where appropriate, when it's commercially viable, we are good stewards of capital, where it's scientifically transformative. So just starting point is the 2019 strategy hasn't changed. A layer underneath is how will it change with me? And obviously, I've come from an environment where I have an insight into biotech. I have an incredible respect for what can happen in nimble, small biotech companies. And I always think that a federated model works best, right? So there are things that Frank and his group are spectacular at, and thank you for recognizing the money we've spent in the last few years has turned into gold. But Frank's work and his team is spectacular, but it's not only spectacular as a silo. As you've seen from Frank's work, we can get insights into what to go out into the ecosystem to interact with. So there's a bidirectional flow. It's fenestrated. We will continue doing a great deal with the external environment. We might do it a little bit differently. And the question on BD is we are super close. So Monika de Virgiliis and I, who's the head of BD, we talk almost every day. We text six or seven times a day. We share emails. We've got a joint list. BD and R&D are totally seamless. Yeah, maybe I can sort of- Please. Comment on that. We call it drug discovery without borders. It's a wrong mindset to think about internal versus external. We're working open innovation framework, and I'll give you two examples of how this plays out. This drug discovery without borders approach is applying to about 25% of what our internal pipeline is running on an external bench. For example, it could be that we are running a small molecule program with an AI biotech, where the therapeutic area head says: Okay, I want to put this target with that player out there, run it in partnership, and I'm going to compete, and I'm going to release the best from our internal folks who are fully up to speed with AI and the external world, and then we run the competition. Another example, where it's very important to have a great internal science is BD. A great BD deal has, for example, been our Kymab acquisition, where we got a phase 2 asset for about $1.1 billion because we saw OX40 ligand as a pathway in atopic dermatitis before anybody else. And that's the other key ingredient you need to make great deals. It's not like herding behind, for example, TL1A, where we then make a very good business deal to get in that, but we are not going to pay a fortune for TL1A because there's a lot of competition. We make our bets in a way that's science-driven and it's prudent capital allocation. Can I just answer the play, the specific play question? Business development isn't in there yet. It is a plan for one of our next minimum viable products, or MVPs, and they come very quickly. So we're doing one every 30 days. So, we are expecting that to be added very shortly. So last question from Seamus. Yeah. Derek, can you? Thanks. Seamus Fernandez at Guggenheim. So, I actually just wanted to ask on your C1s. I don't think anybody asked on it, so we'll jump to, I guess, the immuno team. But can you maybe talk a little bit about, you know, a couple of things? It looks like a good proof of concept from what we can tell. Just interested to know how you're thinking about the pivotal development plan. Is this an opportunity to move straight into phase three from your perspective, given the, the optionality there? And are there other indications for C1s, where, you know, we might be seeing, that are neuromuscular IgG driven, GMG or other opportunities there? Thanks. ... Yeah, so thanks for the question. So yes, we are taking that molecule directly to phase 3. So those two phase 3 designs I showed, we are planning to have the first patient there in the first half next year, okay? So that's... And yes, there is possibility to further for further indications, and I hope we'll be able to discuss that at the future R&D day. Okay, so we could probably go on for another 20 minutes, but I really have to be respectful of time. I really would like to hand over to Paul. Okay. So thank you, and just stay there for a second. I think this is the last session we're all together. Is that correct? So I thought I'd take the opportunity to thank those that were here and asked great questions. I don't think I've seen so many hands go up before in a meeting. Sorry, Pete. And there was quite a lot of enthusiasm for the conversation. Mischievously, sometimes I think to myself, if we anonymize the company on the slides that you've seen today, whether we'd get a different level of confidence in the science that we've shown. And I ask myself that because I, I've been to a few of these with different companies. This is without doubt, the most impressive day that I've been to in terms of the deliberate effort to bring everything together, including AI, all the way through, to make sure that we're really on our game. Many of the people here were just not involved in this company for these two decades of sentiment that flowed around. But it's okay. We know that we're in the words of the Missouri number plate- Show me. So we get that. But I think the quality of the conversation today has been really fabulous. It's as much as I could have hoped for on both sides, to be honest. And as it's the last moment for us all to be together, I just wanted to thank IR, the team, everybody that's done a really fabulous job presenting. I really enjoyed it. And I feel there are sessions this afternoon, and they're good sessions, and you can get to go really deep on Pete, on some of the content with the real experts. I think that'll be fun, too. I said at the beginning of the day, I've waited four years for this type of meeting, where we can be science first, we can be really focused on what we think is gonna drive the company, and that cadence is just gonna build and build. I think we're making really smart choices. I think we're gonna be first and best, and I think people are starting to follow us, as was said earlier. And I think that's a real sentiment, statement rather, of sentiment for how we're going. So you should watch out for what comes next from the new Sanofi. So thank you very much. Thank you. Thank you. Yeah, and so now we're gonna conclude our webcast. I hope you enjoyed, and even more importantly, you—I hope it was worthwhile. And now here, we're going to go for lunch, and I wanted to bring a slide up that just shows that we have about an hour. We have to go in the elevators. I think we're holding some elevators. So if you could just quickly make your way on the fifth floor, and then, you know, we're going to bring all our management again with us. I think actually our external experts are gonna join us as well. And then we'll be back here at two for those scientific sessions that Paul just touched upon. So thank you.