Good morning, everyone, and good afternoon to Europe. Good evening to those listening from Asia. My name is Eva Schaefer-Jansen, and I'm the Head of Sanofi Investor Relations. It's a pleasure to welcome you to Sanofi's Immunology Investor Event here in Boston. Thanks to all of you who took the time to meet with us here, and it's such a pleasure to speak to real people again. Let me start with a few logistical details. First, you have been provided a QR code on the backside of your name badge to directly access the presentation slides. For those on the webcast, you can find the slides on the investors page of the IR section of the website at sanofi.com. Second, during the question and answer session, we would kindly like to ask you to limit your questions to one or two, and if you do ask a question, please identify yourself and use a microphone. For the virtual audience, please use the raise hand function on Zoom, and we will call you up. We're gonna explain the drill again when we go into the Q&A section. Third, we will close the meeting with some breakout sessions for those in attendance. You have each been allotted one of two neighboring rooms here on this floor. Once you have moved to the breakout room, you do not have to move rooms between sessions, as management will rotate between rooms, so you can stay seated. There will be a 10-minute handover between each session. If you have any questions about the logistics, feel free to talk to me or Felix, and we are very happy to help. Moving now to slide two. 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. Now, let me take you briefly through the agenda. Paul Hudson, our Chief Executive Officer, will open the meeting and present Sanofi's path to industry leadership in immunology. Bill Sibold will outline our strategic priorities in achieving those objectives. Brian Foard will discuss Dupixent's leadership in key Type 2 inflammatory diseases, and he will then hand over to Naimish Patel, who will present our ambition to expand beyond Type 2 disease into other areas of high unmet medical need. Frank Nestle will close the main presentation part, highlighting the disruptive technologies we deploy with the aim to improve the standard of care. We will have a short break before John Reed, Head of Sanofi R&D, will open our expert encounter by discussing patient needs in dermatology and respiratory diseases with two renowned external clinicians. You will also be able to ask questions during the session. It will then be directly followed by our main Q&A sessions with all our presenters. At this point, we will close the webcast meeting and will continue with the breakouts here in Boston. A packed program. I really hope you enjoy it. Now please welcome with me on stage Paul Hudson, Sanofi CEO. Thank you. Thanks, Eva. Thank you very much. Good morning, everybody. Thank you for making the effort, those that were able to be here in the room. We actually opened this building last week in this room. We had a patient with Cold Agglutinin Disease, Duffy, who explained to us pretty much fundamentally how our work had changed her life. It was the right way to open the building, frankly. It's a bit of a building site outside. It's a work in progress, much like Sanofi. The R&D building to the left, you'll see if you come out, is an incredible new facility, state-of-the-art, perhaps the biggest in the city, and brings together 2,500 people between both buildings on this site. We finally get to bring everybody together. We finally get to reflect on the progress made and to set a new standard. Very exciting. For me, I've been on the road a little while since last Monday, I was at AAD all weekend. I'll touch on it in a moment. What a brilliant meeting for us. I think some of you attended it as well. You know, it's very clear that Dupixent is gonna be the backbone of therapy to the end of the decade and probably beyond. We'll talk about that. Exciting times to be part of the company. We showed this slide in 2019. December 2019. We said this is what we're gonna try and do as a company. In fact, back then, I think consensus was less than $7 billion for Dupixent when we rolled this out in 2019. A lot of raised eyebrows, in fact, at the time. We've made a lot of choices since then. We bought 14 different companies in two years. We have redeployed EUR 2 billion worth of expenses towards our R&D effort, and of course, we've spun out our EUROAPI business. While that may be not important to you, what it should tell you is we're not frightened of tough calls, and we're not frightened of making sure that our business is fit for the future. What's also important is we said this very clearly, that we were at a point that we wanted to get to 2022 and be on the edge of what comes next in the next chapter. We routinely recommit to our midterm financial guidance, both for 2022 and for 2025. Everything on track, as you would imagine. At the same time, you know, I can't believe how much progress we've made from 2019 to this point here. You're gonna see today, I hope and feel, and some of you saw it over at AAD, you know, we're really building the industry-leading immunology company. I think it's now sort of the time to start trying to calibrate how big our pipeline is. We're right at the beginning of a launch sequence, and we move into that for us in 2023 with everything we have ahead of us. It's really, really exciting for us. We identified these three areas as being part of our strategic focus, and we said back in 2019 that these were important to us. I refer back to it, and the reason I refer back to it is because I think the transformation of Sanofi is one of hard-earned credibility gaining and, of course, R&D productivity and delivery of financials. Not a surprise to any of you, but what we have tried to do, I think, at every turn is to do exactly what we said we would do. We try not to miss a beat. I like to look back at what we said we will do and then be able to show the progress made. I think we made incredible progress. If we start with vaccines, we'd predicted a high single-digit CAGR through 2025. We've now announced that, those of you that joined December 1st last year, that we would double the size of the vaccine business by the end of the decade. In fact, on December 1st, for those that can remember, we also made a prediction about how quickly the pandemic would start to move to endemic. We made a prediction about mRNA flu. We made several predictions that I hope you see came true because that's exactly what we need to do as a team. We're delighted with how vaccine is progressing. For pipeline, greater than 90 projects, which is a record for us, not least the 10 first-in-human in 2021. Never been done before in the company. Before that, the average was three per year. A company our size just simply can't operate at that sort of level, 10 in 2021. To Dupixent, EUR 13 billion, we're signaling. Now, here's a really important point, I think, for everybody to remember. I was, of course, accosted over dinner last night. Yes, I'm looking at you. Pressed on how big will it be? Pushed on how big will the number be that you announced. It's really fascinating for me. Like I said, when we announced 10, we were, the consensus was seven. Only six months ago, the midterm, the mid-decade consensus was less than 10. Now everybody's getting excited because you're starting to believe what is possible with this incredible medicine. I said earlier, if you were at AAD, you know how this medicine steps forward, and you know how the competitors have effectively stepped backwards. Really important for us to understand. A new expression that I want to introduce, which is this is less about peak year, and this is more a waypoint in the Dupixent journey. Think about it. We signaled greater than 10. Now we're saying to everybody to fully understand, given how low biologic penetrations are, how many more indications are to come, this is less about peak year sales. This is the next set of coordinates on the journey for Dupixent. This is what is our minimum expectation. Frankly, our expectation is to go way beyond that number. Now, that is a pivot, I think, for some of you who prefer just to update the model with the 13 and move on. For us, it's just a moment to say it's the next step on the journey before we update you again. We're delighted with that. Of course, COPD will have to be added to that. People have asked me already this morning, "Why did you not add COPD?" The bottom line was quite simple, which was, you know, we'll know when we get the data. If the profile in COPD is fantastic, you'll know what we know. There are no biologics in COPD. It's a huge unmet need with huge medical cost that needs to be offset. It's impossible to calibrate it at this point. When we get the data, we get the profile, then we'll share with you what we think the next set of coordinates are for Dupixent. This number alone, I think, would put us in the top five medicines, which is quite interesting. It's interesting that expectation is even higher than that. Just to remind everybody that we've made stunning progress, but there's some really important fundamentals about how we manage Dupixent. Not least, we declared that we'll be accretive to margin on to BOI margin in 2022. On track, of course. The scale of the volume improvement means that the efficiencies that come with that are now ramping up, which is great for us. The manufacturing improvements which we signaled before, several times actually, that is the equivalent of adding a blockbuster in terms of incremental opportunity for us just because we've been improving the process. I took the time recently to visit our great people in Belgium who are responsible for improving the process, just to remind everybody how important this was to the future of the company, and all is on track. Finally, and I've already touched on COPD, but I think you can understand how excited we are about that, particularly if we get to where we need to get to. With the last slide, it's a simple slide, and I think it's pretty clear, though, for me at least leading the company, that there is more of an expectation for us to recognize that we're thinking way beyond Dupixent. It's an incredible medicine, as I've said. I think it's time for everybody to start appreciating that our immunology pipeline is not early just because we've skipped phase II or accelerated development. It's late. It's not late, as I was told, but it's late. We're getting to the point now of being able to change what we think could be the future of immunology and offerings. Now this is really important because while we have a great asset in Dupixent, you know, our story is much bolder. We thought it was important to anchor everybody about what immunology looks like. We've said greater than four-fold versus 2021 of $5.5 billion by the end of the decade. Those numbers would make us bigger than Novo and almost as big as Amgen just in immunology for us. This is a game changer. Those that know us well and me well, you know we like to put a nice big goal out there and go crashing through it. This is our next expectation. Have our pipeline well understood, people knowing how Dupixent fits into it, properly recognize what comes next, and then propel us beyond there. As I said, I've just been to AAD, and maybe I'll finish on this point, which is, we hosted a group of dermatologists to go much deeper into the pipeline last, the end of last week. I think it's fair to say that the excitement was pretty incredible. You know, everybody's starting to recognize our place and what we're gonna do, and it's brilliant for us. As I ran into those dermatologists through the convention at AAD, everybody stopped me. "I've got an idea for this. I think you should be looking at that. How do I get involved in this? I've got these biomarker samples. I've got these tissue samples. What can we do?" For me, that takes us to the next level. Having been around in the industry for too long, you know when physician populations are starting to get excited, not only about what you're doing for patients today, but fundamentally, what you're gonna offer over the long term and why they would like to collaborate with you. We've reached that point, and that's a really important point for us. Spend some time, I would hope, on this greater than 4x because this is the next big marker for us in what we're gonna do, and it's really, really exciting. I've mentioned the science. We have a world-class team, we have Dupixent at the center, and we know what we're doing. With that, I think I'm gonna hand over to. If I've got that right. Yes. Bill Sibold, our Head of Specialty. Sadly, Bill has the virus, so Bill cannot. We thought it better that he did not come. So he is in good shape. We gave him the opportunity of not commenting, but he couldn't resist it. With that, Bill, maybe I'll hand to you. Well, Paul, thank you very much. Can you hear me okay? I'll take that as a yes. It's a real pleasure to be here, at least virtually today. I thought I would go old school and do Zoom rather than being face-to-face. It would be great to be with you all, but it really is an exciting day for us, and I hope you'll see that as you look at the rest of the presentations. I'm gonna take you through our strategic priorities. You obviously know us well for our rocket ship, Dupixent. But today I'll have a chance to see how we've built on that and really positioned ourselves to become the leaders in immunology for the next 25 years. We believe it. We believe that we're well on the path, and as Paul mentioned, AAD, this past weekend, there was a lot of excitement around everything that we talked about and presented, and I think the community is expecting us to take that position for the future. We've built a great team. You'll meet some of them today, and we've created a pipeline that looks ahead to the future, really serving unmet needs in these immunological diseases. Looking at this slide, you know, the immunology market is highly attractive and growing. It's expected to grow to over $115 billion by 2026. This is according to Evaluate Pharma. Where it is growing is where we've prioritized, dermatology and respiratory and where we've already helped to expand these markets with the success of Dupixent. We believe this market growth will be further accelerated by new product entries in AD and, notably by potential innovation in high unmet need diseases such as COPD, which we'll talk a little bit about in a few minutes and what Paul's already mentioned. Let's move on to slide 11, and we'll zoom into the advanced therapy AD market, since it is a market that we created through the innovation of Dupixent and really our launch excellence. Advanced therapy penetration is an important marker of both potential and success in a given market. This slide is to give you a sense of how the AD market has evolved compared to psoriasis and where we expect it to be headed. Psoriasis, we think, is a good comparator based on it being a skin disease of similar size, and here we're comparing the adult population. You can see that with just one product, Dupixent, on the market until very recently, we have reached higher penetration versus the psoriasis market at the five-year point, so 8% versus 5%. That gives you a sense of our performance. A really remarkable effort here to have built this market on our own and to have outpaced what psoriasis had laid down over the past years. This year, we expect to see significant market growth in AD as three additional therapies have entered the U.S. market. Now, looking towards the future, we expect AD to continue to progress faster than the psoriasis market and reach at least 25% advanced therapy penetration in 10 years. It's already a big market growing fast, and we expect it to be bigger. Let's move on to slide 12. The next market that represents significant potential is COPD, which is another devastating disease that's in desperate need of innovative therapies. Now, it's the third leading cause of death worldwide, and there hasn't been innovation in more than a decade. The unmet need is really there. We are advancing two unique targeted therapies for the potential treatment of the approximately 2 million moderate to severe patients in need, and that's in the G7 alone. On the left slide of the slide here, you see the GOLD guidelines with the most severe patients in the Group D, and that's where we will be focused. Let's go to the next slide 13. You see that Dupixent and itepekimab, we could cover more than 80% of the most in-need COPD patients. That's the GOLD D Group. The way we think about the market is Type 2 versus Non-Type 2 and current smoker versus former smoker, and you can see where both products play. Dupixent will address the Type 2 COPD patient, and itepekimab largely addresses the Non-Type 2 disease. We see this as a great opportunity based on the unmet need and the size of the market. You know, a couple slides ago, I discussed the importance of advanced therapy penetration in assessing the potential of the market. In COPD, we would expect advanced therapy penetration to approach 35%-40%, much like what we expect to see in asthma. The opportunity is very significant, and we have two assets covering the overwhelming majority of the market. We're really excited about this, and as Paul said, let's see what the data says. Now, let's move on to slide 14 here. If we step back a little bit and put this all into perspective and really show our strategic approach to immunology, let's start here. You know, historically, companies with multi-disease targeting products have focused almost exclusively on adding new indications, then looking for the next product late in the life cycle of the first. Look, I think we've done a great job. We've aggressively expanded indications for Dupixent following the biology, really, and we've done so at an accelerated pace. Because of its safety profile, we've also been able to expand to younger ages. We've now filed for kids as young as six months old in atopic dermatitis. However, Dupixent is just the beginning of our broader immunology story. If we click onto the next slide, please. The next piece of the story is where we are really headed, and we're taking a long-term approach across the full spectrum of diseases that we prioritize. Dupixent has been really transformative in Type 2 disease, and our pipeline extends beyond Type 2. We have 10 different molecules in development, five of which are targeted for unique and emerging segments of Atopic Dermatitis. In AD, we have a topical, orals, injectables, all aimed at satisfying the unmet needs of this heterogeneous disease. I think this approach of looking at the complete disease end to end and putting innovation towards that's how we have thought about AD, and that's how we'll think about the other areas that we're going to be going. We have four programs in asthma. I covered COPD previously, and we have three in gastroenterology. You'll hear from Naimish and the team about some of these assets and begin to understand why we're so excited and confident about the future of immunology. They address key pathways in unique ways, such as our nanobody programs. I think these conscious effort of building the capabilities to be able to go after the innovation that exists, that's really been the approach with everything that we've built. Now, what we have with Dupixent is obviously a fantastic product that has set the bar very high in both efficacy and safety, and it really raises our level of expectation and hurdle for each of the other programs that we have. You know, unlike other companies, we're starting with a very effective and a very safe product. So we're in an enviable position. We have great capabilities that I think will allow us to achieve this objective of being the leader in immunology. I hope this gives you a good sense of where we're headed, why we're so excited. As I said, we have great products in the pipeline. We know that we have a great team that's going to discover, develop, and launch them, and you'll get to meet some of them today. Next, I will pass it over to Brian Foard. Brian? All right. Thanks, Bill. Hope you're feeling well. Good morning, good afternoon, good evening, everybody. Thank you again so much for joining us here in person and online. As Bill said, he was talking about this rocket ship of Dupixent. I'll focus in on that a little bit for our time and tell you a little bit about how we're proud about the progress that we've made thus far and our ambition to be the leader in Type 2 inflammatory diseases, but we're also inspired about the opportunity that still remains ahead. I'll highlight some of the key milestones, as you'll see here on the screen in front of you. Obviously, we start with indications. We've moved from four to six indications. This is really just since the last time we came together in person at our old building, as a matter of fact, not at this new facility. Four-six, which is quite impressive, to say the least, but our development program has been incredibly busy over the last couple of years as well. Seven new positive pivotal readouts, and I'll speak a little bit about those here in a moment. 12 new trials achieving FPI, and then finally, seven new additional indications initiated. However, I think as Paul started with patients, we're probably most proud of the fact that we've nearly tripled or more than tripled the number of patients actively on therapy around the world for this amazing medicine. Still just getting started. At the same time, we've nearly tripled the number of markets around the world. Importantly, a market like China, and I'll Zoom in on China here in just a bit, being one of those marketplaces, but this allows us to reach more patients. Finally, one of the things that I'd like to highlight is over the last two years, our profile has actually only gotten stronger for Type 2 inflammatory diseases. Not only have we gone down now to the age of six months in our recent submission in atopic dermatitis, but expanded into other indications with positive pivotal trials, at least for now, in Eosinophilic Esophagitis, CSU, and as well in Prurigo Nodularis. Our profile is only getting stronger, while at the same time, if you look at the competitive landscape, seven new competitors have entered over the last several years, and I would say that their profiles, from what we assumed then, have actually only gotten weaker. We can certainly talk about that a little bit today as well. Very pleased with the progress we've made again, but as I said, much more still to come. I'll zoom in on another really important milestone as well. We're not complacent in the least, as you might imagine, but it is very nice for us to achieve milestones like this as well, to be the leading immunology brand in specialty dermatology. I think Paul mentioned that. You really start to feel it now at congresses like the American Academy of Dermatology. We've gone from maybe not being a known entity in the space to being as the company to watch for what we're gonna do next. Achieving this leadership position while at the same time, this is really with one real dermatology indication, if you think about it. It's really not against what we would classify as competitors, but very respected brands that have been extremely successful in there, no doubt, Humira, Cosentyx, and Stelara of the world. This is with our first indication now down to the age of six, of course, but we have bigger ambitions there in others, and I'll speak about that in just a moment. I do wanna go back and really reiterate the point that Bill was making, and that is that in this patient population, now if you go down to the age of six, the advanced therapy penetration's only 7%. Significant potential there in this patient population for expanded growth, and we're outpacing psoriasis, as Bill also alluded to. With that trend, again, we think there are significant opportunities remaining in Atopic Dermatitis. Two years ago, at this same event, I think it was actually Graham that actually said this to us, "Don't you actually want competition in AD? Because won't it help you grow the marketplace?" I'm not sure if we confirmed he was right at the time or not, but he was. Competition is good for the marketplace, especially a marketplace like this, where patients need to be motivated to seek treatment into the offices. As you bring more companies in, what we saw even this past year in both Germany and Japan, where we saw competition for the full year, we saw those marketplaces grow greater than 50% versus previous year. Now one of the final points that I'll make as it relates to that's good as long as your profile remains extremely strong as ours has. Not only has our profile in atopic dermatitis gotten stronger, as we said, with the data that we've generated now out to four years, efficacy and safety data, which is fantastic, but also going down as young as six months of age in the data we've generated in recent submissions in the U.S. and Europe, that gives us further confidence that our profile is strengthening. Again, I think as you, many of you have written, you would all agree that our competitors in the atopic dermatitis space, their profiles from what we assumed two years ago, have actually only gotten weaker. Now I'll zoom in on one of the indications that we're also really excited about going beyond atopic dermatitis. Now I'd be remiss if I didn't mention Prurigo Nodularis. This past weekend at the American Academy of Dermatology, for those of you who join sometimes the late breaker sessions, I've been to a lot of those in my career. I've never heard applause. We were met with applause when the moderator, Dr. Blauvelt, actually said, "Is this the first positive pivotal trial in Prurigo Nodularis?" When the investigator confirmed yes, the group applauded. I'd be remiss if I didn't mention that about Prurigo Nodularis, although I know there's a lot of interest in CSU, but that's at a very important point. These two indications are very important indications for us in the dermatology space. Why? Because of the unmet medical need and the lack of innovation in the space. I'll zoom in now on CSU as well. As we know, CSU is a debilitating Type 2 inflammatory disease, but it's quite complicated. It's also met with itch and hives, so very common as you think about atopic dermatitis, even Prurigo Nodularis. Really what Dupixent proved is it was the first new mechanism of action in more than a decade to have a positive Phase III data in bio-naive patients. I'll share with you the data down at the bottom left-hand side, and again, as you can see, in itch first and foremost, in placebo versus Dupixent, and placebo versus placebo plus standard of care, which is antihistamines. It's actually an active in the placebo as well. You'll see more than 2x, excuse me, in itch alone, but also approximately 2x as well in itch and hives as well, which is the UAS7 score. This data is incredibly impressive for biologic naive. Now we said we wanna be the leader in Type 2 inflammatory diseases, and you're not gonna be the leader in Type 2 inflammatory diseases unless you're bold. We also boldly went into the most recalcitrant patient population, which are those non-responders, right, to not only antihistamines, but omalizumab. As you speak to physicians, many of these patients have been on steroids before in the past as well. These are very difficult to treat patients. While we saw numerical trends, it didn't reach the interim analysis bar that we had set. While that may be what it is, we've learned a lot from that, and I think we're extremely positive about this indication and committed across the alliance to bringing Dupixent, the first new mechanism of action, to these desperate patients as a first-line therapy for those bio-naive patients. Stay tuned for our next steps, actually, in CSU. Now I'll move on to respiratory. Actually, this is respiratory. This is leadership in respiratory as well. You know, again, another commercial priority for us was in AD. We were building a marketplace. In respiratory, we entered as the fifth biologic, but with still a huge amount of potential for that marketplace to grow. The biologic penetration rate, as you'll see, is still only 19% in the U.S. If you go ex-US, it goes down into the 11%-12%, and even high single digits in many marketplaces. Much potential there for us to still continue to grow this marketplace. I wanna highlight what we've not only done over the last few years is achieve leadership, but we've accelerated our leadership position versus very reputable organizations and very reputable brands, I might say. What you've seen here is how was that done, actually. First and foremost, it was with our asthma indication. We went into this asthma patient population, again, very competitive space. Over a short period of time, we've continued to build data around our product and show, and I'll talk to you about that in a minute, how our profile is continuing to get stronger in asthma as we even go younger now into the six- to 11-year-olds. We've actually now achieved that leadership in NBRx position in the U.S. and a few other markets, which I'll share with you here in a moment. Again, that is something that has to be done due to the execution out in the marketplace. We're very pleased with the performance that we're seeing as well in the asthma indication. We've also achieved this leadership position not only in Germany, but also in Japan. In Japan, we've even achieved it now in total prescriptions. Again, very proud of the team's efforts around the world to go into this extremely competitive space and also have success. Beyond that, as I said, we're continuing to strengthen our profile as we go younger into the six years of age, six to 12 years of age, but also highlighting as well the other respiratory condition, if you will, or the one airway condition in chronic rhinosinusitis with nasal polyps. We've been extremely pleased with our progress there, bringing the first biologic to market. I think as you've seen from some of the recent data that's come out, still the best-in-class profile for chronic rhinosinusitis with nasal polyps. It wouldn't be a Dupixent presentation if I didn't also have more data to share. I'll share with you a little bit more data about our asthma profile and again, why we believe we have potentially the best-in-class for Type 2 asthma profile. I wanna highlight two key data points here. First and foremost, on the left-hand side, you'll see exacerbation rate reduction. This is in our greater than 18 years of age over a three-year period. You know, exacerbations are those things that send you into the hospital typically and adds cost to the healthcare systems, but it's what patients likely most fear, right? Is that exacerbation around the corner. What you see here is about 60% of the patients experience zero exacerbations over a three-year period. Now we're starting to get to the point where maybe patients with effective therapies can start to worry less about that exacerbation. I'd be remiss if I didn't also highlight lung function on the right-hand side, because lung function, and this is in our six-11-year-olds, you know, when you talk to patients and physicians, you talk to patients about this, it's the lung function that really can determine how bad is your day gonna be. If your lung function impairment is bad, you're likely gonna have a bad day, a very inactive day, might I add. Especially for these six-11-year-olds, I've got a couple of these, they like to be active, and we want them to be active. What you see here is that we had a very rapid improvement in lung function and sustained over a year. One of the points that a pulmonologist friend of mine mentioned to me that was so important was, with these patients, you want them to have this so that they can go be active, because if not, it leads to other issues. Actually even patients this young could lead to other types of respiratory conditions, more serious ones, by losing, continuing to lose lung function over your life. This is a very important data point that we'd be remiss if we didn't highlight, and we believe we have the best profile here, especially as it pertains to lung function. Last data point, I promise, as it relates to EoE, we're extremely excited about the opportunity that we now have potentially with our recent filing or recent submission of Eosinophilic Esophagitis. Again, I'll remind you this had breakthrough designation and orphan status as well. It was really founded off of this incredible data now that we have. Again, I think it really reconfirms the breakthrough designation for us. What you see is on the left-hand side, this is the proportion of patients achieving peak esophageal eosinophil count of less than or equal to 6 eos. Look at how statistically significant that is versus placebo. This is in part A, and then you see it in part B as well. This is in our QD dosing. Then if you look at the right-hand side, absolute change from baseline in DSQ, and this is a patient-reported outcome. Again, very impressive improvement both on part A and on part B versus placebo. Again, what this does for us is, of course, this allows us to meet these patients' needs, hopefully, again, assuming a potential approval, but it takes us as well into the GI space in a desperately underserved patient population who has had no advanced therapies to date. We're extremely excited about the potential to move into Eosinophilic Esophagitis and our first indication into the GI space. Last couple of slides here before I wrap up and hand over to Naimish is I wanted to make sure that I zoomed in on China. As you see from the title, we of course are all in on China for a blockbuster plus. In China, we're extremely excited about the achievement that the teams has have made in really a short period of time. I'll tell you, we're just at the beginning of the journey in China for sure as well. In less than two years, we've not only gained regulatory approval for AD across three age groups, but also achieved public reimbursement in record time, in five months. Normally, again, when you look at an NRDL, it's typically around an average of two years. Extremely pleased with what the teams have done there. Our launch execution is also, and again, it's standing on the shoulders of the long and well-established relationships and reputation that Sanofi has in China, nearly 40 years now, I believe it is. If you look at our coverage, we have over 3,000 hospitals now, over 15,000 HCPs with access, and 1,000 hospitals listed. We have opened up one-third of that accessible opportunity already. You can see this has allowed us to achieve over just over 30,000 patients by the end of 2021. Again, we're just getting started in China. We have other indications that we're very excited about bringing Dupixent to hopefully, not only in the AD infant population, but asthma as well as COPD. My final slide I'll wrap up with is it says it in the title, of course, we're just at the beginning of the journey. While we're proud of the progress that we've made by already being approved in these first six indications, there's a lot of opportunity ahead. I'd be remiss if I didn't highlight that in the indications that we're in today as well, these first six that were already approved, as we've mentioned, there's significant growth potential there, first and foremost. Then beyond that, if approved in these additional indications, either the two that we've already filed or submitted or are under review, or the others that are investigational, that could unlock, if approved, an additional 1.5 million patients as potential. Again, as we said, proud of what we've achieved, humbled by what we've achieved, but also inspired about the potential ahead of us. Speaking about the potential ahead of us, I'll actually. It's my great pleasure to pass it over to Naimish Patel. Thanks, Brian. Good morning, good afternoon, good evening, everyone. Really a pleasure to be able to do this face-to-face after doing it over Zoom for a couple of years. To pick up on Paul's point earlier, I'd like to start sort of updating you from what we promised the year before. Last year, we went fairly deeply into the Type 2 science, the science we've discovered with the development of Dupixent and where Dupixent sits in the Type 2 pathways. We used that as a framework to overlay the new pipeline molecules we have and where we think they fit in this Type 2 puzzle, really leading to a place where we want in the leadership in the dermatology and respiratory space. We talked a lot on the early pipeline about an IRAK4 degrader that had not yet come into phase I in our collaboration with Kymera. We also talked about a nanobody platform and a number of nanobody molecules looking to hit two targets to provide breakthrough in two validated targets in various indications to provide breakthrough efficacy. Those programs have all come into phase I this year as an achievement since last year. In total, seven phase I studies were started this past year. In the phase II realm, we talked about rilzabrutinib, our excitement about this oral BTKi inhibitor and the potential for this also in the Type 2 space. We talked about how we were gonna start studies in Atopic Dermatitis, CSU, and asthma. All three of these programs have started dose range finding studies this past year to enable phase III programs upon readout. Last year, we had announced the looming acquisition of Kymab and our incorporation of amlitelimab into our portfolio, but we didn't get into much detail on it, and I will spend some time this year talking about that. Excuse me. In the phase III realm, we talked about our excitement around itepekimab, the anti-IL-33 targeting former smokers, and the really exciting phase II data that we had around this in COPD, and we're really excited to announce that we've started both phase III trials this past year. As Brian has gone into a lot of detail, we've started three new Phase III studies for a total of four Phase III with Dupixent for a total of four this year in terms of Phase III programs. We had four pivotal positive readouts across four indications. We had five regulatory submissions and three approvals for Dupixent. Most notably, I also wanna announce that just this past February, we completed the enrollment of the first COPD study for Dupixent BOREAS, and so we should expect a readout for that in the first half of next year. Really excited that COPD now is really coming to a forefront and is inching very close. Bill talked a bit about our ambition and really to establish and spread our leadership in both atopic dermatitis and asthma. As a core part of this is to develop MOAs, different medicines across the spectrum of severity for atopic dermatitis. Starting with a topical BTKi that we're very excited about, this offers a potentially very safe topical alternative to topical corticosteroids in patients with mild disease. Even more importantly, in patients with moderate to severe disease, it provides a topical therapy for breakthrough disease, so keeping patients persistent on their systemic medicine by adding a topical. We're really excited about the potential for that program. That's scheduled for a Phase II readout in 2023. In the area of safe oral, we know there are a lot of patients with moderate to severe atopic dermatitis that are a little bit hesitant to start injectables as their first systemic therapy, but they do have uncontrolled disease. This is one of the areas that's probably the most difficult puzzle to solve for us, a safe oral. Unlike antibodies that can be engineered very specifically to just hit the target and nothing else, it's much harder to do that with a oral small molecule. Invariably, whatever you're targeting with the small molecule will have potential effects on other molecules, and you get these off-target safety issues as we've seen with other orals in this space. We are really hoping to thread that needle and produce some safe orals. For this, to do this effectively, we need more than one program to really get there. We have two very exciting programs with rilzabrutinib, the oral BTKi, as well as the IRAK4 degrader program with Kymera that Frank will detail in his section. In the injectable area, we recognize that atopic dermatitis is still a huge too, estimated 2 million patients in the U.S. eligible for biologic. It is a much more heterogeneous disease, and we recognize the need to offer patients with different choices. Dupixent, of course, is still our mainstay for atopic dermatitis, the most potent anti-Type 2 mechanism that we know of, but we understand that there's heterogeneity in the biology of atopic dermatitis. Some patients have a mixture of type 2 and Non-Type 2 disease, and this is where amlitelimab, which I'll get into more detail, really offers promise both in addressing a different patient population to Dupixent, also offering different choices like infrequent needle burden, and I'll get to that. Of course, the ultimate objective as we expand our leadership in dermatology and atopic dermatitis is to raise the bar on the efficacy ceiling. Find the next generation of molecules that's even better than what we have on market today. We think the nanobody platform hitting two validated targets offers the promise to really raise that efficacy ceiling, and Frank will talk about that in his section. Asthma is a similarly large indication and underpenetrated despite biologics being there for almost 20 years now. In a very parallel way to atopic dermatitis, we think safe orals is also something that's very lacking in that market. There are many patients with poorly controlled asthma hesitant to come on to injectables and very ripe for a safe oral that's been very elusive. We think rilzabrutinib has the potential for the asthma market as well. For the injectables, amlitelimab has a potential to cover both that Type 2 and Non-Type 2 population, as well as the infrequent needle burden, offering a different choice to patients. Raising that efficacy ceiling as well with the nanobody program. A lot of parallels between asthma and AD, but we really have a comprehensive strategy to try to continue to win and expand our leadership in both these key areas for us. Diving a little bit into the pathogenesis of Atopic Dermatitis, I'd love to talk to you about the opportunity for both amlitelimab and rilzabrutinib in patients with mixed inflammatory response. As you can see, the Atopic Dermatitis is still largely driven by Type 2 disease. Almost every patient with AD has underlying Type 2 biology. For these patients, Dupixent, of course, is still our mainstay, the most potent molecule for Type 2 inflammation. We've seen repeatedly, if you target just one aspect of it, just an IL-13, just an IL-5, you're not gonna get the efficacy that's possible by targeting both IL-4 and 13 for the most potent anti-Type 2 biologic. This is apparent if you look across indications. There's only one biologic that gets Type 2 inflammatory disease across indications. Type 2 inflammatory disease at the end of the day is a systemic disease. It's not a disease just of the skin. It's not a disease just to the lungs. It's every patient has multiple Type 2 diseases, and Dupixent is the biologic for them. Beyond this, we recognize that there are patients in atopic dermatitis who have biology that's Type 2, but also features of non-Type2, Type 17, Type 22. That's where this pathway, the OX40 ligand, OX40 receptor interaction, is a key early step in the initiation of inflammation. Because it is an early step, it occurs at the point right before the expansion of T cells and really the amplification of inflammation and all those T cells in turn lead to the cytokine production that lead to disease in the tissues. By inhibiting this early step, by blocking OX40 ligand, we have evidence that we can block both the Type 2 pathways, but also these non-Type2 pathways. I'll show you some of that evidence in the next few slides. Rilsabrutinib similarly, as a BTKI, it hits very effectively both the innate and adaptive immune responses, hitting a lot of specific innate cells involved in atopic dermatitis, such as eosinophils, mast cells, basophils, but also getting the B cells that make IgE. Thus rilsabrutinib, both the topical oral BTKi as well as the topical, has the ability to span this sort of mixed inflammatory population as well. Why do we think targeting OX40 ligand in particular is the best strategy for hitting this very important pathway? Well, I remind you that the key aspect of developing a biologic or really any medicine for atopic dermatitis is both efficacy but also very pristine safety. This is what dermatologists demand, and we think targeting the ligand is the way to the best safety. The ligand, as I mentioned, is expressed on antigen-presenting cells at the sites of inflammation. If you block the ligand, it's very specific for sites of inflammation, but it limits effects on immune cells that are not involved in Atopic Dermatitis. On the flip side, if you develop a biologic that is a OX40 receptor blocker that actually depletes T cells, the risk is that you're depleting T cells not only involved in atopic dermatitis, but also bystander T cells that might be important for other immune functions such as immunity against infection. We believe that T cell depletion is a big risk in terms of the potential for immunosuppression, whereas hitting the ligand, as we do by blocking ligand, there's no evidence of cell depletion at all. Our antibody has been engineered like that to not deplete cells. It's the most effective strategy for preserving safety. The other interesting aspect is that OX40 ligand, by blocking it, you actually increase T regulatory cell activity. This is an important natural mechanism for putting the brakes on inflammation. In a sense, by blocking the ligand, you're actually bringing the immune system back to a more natural homeostatic state that might occur when you don't have atopic dermatitis. A more natural state, whereas on the other hand, if you're gonna deplete T cells, you're also gonna deplete T regulatory cells, and ultimately, this may limit long-term efficacy by inhibiting these key regulatory cells, and also may lead to other issues, because T regulatory cells are very important, for example, preventing autoimmunity. One good piece of evidence to differentiate these two strategies is looking at the clinical studies where we know that biologics that do deplete cells tend to cause fevers, chills, cytokine release 'cause there's an inflammatory reaction when you deplete cells. You'll notice that in our studies, there's no evidence of this when we gave the drug, no cytokine release fevers or chills. For a number of reasons, we think OX40 is the way to block this very critical pathway in the safest way. Here's some biomarker data from our phase II study that I'll go into with some more detail with amlitelimab. In patients with moderate to severe atopic dermatitis who are treated for, excuse me, 12 weeks of drug, at week 16, if you look at specific serum cytokines such as IL-13, a prototypical Type 2 cytokine, amlitelimab patients treated with amlitelimab have decreased blood levels of IL-13, also decreased levels of IL-22, which is a Type 22 cytokine, as well as IL-17, a Th17 cytokine. This provides some evidence to what I spoke about before about the ability to get Type 2 pathways, but also the Non-Type 2 pathways addressing a population that's different from Dupixent. If you look at the sum total, the results of our phase II study. This study was a relatively small phase II study with the goal of just providing proof of mechanism for patients with atopic dermatitis. Because of the efficacy we saw in this study, looking at probably the most difficult endpoint to achieve, the IGA 0/1, clear, almost clear skin at week 16, we were able to achieve this very difficult endpoint in this study, speaking to the level of treatment effect we're seeing. In patients treated with either dose of amlitelimab or low dose or high dose, we saw 44% and 37% of patients with clear or almost clear skin. This is a very competitive profile compared to anything we've seen in the market today for atopic dermatitis. The efficacy is clearly there. Interestingly, we also took patients who had clear, almost clear skin and followed them for additional 24 weeks off drug, and 70% of these patients had a sustained response, continued clear, almost clear skin 24 weeks after drug. This speaks to a potential to reach what we might term as disease modification. Great efficacy, but also persistence of efficacy and the potential for allowing patients to not have not only decreased disease burden, but also decreased treatment burden with very infrequent needle frequency. That goal of all treatment for, I think, chronic inflammatory disease is really disease modification. This is a potential first step to getting there. We're very excited about these results, and we believe it's a highly competitive profile 'cause we can get these results by but still preserving that safety aspect, as I mentioned already. We're very excited about this compound and this pathway, and we've decided to announce that we're accelerating development of amlitelimab. We are going to engage the health authorities to have the discussions needed to start phase III this year. Whether or not we can do that, of course, is dependent on these discussions, but our ambition is to start phase III, which is two years ahead of the planned schedule 'cause we feel that this is a compelling, important MOA that we need to bring to patients as soon as possible. We're very excited about initiating this. We will start our asthma program as well, phase IIb asthma program this year. We're well aligned to do that, and we are looking forward to exploring additional indications for this very interesting mechanism of action and looking to start those next year. We're committing amlitelimab as a priority corporate asset and putting the people and the resources behind it to really accelerate it and bring it to patients. Changing back on the other topic, briefly touching upon that earlier stage disease, we very strongly believe in our BTKi program, both the topical and the rilzabrutinib for the reasons I mentioned, able to cover both innate and adaptive immunity and different aspects of Type 2 inflammation as well as non-Type 2 inflammation. The topical BTKi program, SAR444727, we're looking forward to a phase II readout in the first half of 2023, as well as rilzabrutinib for our phase IIb in moderate to severe atopic dermatitis with a readout in 2023. If you look at the rilzabrutinib program in total, we have the AD asthma and CSU programs all going currently, all phase III-enabling studies and looking for readouts for all three of those programs in 2023, and another program in IgG4-related disease to read out in 2024. Lots of excitement with that oral program. Finally, the last topic I'll touch upon is COPD. As Bill mentioned in his section, COPD, huge health problem. Third really leading cause of death in the world. Lots of patients suffering in and out of the hospital, daily symptoms, huge impact on quality of life, and surprisingly, almost no innovation in this space for years and years. No new mechanism of action and no real hope in the future until recently. We're excited that we're bringing two biologics to this population. The second of which, itepekimab, a very potent IL-33 blocker. It very potently blocks IL-33, and IL-33 is a key mediator in airway inflammation, activating both non type two and type two pathways. This is very consistent with the results we saw in our phase II study that I'll get into detail in a second. But we have high belief that IL-33 and itepekimab in particular has the potential to be the best in class and first in class IL-33 blocker in COPD. We noted that our There are several competitors now that are coming in behind us in the COPD space because these are exciting results and the potential for this mechanism, but we're still out in the lead, and we plan to be first to market for this very important indication. This slide I have some new data for itepekimab and our own internal data generated looking at IL-33 expression in the lungs of patients with COPD, comparing former smokers to current smokers. You see in general higher IL-33 expression in the lungs, adding further rationale to the results we saw in our Phase II-a study. We've... This past year also published our Phase II-a study as one of our notable accomplishments of the year in The Lancet. Our 24-week study of patients with recurrent COPD exacerbations and treatment with itepekimab had a 42.5% reduction in exacerbations in these patients. That level of improvement in former smokers has not been seen really with any biologic in this space. It was a very exciting result. If you look at across, and this data was not in the paper, the subtypes of patients with non-Type 2 inflammation, low blood eosinophils versus greater than 250 eosinophils, high Type 2 inflammation, the treatment effect was relatively consistent across these different subgroups. Just seeing really robustness of the results. When you see the same result across different subgroups, it means the results that you have is robust, but also to us, it confirms that itepekimab has real potential in this patient population that's different than the type 2 Dupixent population, the non-Type 2 COPD population. If you're a patient, Bill referred to the GOLD D COPD patient. These are the sickest patients with COPD. Patients who've had long-standing COPD, multiple exacerbations for years, visiting their doctor frequently, in and out of the hospital, daily symptoms. Despite taking every standard of care therapy, adhering to it very well, there's still no hope for these patients today. Our ambition is in the future to have choices for these patients and direct them to the best therapy possible. One is if you're an active smoker with high blood eos, Dupixent would be the drug for you if you're in this COPD category. For former smokers and low blood eos, itepekimab is the drug for you. If you're a former smoker in high blood eos, you actually have a choice between Dupixent and itepekimab. I think this is very important for this patient population with such severe disease, having more choices because there will be patients that will probably preferably want one drug versus the other. We look forward to offering both of these for the COPD population. This is really greater than 80% of that GOLD population. Covering almost the most patients really and of any pharmaceutical company out there, we are probably in the lead in COPD. If you think about COPD, it's probably where atopic dermatitis was about six or seven years ago. A disease of incredibly high unmet need, no advanced therapies, not a lot of innovation that happened. We're really poised to bring two potentially transformative drugs to this population. This slide here lays out our plans and the timelines. As I mentioned, very exciting. The BOREAS study has just finished enrollment, and we look forward to the first readout of our COPD programs in the first half of next year. The NOTUS study should come after that. Then the both itepekimab studies which are actively enrolling already coming sometime after that. We're very lined up over the next couple of years to have a lot of key readouts across COPD and really lead in terms of defining subtypes of COPD, which I think is really the way to attack this very difficult to treat disease. Thank you very much for your time, and I will hand over to Frank Nestle. Very good. Last but not least, thank you very much, Naimish. We're coming to the research part. On a crisp Boston morning, you're here in the business building, but if you look next door is what we affectionately call the lab building. The lab building will house about 800 people of the whole R&D spectrum to chase the miracles of science to impact people's lives. If you haven't heard that sentence, this is what it's all about in my section and what you've heard before. How do we break into new immunology frontiers in immunology? We've assembled over the last few years at Sanofi an incredible disruptive technology toolbox driving first-in-best-in-class medicines. What this allows us to do to have really a proprietary, often proprietary approach to unlock novel biology. It also gives us a scalable opportunity to go into multiple disease indications in areas. For example, if you look at small molecules, we have our rilzabrutinib molecule, which benefits from a unique covalency, reversible covalency approach, and we have our TNF- alpha inhibitor and IL-17A blocker, which essentially interacts with cytokine ligand and receptor interaction and can block this very efficiently based on breakthrough chemistry. Now we also were pioneering, and we are pioneering with our partner, Kymera, the application of protein degraders. Nobody has moved an oral protein degrader into chronic inflammation. We are doing this via targeting IRAK4, and I'm going to go into more details about that. Now, if we move from small molecules to large molecules, we have established an incredible nanobody molecule platform which allows us to essentially combination therapy in a single molecule. We've also pushed the borders with our Synthorin platform to apply synthetic design principles to get to a non-beta IL-2, which drives selectively regulatory T-cells for patient impact. Now, last year, I discussed with you precision immunology. Precision immunology is about tailoring medicines to patients' needs using our toolbox. Today, I wanna go a little bit deeper and explain to you what's behind the curtain in terms of our AI research factory, which improves quality and productivity of our immunology research portfolio. AI, artificial intelligence, empowers everything we do, from target discovery to making molecules to clinical translation. For example, our target identification engine really goes through thousands of samples and applies AI scoring to come up with new first-in-best-in-class targets. OX40 ligand, for example, has been found via such an approach. We also apply single cell disease maps. We go into disease and apply our very own AI algorithm to identify immune cell subsets which are different between normal and diseased skin. We apply AI across the whole range of our molecular design principles, from design, to basically, collaborations, with Exscientia to really rub shoulders with the best in the industry. We are also applying digital pathology principles and extracting information to identify new patient subsets and new targets, and we do this, again, working with some of the best in the industry, such as Owkin. Finally, we're applying disease endotyping, really trying to find enriched patient population for the mechanisms we are targeting. This is a holy grail, and we're currently doing this in our systemic lupus erythematosus trial using our anti-CD40 ligand monoclonal antibody. All of this reduces timelines and increases probability of success in drug discovery, which again, is one of the key goals we are having. Now, I'm very proud that our nanobody molecule platform has now really moved into the clinic, providing a strong early clinical pipeline delivering transformative medicines. Just to remind you, nanobodies are about one-tenth of the size of a monoclonal antibody. They're very effective binders, and you can align them like beads on a string to combine target one, target two. You can even dial in half-life extension. What we can do with such a platform is you can think about multi-targeting, for example, to break efficacy ceilings. But these molecules also have other properties. They have convenience of dosing. It's very important in clinical reality that you can, for example, dose once a month. We can do this with our half-life extension property. It's important that we have convenience of administration. Think about the properties of these molecules. We can concentrate them to a degree that we can put them into an auto-injector. Think about this once monthly or every other month dosing with an auto-injector. That's the future of biologics enabled via this nanobody platform. We can simplify our development approach, and what's also quite important is we have favorable economics and cost of goods with our revolutionary Pichia expression system. Now you can then move these multi-targeting nanobodies in a range of chronic inflammatory diseases with unmet need. You can think about aspirational treatment profiles we were not able to tackle before. Breaking efficacy ceilings, broadening patient populations, durable disease remission, addressing non-response. These are all important areas where we want to move in the future with this platform. Now one example here is our anti-IL-13 OX40 ligand bispecific nanobody with the potential to break efficacy ceilings in Type 2 inflammation. As you know, IL-13 is a very important Type 2 cytokine, and OX40 ligand is a very important costimulatory molecule in a Type 2 inflammatory cascade. As Naimish told you, OX40 ligand blocks upstream and has a footprint not only in Ty pe 2 immunity, but also in Type 17 and type 22 immunity. By adding in an anti-IL-13 blocker, we can also go for other cells which might not be responsive to OX40 ligand blockade, such as innate cells, mast cells. Now in the middle panel, you see an experiment we've been doing, essentially looking at a house dust mite-induced atopic inflammation model. We're looking at gene expression. On the left in green, you see homeostasis. This is normal skin. Everything is green, everything is quiet. If we induce inflammation, you see the red part, when we apply the allergen, and this is when all these pro-inflammatory genes are activated. Now, if you go further into the panel, you see that only our SAR443726 molecule is very effective, this is the bispecific, to returning the red inflammatory signal into green homeostasis. That's the future where we wanna go in treatment of atopic dermatitis. Now, another molecule in our large molecule toolbox is SAR444336 or THOR-809. This really takes advantage of our Synthorin platform to precisely engineer non-beta IL-2. This allows us to selectively target regulatory T-cells to restore immune homeostasis. If you target alpha, the alpha chain of the IL-2 receptor, you drive regulatory T-cells. If you target the beta chain of the IL-2 receptor, you drive effector T-cells. With our precisely engineered molecule, we can specifically expand regulatory T-cells and leave activated T-cells intact. I discussed with you last year how effective this expansion of Tregs is in a preclinical model. You can see this here again. We are also very effective in blocking inflammation in a preclinical skin inflammation model. Today, I want to share with you that these Tregs also are functionally very active. It's very important to have functional Tregs circulating doing their job, and you can see this here in a human T-cell suppression assay, also looking at FoxP3 demethylation. This is looking at an epigenetic level to confirm that these Tregs are highly functional. Now finally, Naimish told you already about the preference for orals and how orals are important if you think about our future portfolio, both from a patient perspective, but also from a physician perspective, and how difficult it is. We have 300 chemists every day thinking about orals. I'm very proud to share with you here for the first time, our next generation oral pathway medicine portfolio. Essentially, if you think about these medicines, you can put them into two buckets. One is antibody-like efficacy with oral convenience. This has not been done before. We have a soluble TNF-alpha inhibitor, which I'm going to go more in detail with you in a minute, but we also have an oral IL-17A blocker. We also, in the other bucket, tackling nodal targets, for example, the RIPK1 inhibitor, which is essentially tackling inflammatory cell death, and then we already heard about rilzabrutinib, and I'm going to go into more detail about the IRAK4 degrader. Now, here I present to you for the very first time, our oral TNF-alpha inhibitor, tackling the largest therapeutic class in immunology. This inhibitor benefits from a unique molecular design. It binds to the TNF trimer and then selectively inhibits TNFR1 signaling, but not TNFR2 signaling. Why is this important? TNFR1 signaling is essentially pro-inflammatory, but TNFR2 signaling is essentially conferring tissue repair and regulatory T-cell expansion. This is really playing out, you can see in a Listeria infection model. As you know, with anti-TNF biologic treatment, one of the side effects is opportunistic infections, such as Listeria infection. You can see here in blue that indeed, in this model, mice succumb from if you treat an anti-TNF monoclonal antibody. This is not the case if we apply our oral TNF inhibitor. This inhibitor, as you can also see, has antibody-like efficacy in an arthritis model. It is currently in phase I in healthy subjects and will have a proof-of-mechanism readout in psoriasis in early 2023. Now last but not least, a very exciting molecule, we are moving forward with our colleagues at Kymera. We have a very potent orally bioavailable IRAK4 degrader, which is actually a first-in-class molecule. Nobody has managed to make a protein degrader orally bioavailable. With IRAK4, we have a master regulator of inflammation, which is downstream of both TLR signaling, but also IL-1 family signaling. Our scientists also working with colleagues at Chimaera found that it's really important to address two aspects of IRAK4, both the scaffold function as well as the kinase function. Our protein degrader is currently in phase I. You can see here protein degradation data. We daily dose over 14 days, and you can see a very potent degradation of IRAK4 protein here in blood, but also in skin of healthy volunteers. Now finally, I don't have the time to discuss with you all our molecules in the pipeline, but here you can see essentially all the readouts we are expecting over the next few years, next two years. Six Phase I readouts. We have three Phase I-b readouts. These are small POM proof-of-mechanism studies. We have in 2022, our anti-IL-13 TSLP nanobody in asthma. In 2023, we have our TNF-alpha inhibitor in psoriasis. In 2024, we have the anti-IL-4/13 OX40 ligand nanobody tackling AD. We also have eight Phase II readouts. In 2022, the topical BTKi in AD. In 2023, multiple readouts across our RIPK1 inhibitor, our anti-CD40 ligand monoclonal antibody, and the rilzabrutinib molecule. In 2024, again, another readout for rilzabrutinib in IgG4 disease. I would like to close by showing you our roadmap for leadership in immunology research, breaking new frontiers in immunology by focusing on key nodal pathways. This is essentially a following the science approach. Think about Dupixent. It takes IL-4 and IL-13 to break into multiple indications related to Type 2 inflammation. We have many of those pathway medicines ready to go. We are also accelerating technology innovation by applying our technology toolbox, and do this in a proprietary manner to unlock novel biology and to drug the undruggable. We are finally in a patient-first approach, leveraging precision immunology. You saw all the data sets we are mining. We are applying single-cell disease maps. We are running AI algorithms to come up with first-in-best-in-class medicines. Finally, all of this leads to our key clinical ambition, which is breaking efficacy ceilings, achieving durable response, and expanding into new indications. Thank you very much for your attention. Handing over to Eva. Thank you. I may be old-fashioned, but since we're back in person, since we are at the end of our presentation section. Yeah. Thank you very much. Thank you to all the presenters, and I also personally want to thank everybody in Sanofi who has helped putting all of this together. Yeah, back to in-person means we're running a little late, but we will be fine. So we are now breaking for really like a five-seven minute break for you to grab another coffee. That's that direction. If you have to go to a bathroom, it's more that direction or just stretch your legs. If we could ask you by 9:25 that we have you back in, and then we're gonna start with the second part of our three-part event today, the expert encounter. Thank you. I have my notes. Okay. Welcome back. We would like to get started again. If I could ask you, ladies and gentlemen, to take your seats, please. Thank you. We're now going to move, as I said, into part two. It's split in what we call an expert encounter. We're going to do this in a sort of fireside chat, inspiration from a lot of the recent broker conferences that we had. We planned for this part around 40 minutes. We will split it into a part that's gonna be moderated by John, and then also we're going to open up for Q&A here from the audience. For that Q&A, we would like to ask you to focus your questions on clinical topics, clinical experience, products in development. It's immediately followed by 30 minutes of additional Q&A, where we have all our presenters present. The idea is to have that more dedicated and also to commercial topics. After that, we will close the webcast. We're gonna continue here in Boston and go to the breakout rooms. I'm gonna talk more about this, and we also have a light lunch planned in the end. I think there's certainly here lots more discussions to discuss the topics of today. For the session right now, we are very pleased to have with us two renowned experts in their respective fields. On the one hand, we have Dr. Bart Celli, who's a pulmonologist at the Brigham and Women's Hospital, and he's also a professor of medicine at Harvard Medical School. We have a dermatologist with us, Dr. Joseph Merola, also from Brigham and Women's Hospital and associate professor at Harvard Medical School. As said, it's going to be moderated by our own Dr. John Reed, Global Head of R&D. John, over to you. Thank you, Eva. Well, what a treat it is to be here in person and to have this opportunity to do a kind of a fireside chat with two esteemed physicians, a pulmonologist and a dermatologist. I'd like to start off with maybe asking Dr. Merola and Dr. Celli just to say a word or two about your areas of expertise. You've both been very involved in obviously the leading edge of defining what the best practice is for treating patients and in clinical research. So maybe just you know, a couple sentences about that. I'll start with you, Bart. Well, I'm the oldest guy here. I've been doing pulmonary diseases for 48 years. Within pulmonary, I've centered my research field and my clinical field in COPD and asthma because it is also an airways disease. I bring the expertise of somebody in the trenches who's done a bit of research, and I'm awed by all the molecules I was learning about today. Joe? Yeah, I think that we were talking yesterday. I think this might be intentional. They found two Italian-American physicians here from the Brigham, and anyway, we're bonding over that. Joe Merola. I'm a dermatologist. I'm also a rheumatologist, which may be relevant a little bit to some of the pipeline discussions later. I'm the Vice Chair for clinical trials and innovation in dermatology at the Brigham. Been there now for 15, almost 15 years, 12 years. You know, I actually a lot of my career is around psoriasis, psoriatic arthritis work. I do some connective tissue disease work, and it's interesting to have that perspective and now really be almost all of the trials that we do, we oversee, and a lot of the translational work has shifted over to atopic dermatitis because, as you can see, I mean, it's really the pipeline's exciting for us. The patient need is obviously there, and we're very excited to be part of that work, so. Yeah, I'm glad you mentioned some of these other areas of immunology, like, rheumatology, because we didn't really focus on that today. We focused on respiratory and dermatology because that's really where Dupixent has really shown impressive benefits for patients. But we are very active in those spaces as well. If you add that up, if you add those molecules to the ones you heard about today all together, Sanofi has 16 molecules in clinical development touching on various immunological targets. So let's spend a few minutes really talking about and educating our audience about the patient burden of diseases that we're focusing on today. I'll start with you, Joe, with Atopic Dermatitis. Maybe rather than asking specifically about a patient's journey here, let's talk about the parents of a child with severe AD, because these are diseases that typically strike very early in life, can be even within a few months after birth. Help our audiences understand a bit what that circumstance is like for families. Yeah. I'm happy to. I was trying to think, you know, honestly, on the drive over of a really good example of this in the pediatric space. You know, I have to fast-forward a little bit to someone that particularly stuck with me, who was a high school student. She came, I remember, a number of years ago now, came with her father to our clinic at the Brigham. What was really compelling was she had been through endless, like so many of our patients, topicals. You know, the parents were sort of talking about, her dad at the time was talking about the bleach baths that they had done repeatedly. Frustrated wasn't the word, I think, for both, you know, she and the parents and dad who was in the room. Endless topicals, you know, endless prednisone tapers, had eventually made her way to cyclosporine. They thought there was some hope in that she had done well for a little bit, and then ultimately was admitted with a Staph bacteremia to the hospital, and, you know, that was a major setback for them. The impact on both she and the family, I'll tell you, 'cause I think what stuck with me now as a parent, I think, was to hear, you know, how concerned he was. The thing he wanted to convey more than anything else, even beyond symptoms, was how withdrawn she was from school, from friends. She had been very athletic and really had no interest or desire to do any of the things she once was doing, which I know for any, you know, parents, certainly in the audience and myself as one, you know, can be quite heart-wrenching to hear and, you know, underscores impact. Also things we don't always get to hear about. They had a little bit. It's not funny, but they had gotten rid of their Christmas tree because of potential mold allergies. They were convinced that there was. They had tried all these elimination diets, right, which upended the whole family, right? It was terrible. They had, you know, she always wanted a pet. They never got one because they were afraid of the allergic component. You just see all these. It sounds maybe like small things, but in aggregate, really it changed both her and, you know, the sort of family and her siblings' lives. You know, fast-forward, you know where the story's going. You know, I get to ride in as the hero, right? I, you know, she actually was one of our, you know, success stories, of course, with Dupixent. It was tremendous. It was tremendous to see. You know, the nice thing about it is, it's probably how many years of research and how many thousands of people it takes to develop something like that. You know who takes full credit for clearing her? Me, right? I get the full credit and thanks of her and her family. I wanted to share that because her story has always stuck with me. Of course, she's now off in college. You know, we actually do virtual visits because she's so well controlled, and we really don't have a lot to do. We do virtual visits with her at this point, and she's happy, and we just sort of go about, you know. I think that example of an adolescent with severe atopic dermatitis I think is especially poignant, you know, because this is a very delicate time in a young person's development, where they're developing their self-image, where, you know, the social interactions can be so important and often damaging if you have a disease that people can see manifesting your skin. I think that's why the FDA gave Dupixent breakthrough designation for the adolescent indication. We know that adolescents with AD have a much higher rate of suicide, for example. These are devastating diseases. Maybe switching then to you, Bart. You know, in asthma and COPD, our main endpoint is a thing called exacerbations. Maybe help our audience to really appreciate what is an exacerbation really like for a patient- Absolutely. The physicians taking care of them? Yeah. Well, look, it is a big problem. More people died of COPD last year than people died from COVID, in case you don't know. About 3.5 million people die yearly from COPD. Mainly it is the exacerbation. Exacerbation for COPDers is like angina or an MI for a patient with coronary artery disease. That's how bad it is. If you get admitted, you have a higher chance of dying from a COPD problem than if you get admitted with a heart attack today in any part in the world. Having said that, what I wanna do with you guys, just as I do with the students, I'm gonna stand up, and I'm gonna have you breathe and realize that you don't realize you're breathing. If you concentrate, you'll be able to do so. What I want you to do is to take a breath in. Another one. Another one. Another one. One more, and try to breathe. You see how hard it is? You now have COPD. Well, COPDers can't get rid of the air they inhale because of the breathing rate. They become trapped just as I am from here to the ceiling in a very low expiratory reserve. When you have an exacerbation, what actually happen is your head touches the ceiling, and you just can't breathe anymore. It's like having a superb exercise test without being able to get off the bike. It has tremendous consequences on the heart. 30-day MI after an exacerbation of COPD increases your risk of dying 10 x. These events are so bad and so recurrent that Medicare has decided not to pay for readmissions within 30 days for those events in an attempt to decrease the $32 billion a year medical spends in preventing those exacerbations. Anything we can do to break that will be like your patient. I'll take the credit if I could do it. You should. We don't have any. I wish it was just a niche, but it's really bad, and it's a problem that we have to try to control. Well, let's talk about ways to control. What are the treatment options? Maybe I'll you know, maybe start with you, Dr. Bart, in terms of the patients with asthma. You know, what are the treatment options? And also try to think about patients with different kinds of characteristics. I would you know, maybe ask you to first address, okay, you have a patient, severe asthma that's gotten to the point that they're on oral corticosteroids and dependent on those to try to maintain some level of control. What are the treatment options for a patient like that? The beauty of asthma is that having the same pathobiology as COPD in many ways, this air trapping problem and inability to get the air out, it is much more reversible. All the efforts that have been made are to address that reversibility. Indeed, bronchodilators are fairly effective in a big group of individuals. It's topical, but the more severe have been dependent on corticosteroids. Because they're younger, and you give them for longer times, you end up with the problems of corticosteroids, which I'm sure you know as well as I do, osteoporosis, muscle, getting fat, high blood pressure. The advent of medications that could break that cycle has been a tremendous advance. There are now molecules that, given, will break the asthma attacks to a degree that they very seldom need to be admitted. With pride, I will say if you get 140,000 deaths from COPD in the U.S. a year, you have about 3,000 deaths from asthma a year. That's because I think we've been able to control it much better. Here, the story that you heard from Dupixent in atopic dermatitis is the same repeated in asthma. We now have medications that are fairly effective, and I think you showed that Dupixent is right up there in terms of being able to control the Type 2 asthmatics. I'd like to add that some asthmatics are a problem because they may not just respond to Type 2 control. Then the type 1, the ability to tackle Type 1 inflammatory cascades, to us, is very appealing. That may link back to COPD, which is a cousin, a much more severe cousin. Well, you saw our pipeline is replete with a number of molecules that might start to address that. You know, I cited that patient who's dependent on the oral corticosteroids because so far, the only medicine that has been approved for that population is Dupixent. Others have failed to make a dent there. Joe, maybe turning to you to, you know, that young AD patient. You know, with young people, we're particularly mindful of safety. You know, what are the treatment options for these patients with severe AD? I mean, I hate to sound so focused on the reason we're all here. You know, historically, we actually had a paper about this recently 'cause I think the point really comes back to one of safety. You know, we've historically cycled through, and for the dermatologist, it's endless topical steroids, steroid tapers. In some centers or in practices it's use of narrowband UVB and UV treatments for these patients, which, you know, for many patients works, you know, can control disease. It takes a while for it to work, and it's a pretty significant burden. You can imagine having to go to the office two, three times a week, you know, for many months. Risk of burn and other things that would come up. You know, for some patients, again, reasonable options. Then we would get into systemic options, which I would say in this arena certainly left something to be desired, partly because a lot of them are fairly immunosuppressive, have, you know, monitoring requirements, and, you know, infection risk, methotrexate, mycophenolate, cyclosporine, azathioprine, variably used. You know, U.S. has their own trends versus Europe and other places in how they use these things. Those were the tools. I mean, those have been the tools. I was coming back to the point that we've looked at, for example, comparative safety, you know, around many of those agents. You know, it's a very significant challenge there in terms of infection risk, in terms of a lot of the other things that you know, we would see historically before we had the targeted therapy to you know, to really help these patients. Probably not answering your question, but I think you know, in the current era, we are incredibly excited to be able to reach for targeted therapy. Of course, you know, you all, this is really the only targeted therapy that we have presently. We're very excited to reach for this as early as possible. I mean, truly as early as possible, right? We are at the stage where we're having conversations about this at the first visit with the topical prescription, right? for our, you know, particularly our more moderate severe spectrum patients. Well, I thought it was interesting when you told that anecdote about a patient. You mentioned you're now going to virtual follow-up visits, and I assume that's because you can trust the safety of Dupixent in that context. Could you do that with a JAK inhibitor, you think? You know the answer to that. I mean, no, but obviously I wouldn't feel nearly as comfortable. I wouldn't have done it with many of our historic agents, never mind JAK. You know, we don't let patients on methotrexate go that far from the office, right? We wanna see them, we want labs every three to six months, you know, even if they're doing fairly well. Almost all of our oral traditional agents, that was the case. It's pretty remarkable that you can feel that comfortable, that you can. You know, look, we've learned this as well in our psoriasis, where there are a lot of parallels here in, you know, with those of you who follow the psoriasis world with our IL-23 inhibitors, where in many respects, it's also been sort of a set it and forget it mindset, where you can very comfortably start patients on these therapies. You know, we used to have people back multiple times a year, and at this point, it's sort of like, well, it almost, it feels uncomfortable and wrong still, I really mean that, to say, "See you in a year." You kinda get this wince like, "Is that okay?" You think, "I think it is." You know, you sort of talk yourself down in the room, and it's like, "See you in a year. You look great, and just keep on keeping on. It’s pretty remarkable. Yeah. Well, we focused on atopic dermatitis because that's where Dupixent got its start five years ago. We're just on the heels of the AAD meeting here in Boston, and we saw some data on other dermatological conditions with Dupixent in prurigo nodularis, as well as CSU. I just wonder if maybe you could comment a little bit about what your impressions were of those data in the aftermath of that congress. Yeah. I'll get on the soapbox for a moment. I'll start with the CSU bit, if I may, because you can hear I'm losing my voice. This is directly related to the AAD. It was a truly exhausting event. Anyway, here we are. I hope it's not COVID. No, no, not at all. I promise. I'll move a few feet over, but. But so the soapbox moment I was gonna say, CSU is fascinating to me because I, you know, where I trained, CSU and, you know, urticaria was squarely a dermatologic disease the way we thought about it. You know, it is, in my mind, it is a dermatologic disease, period. I don't know if there's any allergists, you know, listening in here, but, what's fascinating to me is that, you know, at least I've come to understand that my colleagues don't all agree with that, or at least don't all own it in the same way that we, I think, as dermatologists need to, should, et cetera. It's been interesting because we, at least at the Brigham, many of my colleagues feel comfortable writing for Xolair, have used Xolair for a number of years now for, you know, more severe, you know, sort of antihistamine failure or other failure type CSU. You know, I'm increasingly told that this is, you know, really the realm of the allergists and, you know, because of the side effect profile, a lot of dermatologists. One of the themes, if anyone has followed the AAD for years, dermatologists are incredibly squeamish. They don't like a lot of monitoring. They don't like to have to deal with side effects. They don't really. Things have to have an incredibly clean profile in order for dermatologists to really adopt them, and some of the JAK discussions that we may or may not get to. Xolair is a substantial issue there. You know, one of the opportunities that I was seeing in the AAD, sort of talking about this with colleagues and hearing some of the data, and I feel like for a drug like Dupixent, where we all have very much adopted this as a dermatology drug. I mean, this, you know, we're comfortable with it. This is something we use. It's very much squarely in our arena. We feel very comfortable with its safety, et cetera. To have something like that facing CSU, where we're comfortable with it, I hope that is a gateway for the dermatologists to re-embrace CSU as a proper dermatology disease, which it is. You know, take that allergists, right? I mean, but it really is. I mean, this is. You know, someone shows up with hives, which is a skin rash, they should be thinking about the dermatologist. I think that's a very logical, you know, connection there. I'm excited about having opportunities to treat CSU comfortably in the dermatology space. You mentioned prurigo as well. Yeah. I'll just say a brief word on that. You can tell I can't be brief. Prurigo is interesting because, you know, I've seen many patients with Prurigo Nodularis. I used to think of it much more as a neuropsychiatric disease than I did as much a neurodermatitis or an inflammatory disorder. I think having seen some of the data over the last few years, it's really changed my thinking about that. I think it's really helped me understand that there is a targetable pathogenesis there that was very different than what my clinical impression has been for a long time about it. Seeing the data and the improvement also has, I think, reinforced this idea that I think we do have, you know, an opportunity to help patients with prurigo. I will tell you, just to color it a little, you know, historically, seeing, you know, the chief complaint of a patient coming in, or past notes from someone else that a patient had prurigo was not exactly, you know, a turn-on. Having now opportunities to, you know, improve that and impact that will very much change the disease state, I think, in the mind of many of us as dermatologists. It's exciting. Yeah. I think it's kind of interesting how connected all the biology is. We have these different disorders that manifest with, you know, different types of skin lesions and, clinical courses, but somehow, you know, they have this common connection that Dupixent is able to address. Let's, Bart, ask you a bit to you know, looking, having come out of a medical conference for dermatology, you know, of course, you attend all the pulmonary ones as well, and you get to see sort of what the next exciting therapeutics and the promising targets are. Just kind of wondering how you're looking at the asthma and COPD space today. What do you see as promising next frontiers? And in particular, if you could also answer that in the context of how you might see patients getting segmented in the future in these disorders. Well, very good. I do believe the picture in asthma is pretty much like what's been seen in dermatology. We have molecules that are effective, and I think we can control most patients with what we have today. So that's very, in my opinion, optimistic for our youngsters, who are the ones who suffer from it. I think the biggest problem is the COPD population. We've thought of it of being a disease of the elderly, being caused by smoking and therefore their own sin, and not really seen as other diseases that may also have an environmental agent causing them, such as atherosclerosis from eating too much and high cholesterol or even lung cancer. Therefore there's been a delay. The second fact that I think is important to understand is that we catch them very late when there is little plasticity for therapy to be effective. I truly believe that hopefully reading out, you know, interventions that may be positive for certain segments, for example, the former smokers, as Naimish showed, I think will allow us to select individuals who may be more responsive than others. I think that needs to come into our field. If those were positive, I think the next window is to go upstream. I cannot believe that the Lord up there said the only disease that has to be treated late is COPD. Every other disease in the world catch it early. Cancer, you know, dermatitis. COPD, no, wait till they're elderly and fragile, then you treat them. I believe that if we prove that some of those agents are effective, moving them upstream will be the next thing. 'Cause I think we could then modify the progression, so we avoid ending up with all these individuals who require multiple admissions. Some of them, I don't know how many of you know that emphysema is still the leading cause of lung transplant in the U.S. You know, IPF is coming up there, but emphysema still remains a humongous problem of which we know little. I'm very hopeful that we can modify disease by just moving upstream. Yeah, I think that because it is, COPD is a progressive disease, but I think, you know, maybe same thinking around some of the other type two diseases which again strike early in life. Can we nip it in the bud? The dermatology space, for example, Joe, how do you think about that? Yeah, I was gonna say, am I allowed to comment on the comment? Absolutely. Well said. No, no. You're younger. You can comment on the early disease, huh? I'm just, you know, I'm actually 75. I'm just a really good dermatologist. You have plastic surgeons that help you. Retin-A every night. No, I was gonna comment on that, you know, this idea of moving earlier and earlier and earlier and the concept of disease modification and the concept of. I mean, that's where we are. I really did get. I truly am very excited to hear this pipeline, to hear the excitement and the opportunities here. Absolutely in the, you know, in the Type 2 atopic march, you know, there's, you know, very little question in my mind that intervening in these pathways earlier and earlier is, has to have impact, you know, over time. I know that sometimes the term is thrown around a little too loosely of disease modification, but very little question in my mind that this is gonna change the way we think about and how we think about early intervention, certainly in these Type 2 diseases. You know, we're having that conversation now how many years into our understanding of psoriatic disease, even, you know, this idea that if we start earlier, are we really changing the natural course of disease? Are we able to prevent? You know, we have ongoing, very exciting stuff, but we have ongoing trials now asking the question of can we prevent, for example, the onset of psoriatic arthritis in our psoriasis patients? That would have been unthinkable, right, a number of years ago. This idea of preventing other comorbidities, you know, by intervening early, I think it's a tremendous point. I even think that we may end up having specialties based on endotypes, on pathways, rather than a dermatologist and a pulmonologist. Yeah, I wouldn't have. Both of us treating asthma at the same time with urticaria. I wouldn't have to do three residencies and fellowships. Absolutely. One residency will do. Well, that's something when we chatted before this. We were talking about how, you know, a patient may present to you, Bart, with asthma, or may present to you, Joe, with AD, but then they also have- Yeah You know, the disorders of the other organ. I know that you see this quite a bit, and these are systemic diseases. They may manifest primarily in one organ than the other, but it is true. I see Eva is advancing towards the stage, probably meaning that we should- Yeah. We should end here and give the audience an opportunity to ask a question or two. I would just remind folks that for this Q&A session, please limit your questions to things that would be relevant to our physician guests. We'll have another Q&A session where you can ask, you know, Brian and Bill about, you know, the commercial expectations around Dupixent and other corporate questions. Let's really focus here on medical and patient issues here. Yeah. Also, if I could really ask you to one question, so we can give more people the opportunity to ask, because I see Elizabeth is ready. Hi. Yes. Elizabeth Walton at Credit Suisse. If I can ask a question to Dr. Merola, please. One of the key debates at the AAD meeting was around conjunctivitis. Given we've got some new molecules coming through, potentially with lower rates of conjunctivitis, with Dupixent, we saw lower rates in the clinical studies, and then with many years of experience, it looks like the actual incidence of that is a little bit higher. So perhaps you could talk about your experience with conjunctivitis with the patients you're treating with Dupixent. Yeah. How do you manage that? Do you think some of the new drugs that are coming that maybe have lower rates of conjunctivitis are more attractive for that reason? Thank you. Sure, sure. Happy to comment. Agree with what you said. I mean, certainly the rates that we saw in the clinical trials were lower, I think, than the true clinical experience. I think that's right. I think some of the real world data has echoed that as well. On the flip side, I would say that I think it's a rare patient that it is severe enough that it inhibits our ability to use it or to continue drug. You know, we are increasingly getting more comfortable with ways to control any symptoms around that. I think you've probably heard that from a lot of the speakers. It was a theme throughout, you know, many different talks. Everything from simple, you know, lubricating eye drops through wetting drops to flaxseed oil. A variety of things that we talk about. I'm still not convinced the mechanism of the side effect is thoroughly understood. You know, we've heard about impact on goblet cells and, you know, et cetera. That said, I, you know, I think there was an initial enthusiasm and excitement that some of our newer therapies, and in particular, some of our IL-13, which you're referring to, targeted therapies might circumvent that particular side effect. What's interesting, and unfortunately, I would say a little disappointing, is I don't believe that that's the case. There was some hand-waving early on that maybe the IL-4 inhibition was part of that story. We would be circumventing that. My interpretation, if I remember right from the lebrikizumab data that was sort of showing that the phase III was like a 7%-8% ish, if I'm remembering right. Don't wanna be misquoted on the stage. If I am, blame Brian Foard. Just joking. 7%-8%, you know, to me, that's going to be, it's going to be more in the real world. It's gonna be more in real practice. I don't see it as a differentiating factor for me. I would say if I have someone uncommonly who has a severe enough conjunctivitis, would I consider switching to one of those to see if it's slightly different? Sure. I'm not sure that will necessarily pan out. I don't think it's a major distinguishing feature at present for me. Thank you. We have the next question from Adam Mikkelson from Camber. If there was a mistake made many years ago when the TNFs were launched, people underestimated the amount of cycling, I guess, that occurred in that class, and that you would move from one to the next, to the next, to the next over the years, and that's why the class became so large. Now, as BIMI launches, people assume generic Humira makes cycling not occur again, and BIMI will never sell. I think that's kind of why there's a lot of concern around the Atopic Derm market that Dupixent's so good that there won't be eventual cycling to the newer agents that they've described today. Maybe kind of if you could draw any parallels from the TNF market to how you envision Atopic Derm evolving, 'cause I feel like there could be that, a similar type of cycling that we're maybe not understanding today. Yeah. It's a wonderful question, and I definitely don't have a crystal ball, but I can say, you know, a little bit of that was I could put my rheumatology hat on as well, a little bit around that. I think that there are two things that have happened. You know, do patients eventually, in the course of their disease, these are all chronic diseases, right? We're not talking about, necessarily even deep remission and cure off drug. Do patients eventually start to see, you know, waning efficacy over the course of many, many years? If psoriasis is a model, they do, right? It's true. It can be many, many years. I think a lot of our new molecules have come a long way in that. You know, we know there are much less anti-drug antibody impacts, and we certainly we're not in the infliximab days anymore of chimerics and other things that may have driven some of the failure of biologics historically. Some of it's maybe mechanism driven. I don't think we know yet how the long-term efficacy data will pan out. So far, and in our practice, and with the long-term efficacy data that we've seen from, you know, our hosts here with Dupixent, it's very reassuring that those who respond, you know, remain responders for quite a long time. How well that will pan out in 5 and 10 years, et cetera, I don't have an easy answer. The other reason that the market, though, I think, moved on from anti-TNFs was also just pushing the efficacy bar. It wasn't just about cycling out of, you know, full failures, but what became an incomplete response was also our ability. It was a little bit of us getting greedy. You know, people were getting PASI 75, then it was PASI 90, now it's PASI 100. It's not just failure of drug, but it's our desire to now push the envelope. We want patients now to have 5% BSA, now it's 3%, now it's 1%. Now they have to be clear. Our current standard is clear. You've heard that at AAD. It wasn't just TNF failure. It was this idea that now I can give you an IL-23 four times a year. You're completely clear. Great. Right? It's also efficacy bar moving. The efficacy bar may move here too. I mean, it should, right? I mean, if the commitment to patients and, you know. That's why I'm excited to hear the pipeline, 'cause I'm also hearing, not only are we saying it's good enough where we are today, but I hear what I'm hearing, I think, is, you know, now let's be creative. Let's think about how some of the nanobodies and other things will help move the bar forward, and they wanna be part of that, which I'm excited about as well. I think that's a very compelling, you know, sort of part of the story. I hope the field will move on 'cause as good as things are today and we're all, you know, excited about where we are in AD, I know the bar will move and I hope it will 'cause we're, you know, we're still talking about EASI 75s of 50-ish%. I hope we're up here in five or 10 years talking about EASI 100s of 90%, which is a little bit where the psoriasis field is now. Okay. If we have yes, Steve. Thank you. Steve Scala from Cowen and Company. A question for Dr. Celli. I'm curious if you think Dupixent will achieve both primary and secondary endpoints in the BOREAS trial. If it didn't hit the secondary endpoint, how would that influence prescribing in your COPD patients? Very good question. I wish I had the data to be able to respond to you with more concrete numbers. Our hope is that because there is a proportion of patients with COPD who manifest TH2, that it will be positive on the exacerbation side. I think what I find from asthma that is very encouraging for COPD is the drop in exacerbation rate, but also the improvement in lung function. If we see that, then you're seeing two outcomes which mirror each other, and I believe that will push it to be a very well-accepted drug for those individuals. I believe we also have a biomarker that is of easy use, which is the eosinophil count. The response to it according to the eosinophil count will allow us to select individuals who may be more appropriate for that medication. I'd like to extend the question to say, if we could go upstream for the other proportion with the anti-IL-33, especially if it happens to be very good for ex-smokers, I think it will have a double whammy in terms of outcome, which is to push people to stop smoking so they can get this medication that will make them feel better. My hope is that both will be positive, as we've seen for derm, and I think we now have a biomarker that is of use, which is the eosinophil that can be obtained in any clinic. Thank you. Pete, Peter. Hi. Peter Welford, Jefferies. Could I just ask, coming back to sort of very related to something you just said about psoriasis, but related to Dupixent dosing. I guess similar to the conjunctivitis question, how different or of benefit would every four-week dosing be in your practice versus every two weeks? I guess the question is every two weeks inconvenient for patients? And bringing into that, you know, is an oral actually preferable? Because you mentioned, you know, an injection every four weeks without twenty. Sorry, every four of the year, without twenty-threes. You sort of almost forget you have disease kind of thinking. Yeah. It's a great question. Let me answer the second part first. Patients do like and would and often prefer oral options. You know, I think once you've broken the barrier and patients are on a biologic and on an injectable, they're more than happy to stay on a biologic and an injectable. It's that first sort of post-topical moment where patients are a little hesitant about injectables. They often feel a bit more that they have a serious illness. It's more severe. They're a little squeamish about the injection, and so they would love oral options, you know, from that perspective. Anyway, oral options would be tremendous. I think we'd love more, you know, more oral options for our patients, no question. With regard to the dose frequency, you know, the difference between two and four to patients is not dramatic. I mean, of course, most people would like four, if they could, and they'd like, you know, Q12 or once a year if they could. I mean, no question about that. I don't think there's a major difference from a quality of life standpoint for our patients between Q2 and Q4-week dosing. You know, the ability to spread it out, I have to tell you, there's been a disconnect between what the data has shown us and what our clinical experience is. I think the data seems to repeatedly be telling us that even more frequent dosing does not seem to make a large impact. Whereas I think all of you have heard from us as clinicians repeatedly that we always have cases of patients where we'd love to give it to them more frequently. We truly feel that there's breakthrough or that they would benefit from more frequent dosing, in fact. Not sure if that answers your question, but I think that's, you know, that's where we're at. Bart, you wanted to Yeah. I wanted to add, in the asthma world, it's been a game changer. Not having to go to the emergency room for younger individuals is a major breakthrough. They take the parenteral dosing much better than repeated doses of oral steroids. It's only the odd patient who may reject that. We've seen that big difference. Yeah. Coming to an emergency room when you're 20 years old and you're working, and then spending 10 hours in there and seeing everybody very sick, doing this and preventing those has been, in my opinion, a tremendous advance for those patients. I hope we can achieve the same for COPD. Okay. Laura. Thanks. Laura Sutcliffe, UBS. Dermatology question, if I can. Just going back to something you alluded to earlier, which is the experience with the JAKs. Arguably, Dupixent had some room to grow given the way things were. With that in mind, what's your view of the potential future for a quote safe oral now that we're where we are? Yeah. I mean, maybe to unpack that a little. I guess one question is where we are with our current JAK maybe use and understanding, and then you wanna know also what might be in the future for an oral. I mean, I'm a little bummed about how the JAK story has turned out. I mean, if I'm honest, you know, it is. They are highly effective therapies, no question about that. They're particularly, I think, probably highly effective therapies from an itch standpoint, from a speed of onset standpoint. You know, where I think it may fall in my practice at this point, and I mentioned at the beginning also that derms are incredibly squeamish, and are not particularly apt to use drugs where there's a lot of monitoring, where there's gonna be safety concerns, et cetera. I unfortunately think that that's gonna heavily impact anyone's use at this point of some of the JAKs. Although I think it's a bit unfortunate because they will help many patients, right, honestly. Those in my practice will certainly fall, no question, post biologic. The question is it even now after one, two, or three different biologics or mechanisms. It may well be. It depends if it's a primary failure versus a secondary failure to, in my mind, of an IL-4 or IL-13, you know, IL-4 13 or 13 mechanism. Which opens up the opportunity for many other oral options in the future and other oral mechanisms that maybe have a slightly different safety tolerability profile. I mean, you're seeing a little bit of a parallel in that with the TYK2, which is still in the JAK family. You know, this early feeling from the AAD as well, that maybe we're differentiating a bit on mechanisms such that it will differentiate on safety tolerability monitoring, and therefore kind of stand apart in our comfort with a group of, again, squeamish prescribers, frankly. I think there's a lot of opportunity for oral agents as such, but. Okay, great. Thanks. The last question for the session is from Seamus. Thanks. Seamus Fernandez from Guggenheim Securities. Dr. Shelley, I was hoping you could just help us understand a little bit the upstream opportunities both in asthma for other potential competitive agents like the anti-TSLP and how you see utilizing that agent relative to Dupixent. And just as a follow-on to that, you mentioned going upstream with IL-33. What really do you see in the data that's unique with that mechanism? Thanks. Well, unfortunately with the IL-33 data, I don't see too much of anything right now except what's being published in one paper that you just saw the data from, that it was fairly effective in preventing exacerbations and at the same time in improving the FEV1. To me, that's very telling, even for individuals who have very obstructed disease. These are COPDers. The data is certainly much better for asthma. Unfortunately, regulators will tell you that you cannot give these medications unless a patient has been on steroids or has been admitted several times. In my opinion, changing that state of mind is our duty as physicians. Our organizations ought to state, just like the cardiologists have, we cannot wait for somebody to be admitted or to be very sick to be started on this. I think if we could prove that going upstream at a younger age and just when the individual has certain limitation, let us say, in exercise, like our brothers, the cardiologists, do, then we will have gained, in my opinion, disease progression. We will have modified the outcomes. Now, comparing one molecule to the other, I would say that the more specific you are, if you're effective, the better off you are. If you just go upstream, you may modulate more, let us say, pathways simultaneously, which is the case perhaps for COPD, but there is always the chance of a little more side effects, in my opinion. We will have to see who is the right patient that may get the right medication. This has been achieved, I think, in my opinion, in oncology fairly well. They're very good in determining specific, you know, types, endotypes that will receive specific medications. I don't see why it won't happen to us. I think learning from derm, I find the field of asthma very close to yours, and that perhaps we'll reach that stage, not wait till the disease is very severe before we start treating. These are decisions that will carry an economic input, a societal perception, and perhaps also the ability of physicians to digest that this is the new world. I mean, we've been used to certain specific little niches. You know, I'll send you my asthma patients so you can take care of the skin, and you send me your wheezy patients so I can take it. When they have similar diseases caused by similar pathways, I think those changes will happen, the more data we come up with. I hope that helps you. I'm very optimistic that those trials will be positive for certain phenotypes and that we'll be able to select them based on that. Good. We need to end there, I assume, Eva. Exactly. A round of applause for Doctors Celli and Merola. Thank you once again. We are going to move seamlessly into the next Q&A session. Yeah. Please take the stairs. No, no. Just don't. Don't take the direct way. Back to your. Cheers. If I could ask Brian, Frank, and Naimish now up on stage. We obviously also have the presenters, Paul, and I think we still also have Bill on the line. We're gonna start again. Do you wanna be up here? No. As you wish. We're gonna start again here. I mean, it's really open for all questions. Obviously, we have also our scientists and development experts here. As we said, also, you know, if you wanna dive more into some of the commercial topics. Who wants to get us started with some more questions? If I start with Vimal, maybe? You didn't have a question yet, and then Pete. Wimal is just on the... Yeah. Oh, great. Thank you very much. Wimal Kapadia from Bernstein. It's not a commercial question, actually, but it's on IRAK4. Like, protein degradation is a, you know, really interesting approach. Just my question is on safety. You know, IRAK4 has quite a broad spectrum of activity. You know, immunosuppression of blocking IRAK4 it seems to cause an increased rate of infection. I'm just curious, you know, your thoughts here, because you're, you know, the way you're inhibiting IRAK4- You're really targeting the scaffold as well, so it's complete inhibition. How do you think about the risk of infection? Also, if you look at some of the literature, malignancies is also something that comes up. Just curious to hear your thoughts there. Thank you. Yeah. Frank? Maybe I can kick off and then Naimish can chip in. What's absolutely clear is with protein degradation, what we're doing, we are not creating a human knockout. There are human knockouts for IRAK4 who are actually there and who are very well managed. Even if you create a complete knockout of the protein, you can manage any infections. Now, we're not doing this. We're essentially creating a protein degrader. I think what we are seeing so far is that we can manage those side effects, if any, very well. We're early days, but we also know from, for example, IRAK4 catalytic inhibitors, which have been in much larger patient populations, that this can be managed very well. Yeah. Now, you referenced patients who have a sort of a genetic mutation of IRAK4 and deletion mutants and very little expression. In general, the adults with that phenotype are fairly benign. They're not getting recurrent infections. Remember, as Frank mentioned, we're fine-tuning where we're gonna be in terms of getting efficacy, but not necessarily requiring complete knockdown long term. It's reassuring that those patients are doing fairly well, but it's a little bit different than when you're drugging a target and you have the ability to sort of fine-tune where you are. Okay. Where do we have the next? We have Peter Verdult. Thank you. I'm Peter Verdult, Citi. Just two quick ones. On amlitelimab, the OX40, the accelerated development, if you execute according to your plans, Naimish, will you be within a year of your key competitor, or are you hoping to be nearer in terms of filing? Then secondly, just broader topic on topical BTKi. When you speak to docs, they always say that compliance on topicals is terrible, it's lousy. The payers will want you to cycle through two or three steroids. You're basically self-selecting for the worst patients, and most poorly compliant. So just how you're thinking about the commercial opportunity of the topical BTKi. Thank you. Maybe topical to you. Yeah. First to Naimish on amlitelimab launch dates. Yeah. I mean, we don't completely have the dates in front of my mind, but we're talking about a two-year acceleration. We're looking to match where they can. Like you said, within the year is maybe a good goalpost. Of course, this depends a bit on our conversations with regulators, and we'll determine that within the next year. That's our ambition, to launch roughly the same time. Right. As it relates to the topical, I mean, I think it goes back to, as we talked about being the leaders in immunology, talk about atopic dermatitis. You know, we need to be there for those patients across the whole spectrum. I think, Naimish, you nicely framed it in one of those slides, is the way that topicals work in dermatology, as you probably all well know, is that it goes from mild all the way through to severe. They're commonly used as monotherapy in the milder patients, but they're typically used as combination therapy. It's the reason why we did our CHRONOS study at the time with Dupixent, with topical corticosteroids. I think as these interesting mechanisms come to the marketplace from a topical standpoint, we, as the leader in this space, have to be looking at it and have to be trying to bring those things to market to complement the agents that we're gonna have. 'Cause I mean, again, dermatologists, and I think Joe is probably still here, he'd probably comment on this as well, is they tend to prescribe a lot of agents in combination. That's how we're kinda thinking about it from BTKi- Yeah. Maybe Topically. Maybe I can also- Oh, as a- As a previously practicing dermatologist, matter of fact, nobody leaves the dermatology office without a topical prescription. Nothing has really moved in the topical space for many years. Yeah. here's all of a sudden opportunity that we take the same exquisitely targeted therapies we are using systemically, put it into a topical. We are committed to the dermatology space, so there are huge potential synergies. Might not be the home run, you know, in some of the commercial expectations, but from a patient need, from a commitment where we are in dermatology and from the opportunity of a targeted therapeutic and really reinventing the topical space too, it's something where we are fully committed to. Okay, great. Next one, I think, Mark, and then we go back to Steve. Mark Purcell in the back. Yeah. Thank you. It's Mark Purcell from Morgan Stanley. A quick follow-up and then a different question. In terms of the OX40 ligand, what are the data requirements that are required for acceleration into phase III, if you could help us understand that? And then a sort of broader question. You've given us the coordinates of greater than EUR 13 billion for DP and greater than EUR 22 billion for immunology by 2030. Could you help us understand how diversified the latter number you hope to be, particularly in atopic dermatitis, just how diversified the franchise could be relative to the DP concentration today? Brian, you wanna start on this? Yeah, I can start with that first. I think as Paul mentioned, Dupixent is a waypoint. The number that we gave today too, which that's a big part of that, if you think about that from an immunology standpoint. That's an important foundational element of that 22, if you will, or so by 2030. As we think about it, what's in that number for us is these key agents that are closer to the marketplace. Agents like amlitelimab, rilzabrutinib, of course, and topical BTKi as well, as we know, and itepekimab, I should say. It's hard actually. There's so many. You know, it's easy to forget one of these, by the way. It's a good problem to have, but those are the ones that we've included in that for today. I imagine like the Dupixent number, we will be updating along the way. Paul, you want to add? Well, oh, can anybody hear me? Yeah, yeah. We can. Yeah. Only to add, Frank's spot on. Most of those mechanisms will be in the early stage of launch. Yeah. at that point. While the waypoint is 2022 in 2030, we'll be in full launch sequence, you know, maybe two, three, four years in for many of them. The potential straight after 2030 is really significant. The blend is depending on launch timing and profiles. But, you know, it was greater than four times, just to be clear. Okay. Steve? Thanks. Steve Scala from Cowen and Company. Two questions. First, I'd like to follow up on something Paul said at the beginning of the meeting, and that was that Dupixent would lead through the end of the decade and probably beyond. The question is about the probably beyond phrase. Is probably beyond due to the portfolio of molecules that we heard about today? Is it simply pediatric extension, or is it a patent extension strategy that you've yet to clarify, or is it something else? The second question is on Dupixent. Can you please just clarify what is the main flaw that Sanofi is attempting to address with the follow-on molecules? We heard in the last session the desire to achieve greater clearance. Is it disease modification? What is the key flaw that you're seeking to fulfill? Thank you. Okay. Maybe if we hand it first to Paul. Yeah, sure. The IP goes beyond, is the first thing. As you would imagine, we've been thinking about that from the beginning. You know, we have quite a skilled team that have worked on a major monoclonal antibody that had a long life. Second thing, you know, it was touched on actually about psoriasis and other things. For me, at least, the propensity to cycle is greater in psoriasis as is in AD, but the opportunity to improve efficacy will always be there. You know, there are a group of patients that will always be on Dupixent, and should be if they're well controlled. It'll be what comes next or what gets added on that I think is gonna be the most fascinating thing. You know, my take-home from AD was everybody just saying to me, "You're the backbone. That's how it's gonna be." We'll play around that with interval amlitelimab, for example. I'm not sure we've shared interval. Have we on amlitelimab? No. Intervals with amlitelimab and going for additional efficacy and what that could mean. They're really interesting. There will be some patients that cycle right. For sure. Just less. Dupixent is gonna be around. Yeah. I think it's hard to answer a question as a Dupixent person with flaw in it. Around Dupixent it's kind of hard to find one. I think it was nicely framed. You know, we're at the beginning of the journey in atopic dermatitis as well, and we know that this is gonna be a very big disease state. It's a very heterogeneous disease state as well. I think probably as Naimish and Frank alluded to as well, we're gonna learn a lot along the way. Mm-hmm. We're probably gonna identify these unique patient populations that a unique target may work a bit better on those patients that are maybe a little bit less type two, if you will. So I think that's first and foremost, and I think Joe actually nicely phrased it, is we're gonna be keep looking to try and raise that efficacy ceiling as we can, you know, for patients at the end of the day. Then I think there is a dosing or more of a disease modification ambition as well along the way is could you actually get to some form of disease modification? The final point I'll make, and I'll turn it back to Naimish, is, you know, we're in such a luxury position having Dupixent. We can really think about... You know, we don't need to just go, "Oh, we need this follow-on." We can really think about what's differentiated, not versus the flaws of Dupixent, but maybe what could be differentiated, you know, for this heterogeneous disease state. I don't know if Naimish wants to- I mean, Frank addressed it in his presentation. I mean, we're addressing it very scientifically. Yeah. Very medically. Do you just wanna? Exactly. Yeah. I just would like to also sing the praises of Dupixent for a moment because I think Dupixent has not yet seen where it could go. Yeah. What personally excites me is, you know, Type 2 inflammation is essentially underlying scientific cause that we get skin inflammation, we break out in asthma, that we have, you know, nasal polyps. Dupixent is addressing all of that. If you think holistically about a patient walking into your office, either, you know, in a pulmonary office or in a dermatology office, if you want to holistically address the disease, you go for Dupixent. Now, the other thing about Dupixent is that we're moving to where actually the causal nature of the disease is. It's actually in the early infant stage. It's in- Yeah. When you have children. We don't know what will happen if we treat at this moment in time. We could actually just abolish the whole trajectory, and we're talking about prevention in terms of as opposed to fixing what is broken. We go into totally different treatment territory with Dupixent. It's a one of a kind drug. But at the same time, we have about four-5 million atopic dermatitis patients who are addressable, and we know a lot about their mechanism. We are creating molecular disease maps. We're understanding patient subset, and we heard about endotypes, you know, that our physician experts were talking about that there might be another dermatology office or a respiratory office. There might be a Type 2 axis or, you know, a IRAK4 pathway axis. Mm-hmm. Somewhere near you. We are ready for that moment, and we're doing these types of trials, and we want to break efficacy ceilings. We want to have durable disease remission, which is where the sequencing comes in. Ultimately, we also want to go into new indication. This is where the science takes us. I think there's a lot for all of these molecules. I always say, give them all a fair chance, Naimish, in the development program. We will update you on what these fair chances will mean for those molecules. How can you pick among your children? Okay. We're gonna try Because I see a few raised hands on the webcast to probably squeeze in two or three from the webcast. If we have Graham Parry, and also if you unmute your line and ask your question. Great. Thanks very much for taking the questions, and apologies for not being there in person. On OX40 ligand, is the Phase III intended to be only subcut, or are you looking at subcut and IV? What's the basis of the regulatory discussion around starting Phase III? Is it to start with infusional study and run a later bridge to subcut once you've got the Phase II-b, or are you starting in the subcut but based on some interim data from phase IIb. Second question is on dose frequency. Are you looking at sub-six monthly subcut, or would that have to be IV to go that far out? Last question is on the bispecific and just adverse event risk. You know, these are quite immunosuppressive mechanisms that you're combining. Historically, FDA has been really quite keen to understand what the adverse event profile of the two different moieties would be or their contribution to adverse event profile. Can you just talk to how you've managed to tease that out and what you'll be presenting to regulators further down the line, if you get that far with them? Thanks. Okay, thanks, Graham. Three questions. If I give it to Naimish, the OX40 ligand, what can we say right now about our phase III trial design plan, specifically mode of administration? Also, what will be the dosing interval most likely looking? For Frank, some comments on nanobodies and adverse event profile. Sure. So we have already started the Phase II-b program for amlitelimab, and it's all subcutaneous dosing, so that's not an issue. I think the goal with our regulatory meetings is to agree that the designs that we're setting will meet the goals of the study. That's largely what the discussion will be. We'll see what they ask us. If they need more data, we'll provide it. I think we're pretty confident on the dosing schedule and these other things to allow us to go to Phase III. Yeah, on the bispecific, I mean, the good news is that we're venturing into very well-known territory. We have very well-established targets where we know the safety profile pretty well. If you look at the Mil-14 OX40 ligand nanobody I was discussing today, you know, individually, we see basically a very flat safety signal. So we've done obviously preclinical models, and we don't see any signals. We see signals of added efficacy, but we don't see signals of any- Mm-hmm. Added safety concerns. While this is something we keep in mind, we are very confident that we're venturing. This was actually by design. We wanted. You will see a new generation of nanobodies with much more sort of less explored and interesting first-in-class targets. The first building phase was taking very well-validated targets, combining them. What we're seeing is that they are very effective. From all we know from the clinic is that they, these individual targets don't have a safety element. The combination, we'll see where it goes, but I think we go into very well-charted territory here. If I could add one more piece to Frank's. Please. Absolutely. I completely agree with what we say, but I think the beauty and the data that the research group has come forth is that you don't need to fully suppress both targets to get the synergy and the effect. There's actually potential we could get better safety by dosing each moiety lower than you'd otherwise need. It's not, I would say, a given that this is gonna be less safe. It actually might be more safe than trying to just completely target one step in the pathway, as opposed to taking two that are synergistic but not requiring 100% suppression of both targets. That's a good point. Yeah. Naimish is making. For some of those targets, we're applying what we call quantitative systems pharmacology, and we can really very well predict where the dose level lies. What we're finding in some of those target combinations that dose levels are actually lying below what you currently do with individual treatments. So more on that in the future. All right. If we go to another question on the webcast, if we could have Richard Vosser. Richard, if you could limit it to one question or maybe two quick ones. Thanks, Eva. One question on CSU and Dupixent. Do you need to perform an additional trial to get to market? Any thoughts there? A sub part just on Xolair is going generic in CSU or going biosimilar. In naive patients, there's relatively limited extra benefit for Dupixent. Just your thoughts on actually commercially how you compete in CSU for Dupi. Thanks. We start with Naimish. I guess I would just remind you that the result we have in Study B, the Xolair for CSU process, is from an interim analysis. We need to get the final results and take the sum total of data, have the discussion with regulators, and see what's needed. Obviously, our ambition is that we don't need to do any more studies, and the package we have now will be good enough. It depends a bit on the data that we get and the final study results will be available this year. We'll try to get an answer this year about what more is needed. I think commercially from a CSU standpoint, I can't say it as good as Joe did actually earlier. He probably answered the question a lot better than I will. If you think about it today, is that because there really has been no advancement in CSU to speak of for, you know, more than a decade, the biologic penetration rate is still relatively low in CSU patients. I mean, we're talking 15% in this patient population, and the opportunity to grow, like you would see in an atopic dermatitis or more, I think, from a biologic penetration standpoint. If you think about it, what Joe said was so true. Because Xolair was the agent- Had a black box therapy needed to be administered in offices. The dermatology community didn't do this, so it was largely relegated to the allergist community in the U.S. I think as Joe said it very nicely, the dermatology community is excited about having possibly an option in the near future that they already know very well and is safe and it's effective, obviously for another dermatologic condition in AD, to utilize for CSU patients who are in their clinics, they just have not chosen to use Xolair. All right. Another one from the web, Simon Baker. Thank you for taking my question. Apologies I can't be there in person. It's two questions which are kind of connected on potential scope for products. For Dupixent, you published a year and a bit ago, 86 indications which were potentially receptive to Dupixent treatment in a patent application. I just wonder how much of that is realistically addressable and accessible, to give an idea of where. If there's any additional potential above and beyond what you've already outlined. Similarly with amlitelimab, OX40 ligand upregulation is a feature of a number of diseases like Sjögren's, RA, and Lupus. Again, if you could give us an idea on what's the broader potential of that product as well, that'd be really helpful. Thanks so much. Naimish, 86 potential future indications. Paul is back with the R&D budget. I think one of the key aspects of what's driven our indication expansion for Dupixent is we're fortunate enough that it's already been. Now, yesterday was our fifth anniversary for the launch of Dupixent in atopic dermatitis. As we talked about, Type 2 disease is a systemic inflammatory disease. These patients have the other diseases as we're treating their atopic dermatitis. That's really informed the real world evidence, understanding what's happening to these other diseases as we're treating the primary disease, really informed our indication expansion strategy. I think we're up to 11 new indications, six indications done, and we're. I don't think we're done. I think there are certainly more indications in the working that we're looking at. The We'll see what the final number turns out to be, but I think the real-world evidence is a great real source of information to inform what our next steps are. On the amlitelimab, I think we sort of highlighted that we are looking, but we didn't really go into it. Any more color that you can give today, what we're thinking about OX40 ligand? Or maybe also Frank. Yeah, Frank might want to add, but so we talked a little about it. It's fairly upstream, a really novel target in terms of now targeting costimulatory molecules. A step in the early initiation of inflammation. Maybe there's one other example in an RA drug, but really an unexplored area to try to get information at the early stages and hit multiple target areas, Type 2, Type 17, Type 22. I think there are potentials. I think the SLE was brought up. There are a number of other autoimmune disease potentials that we're looking at. I think, looking at a lot of the evidence that we're getting in terms of biomarkers from our AD study, and that will probably fuel what new indications we could learn. Looking at the transcriptomic profile of what we see in patients treated with amlitelimab and how does that match with other diseases, will probably inform our indication strategy. I think there are a lot of potential diseases. Yeah, I mean, as I said, we found OX40 ligand a few years back in our precision immunology studies. It's a very interesting target because essentially it's a costimulator. A costimulator is like the gas pedal and the brake of the immune system. It's one of those costimulatory molecules which is upregulated on antigen-presenting cells. We know from our disease maps that it plays a role in many possible diseases. Atopic dermatitis is just the first step. Asthma is obviously then on the map, and I think we've discussed that. Then, you know, we see signals in RA, we see signals in IBD, we see signals in SLE, and we have the disease models and the prioritization opportunities via our, you know, disease identification engines and target identification engines. There's more to come. This is a potential pathway drug. At the moment, I'm so excited about what I see in atopic dermatitis that I think that's plenty for us to chew on. This is a true pathway drug. I would like to close, as you've seen, we also put it already in our bispecifics. We're ahead of the curve. We're not just now thinking about it. We already have it there. We have a TNF, anti-TNF, OX40 ligand, a bispecific. We have an IL-13 OX40 ligand bispecific. This will be a key plank of our immune regulatory efforts in the future. Thank you, Frank. We have five minutes left. I just wanna check. I know there's more raised hands on the webcast, but are there any more questions here in the audience? I know Elizabeth had another one, and then Peter, but if we can have first Elizabeth. Thanks. Hi. Thank you. Possibly a question for Brian. I think one of the challenges we have as analysts is trying to understand how well Dupixent is penetrating outside of atopic dermatitis, where there are more competitors in the field. Perhaps you can help us understand the penetration rates, specifically for Dupixent in some of the indications outside of atopic dermatitis, and what your progress looks like both in the U.S. and outside of the U.S. as well to help us with our modeling. Thank you. Yeah. Yeah, absolutely. It's a very good question. Yeah, I think it's you know, in atopic dermatitis, it's, you know, we're really the only game in town, and now we're starting to see some competitors come into the space. The marketplace has developed. You know, as we said, it's more of a biologic penetration or advanced therapy penetration question right now because we're at a, you know- You know, nearly 100% share still in that space. Our share will go down over time, of course, as new entrants come into the marketplace, but we intend to maintain leadership share. As it relates to asthma, I think I want specifically to speak to that one because I highlighted it on one of the slides there. Again, make no mistake about it, we have a huge amount of respect for these other agents and companies that have been in the marketplace. To achieve leadership now in NBRXs in the U.S., where it's an extremely competitive marketplace, shows you. Again, if you do order of entry, that's not typically the case. You're typically around 13% or 14% by now, and you saw we're at 28% from an NBRX standpoint. Quite impressive, I think, from a performance. There is a lot of underestimation, I think, about our profile in asthma, and that's why I spent a bit more time highlighting that. I think we're gonna be, again, we are, as you can see, very competitive in that space in all of the major marketplaces around the world. You know, the U.S. dynamics are a little bit different because we do have the allergist and pulmonology community, so it does make it a little bit different what you see in the U.S. Where we've actually seen an acceleration more ex-US into that leadership position, it's gone a little quicker because it's more the pulmonologist community, so they're not splitting things up a little bit. Finally on nasal polyps or chronic rhinosinusitis with nasal polyps, we've seen competitors in that space now for about a year, a little more than a year, with Xolair coming first and then Nucala second. You guys have seen recently what Fasenra's data showed us about that particular target in this disease that, again, it's really not the most ideal, I think, target, the IL-5s, and certainly Xolair as well. We saw that wasn't a very good target either from a performance standpoint as far as efficacy goes. That's proven itself in the commercial landscape. We've actually had very good biopenetration into the patient population there, but the bigger thing too is actually we're holding. We've actually had single-digit share loss in the nasal polyps space in over a year. I mean, very proud, I think, of the performance of the teams, but it goes back to the profile. Okay. Thank you, Brian. We take the last question from Peter Welford. Hi. Thanks. Two very quick ones, I promise. Yeah. First, just on amlitelimab. I can't say that. OX40. Just trying to understand, how confident are you know, the right profile? I guess I'm just curious because there's been a lot of discussion about, you know, safety, the right dosing frequency. I guess, how confident are you know, at this stage the right profile to basically shortcut the phase IIb rather than taking your time, I guess. Mm-hmm. Given you only get one chance to launch a drug? Secondly, just quickly on Dupie in China, you said blockbuster plus. Now I think we're seeing more increasing now, particularly as you get new indications and you sort of roll to other populations, the Chinese have been pretty aggressive in renegotiating that NRDL price. I guess, what sort of pricing assumptions have you made when you make that blockbuster plus aim? Naimish, if you start, and then. Yeah, no, great question. I think if you look at the sum total of the evidence around this interaction, OX40 ligand, OX40 receptor, we have some key pieces of information. The efficacy is highly competitive. The interesting thing is, we did a 16-week study. It's not that the efficacy was plateauing at 16 weeks. I think the mechanism itself sort of, it's an upstream effector that sort of turns off the tap at a level high up. To get the full effects of it, I think it might take some time, and I don't think we've achieved the full efficacy that we might be able to achieve with longer dosing. That's one of the things we certainly wanna explore. We certainly have competitive efficacy. The safety profile looks really outstanding, and we have this sort of prolonged response off drug. I think those key elements are pretty good for us, giving us the confidence that we really have the right target and the right profile in atopic dermatitis. Obviously we have a number of phase III studies, and we'll look at different design elements to actually hone in on certain things, see spacing and dosing and other things to achieve a great profile. I think that the data we have today already gives us good confidence that we can achieve a really very differentiated profile with this drug. Yeah. Brian. Yeah, happy to speak on China. First I'll talk about the plus or greater than. I think Paul was telling us we're using as many of those signs as we possibly can. I think we said greater than, but then I said plus, so one or the other. Anyway, a blockbuster plus or greater than we are committed to in China. I think it goes back to we don't really comment on price per se, but I think the assumption that we've made is that the local authorities will see the value, right? See the value in this level of innovation for patients suffering from Type 2 inflammatory diseases. I maybe stick more to that, and we've seen that actually play out now in the last, probably less than two years already. We've seen the time to approval for NRDL in less than or equal to five months. This is record time. Only one other drug did that at the exact same time as us. As I said before, average of two years beforehand. You really see the Chinese government committing to innovation, and I think that's where our broader immunology portfolio will continue to play in the future as well in a marketplace like China, because it's really I think they're accelerating on the promise for innovation sooner, and seeing maybe some of these future assets as well launch even quicker than some of the other major markets have in years past. You know, a lot of times Europe will be ahead of where China's launched, and now we're gonna start to see them. I think China be much earlier in the stage of launches for specialty agents in the future. All about innovation for us, and I think they'll continue to see the value in it. That's what we're based on. Okay. Thank you. This brings us to the end of our plenary Q&A session. I'm gonna hand it to Paul in a second for just some concluding remarks. I know there are more questions on the web. Please feel free to send them to us, the IR team, and we will get you the answers here from our team. For us here in Boston, the event continues after a very short break in the breakout rooms. I'm gonna say a bit in a second, but I'm gonna hand it to Paul now. Just not really concluding remarks, but fascinating to listen to the conversation plus the conversation at the break. I think all of us included, and all of you need to think of this very differently than you've thought about anything else before. You're still thinking of Humira analogs, you're thinking of IL-17s versus TNFs. Everything has changed. You've really gotta open your minds to that. We've had to internally. Because rarely is the first drug the best drug. We have that with Dupixent, number one. Number two, we have the luxury 'cause we have every relevant mechanism for all of these diseases to be very fussy about the profiles that we go after. We don't need to push efficacy in an oral like a TYK2 with a trade-off. We don't need to underwhelm like an Otezla. We need to be able to take our time to go after perfect profiles for the patient segments that we think still need satisfying. That's a very different approach than you've ever seen before. Because in our industry, when we come after a big drug, you're always pushing something to get there. If we win with all of our new mechanisms, we win. If we don't win with our new mechanisms, we've won. I think people have to get it into their heads. Second thing is about the penetration. This is not a cannibalization exercise. There's just too many patients with too many adjacent diseases that need too many new mechanisms. If you think of it, well, amlitelimab versus Dupixent, for example, you're missing the point. That's the big challenge we've had internally. 'Cause we're very competitive about bringing mechanisms through. As long as there are patients that need extra efficacy or a different interval or a different cycling strategy, it's a different game. My 32 years in the industry, I have never seen first is best with a massively under-penetrated market, with lots of adjacent diseases and mechanisms that give us a huge opportunity. That's why today we tried to lay out briefly that you have to look at our size of our immunology business going forward. You may even have to recalibrate what immunology is. 'Cause you can't keep looking at it, is it conjunctivitis versus this? That game is gone. It's completely gone. That's what's fascinating. That's why I believe in the quality of our people, the science, and everything that's happening. The game has changed for us, so we're excited about it. I think I'll hand it back to you, Eva. Is that all right? I'm gonna officially close the webcast. Thank you very much for attending. As I said, we are continuing here in Boston. Brian has brought his commercial team, so you have the possibility to really exchange with those that are working both on the respiratory and the dermatology side. You know, close to those questions that Elizabeth has raised. The same is true for Naimish and also Frank. We have the GPHs for itepekimab, for Dupixent, for amlitelimab. Then we also have head of research for immunology, so really looking forward to that. If you check your badge, it should say breakout room one or two, which are just on the other side of the coffee area. If you just make your way through the coffee area. As said, you know, you're just gonna stay in the room. We're gonna have like a 20-25-minute breakout, and then the management's gonna change, so you stay in the room. Looking forward to that. Thank you for staying with us.