We're good to kick off. So welcome to the next session. Very pleased to be able to have from Sanofi with us today two different areas to talk about. So we'll probably try and split the timing roughly equally between the two. So we have Naimish Patel, who's the Therapeutic Area Head for Immunology and Inflammation, and then François Sandre, who's the Head of Vaccines in Europe. So probably two of the core pieces of Sanofi that we can get to discuss here. So welcome. Thanks for the time today. I might kick off on the immunology side with you, Naimish. So obviously one of the biggest and best drivers of Sanofi at the moment is DUPIXENT across multiple different indications. Quite a tough act to follow if you're looking at developments, but perhaps you can just run through where you see, particularly in atopic dermatitis to start off with, there's, you know, a level of unmet need, and where the gaps in the market that you're looking to address through Sanofi development. Yeah, sure. Absolutely. Great question. So atopic dermatitis is. Maybe, maybe the easiest way to contextualize is a parallel to, to psoriasis, where there's seven, eight mechanisms in that space, and atopic dermatitis is actually more common than psoriasis. The number I remember off the top of my head is 1.9 million mild to severe patients in the U.S. alone. So it's extremely common disease, and DUPIXENT obviously is a fantastic product. The mechanism of dupilumab is targeting the IL-4 receptor, which is very specific and potent for type 2 inflammation. But in terms of comparison to psoriasis, atopic dermatitis is a more heterogeneous disease in terms of the underlying biology. Some patients have a mix of inflammation type 2, plus type Th17. Some people have described it as almost psoriasis-like in terms of the way the rash is. And it really depends on subpopulations, different ethnicities, different age groups have different driving biologies. So dupilumab, of course, is fantastic efficacy. The IGA 0/1, the patients of clear, almost clear skin, is around 30%-35%, but that leaves us a large swath of the population that has responded partially or incompletely, and we think maybe different underlying biologic drivers are, in part, responsible for explaining this. So a mechanism like amlitelimab, which targets both type 2 inflammatory pathways, but also type 17 inflammatory pathways, has potential to be complementary and address slightly different populations. Because, unlike psoriasis, where the same population, we're just building on the next biologic that's even more effective, I see atopic dermatitis having a variety of mechanisms that probably address different subpopulations, and they might not be identified necessarily by biomarker strategy. It might just be a little bit more trial and error going across. But I think that is one area of unmet need. The other one, if you look at psoriasis, what really opened up that market for advanced or better penetration, where it's 30%-40%, where today in AD is around 12%, is the available safe oral. So a lot of patients with moderate disease either are unwilling to go on a biologic or maybe aren't even eligible for a biologic. An oral drug is very impactful in pulling more patients into the advanced therapy market, and then they might go on to a biologic after that if they get an incomplete response. So we see a definite need for a safe oral in atopic dermatitis. We have a couple of things there, with rilzabrutinib, but also, our chimeric IRAK4 going into that space. So, I would summarize the unmet needs in atopic dermatitis as still, plenty of room to grow, plenty of mechanisms to increase penetration, the need for differentiated mechanisms, better efficacy, and also something for more moderate patients. Got it. A few assets there, I'm sure we'll get onto. I think quite an intense focus, and there is also competition in the atopic dermatitis market as well. We've seen the launch of JAK inhibitors. We'll see the launch of lebrikizumab soon. We've also got Adbry in the market. Mm-hmm. So perhaps you can just run through where you see the differentiation for the competitors or where you think, you know, DUPIXENT perhaps has the best profile in the market. Yeah, no, absolutely. I think, if you look at across the indications, IL-13 blockade enough probably doesn't sufficiently or potently block type 2 inflammation. So you've seen the efficacy of dupilumab in multiple diseases where the IL-13s have shown some efficacy, but not enough to even get to market. So beyond AD, it's asthma, it's EoE, where IL-13s have been tried, but incomplete. And I think that really speaks to the need for the dual targeting to get the most potent effect for in terms of efficacy. The numbers for IL-13 look pretty good in terms of atopic dermatitis, but at this point, it's hard to do exact cross-study comparisons because they're coming so many years after dupilumab being on market. When dupilumab, phase III studies were done, there were no advanced therapies beyond broad immunosuppressive, so you had the sickest of sickest patients participating in those trials and us getting really great efficacy. Where now you see many of those sick patients are already on dupilumab, so they're not coming into clinical trials. It's generally a milder population, and so not easy to do cross-trial comparisons. But if you ask prescribers today, there's dupilumab still is the go-to in terms of both efficacy and safety in the AD market. Mm-hmm. And I think one of the things is the potential to have a four-weekly rather than two-weekly administration label. When you're looking at development, how important do you think it is to have different or less frequent administration with the auto-injectors? I think less frequent administration is something that could make an impact and is important, but I think the difference between two and four weeks isn't really a huge difference. I mean, going to something much less frequent is potentially more impactful, but I don't see that as being a huge differentiator, two to four weeks. It's not that different. Got it. So you touched on amlitelimab and the potential to have a broader mechanism of action. Perhaps you just dig into that a little bit more. So, what's the evidence for broader mechanism of action, both from a biomarker point of view, but also from any kind of clinical efficacy point of view? Yeah, great question. So it gets back to the fundamental mechanism of amlitelimab, which is blocking OX40 ligand. This is a inducible ligand on antigen-presenting cells at the sites of inflammation that will activate both T effector and T memory cells. And I always liken the analogy of the immune response to, like, an emergency response team, like firefighters. And say you have a town atopic dermatitis, where you have a bunch of firefighters, and there's fire alarms going on at houses all over the place, and they go to these places, they spray the house down, they cause all kinds of damage because they think there's a fire there. There's no real fire in the case of atopic dermatitis. Is the body being fooled into activating an immune response that is supposed to be directed toward parasites? But in that case, cytokine blockers, what they do is cut the alarm, and so the firefighters are still sitting in their firehouse, but they're not necessarily going to put out a fire. But the problem could be there, is that if you stop the drug temporarily or you have some stress or response, you could have breakthrough, and then all these firefighters suddenly activate, and you get the whole disease coming back very quickly if you ever stop the drug or try to less frequently dose. What OX40 ligand does is actually downsize the fire department to be much more fit for purpose for what's going on. So immunomodulation, essentially. So if you do get a trigger or if you infrequently dose a drug, there's way fewer firefighters, and they're not... The whole disease is not gonna come back so quickly. And the evidence for this clinically was in the phase II study of amlitelimab, where when patients were moderate to severe AD patients were dosed with 12 weeks, you got a greater than 40% reduction in IGA or IGA response or IGA 0/1 at the end. So greater than 40% of patients had a clear or almost clear skin by the end of the trial. The interesting thing for that trial is we also follow those patients off drug for up to six months, and 70% of those patients off drug still had a durable response, so the disease did not come back. So very well-supporting evidence that they're really resetting the immune system. And so I think this is a potential real differentiating factor for amlitelimab, both in terms of what I mentioned before, about getting different types of inflammatory responses, type 2 and non-type 2, but also resetting the immune response, so you could dose quite infrequently. If you contrast that mechanism with the other biologics targeting the receptor, it's really a different approach in the sense that a T cell that's away from the site of inflammation, it's the antibody only gets the antigen-presenting cell expressing ligand. It doesn't affect that T cell. So, in contrast, the ones targeting the receptor will actually deplete bystander T cells and also deplete regulatory T cells that might be important for fighting infections, but the regulatory T cell is also important for maintaining efficacy. So we think the ligand-targeting strategy is a better way to target this pathway. One of the examples of this is that when you have a cell-depleting agent, you often get cytokine release-type reactions, fevers, chills, and you see this in some of the studies with the receptor-targeting biologics, and you don't really see it with amlitelimab. So, some of the pushback we've had on the idea that this is differentiable broader pathway from KOLs is that, if that was the case, then you'd be expected to have a better EASI response rate or IGA response rate. But actually, when you sort of try and compare cross-trial, amlitelimab looks similar to DP, but just with a much longer duration of action, which sort of speaks to potential disease modification. So, is that... You know, how would you counter that argument? So why wouldn't you or why didn't you see in that phase II-A, you know, just a better response rate, more patients- Mm-hmm. Responding if you have a broader mechanism? A couple of things. I think because of the nature of the mechanism, you will actually keep seeing improved response over time because you're not directly hitting the alarm, but you're actually downsizing the firemen, and that takes some time. And I also think, I mean, dupilumab, for those patients that are largely purely Type 2, is still the most potent Type 2 agent. So it's not surprising that within a segment, it's still highly effective, and amlitelimab is just moving over to a different segment that's also quite effective. So I think for a certain segment of patients, dupilumab will still be probably the best drug for them, but I think a different segment for amlitelimab. Okay. And, so you've got the phase II-B data in-house, which is subcutaneous dosing. Mm-hmm. Perhaps you can just help us understand the difference in the trial design for that phase II-B versus the phase II-A, other than just the administration. And so what you think that was intended to yield in terms of differentiation results versus the phase 2a? Absolutely. Great question. It's a phase II-B study, so it's a dose range finding study. So we have multiple arms with different doses. And also, it's a longer duration study. So the phase II-A only dosed 12 weeks, and then had a readout of 16. This is actually a readout at 24 weeks. Getting to that point I mentioned where we might continue seeing improved efficacy over time. And also, within that study, we had a... After the 24 weeks, the patients who were responders, we randomized them to continue their regimen or withdraw, or stop the drug. That's a way of us understanding much more in a randomized way, what the duration of response will be off drug, compared to patients who are continuing it. So much more sort of a controlled way of actually saying: Yes, out to 24 weeks, compared to patients who are continuing drug, this is what the response in patients who are off drug. And that'll really inform both in terms of if we either have a maintenance induction regimen, what the how might we tend to dose in a maintenance regimen, but also, can we fundamentally start with a different dosing regimen up front? These are sort of the questions we're considering. We don't have answers for them yet. Still data coming in, but we intend to start the phase III by Q1 of 2024, so we'll have much more definite answers on what kind of dosing, the frequency dosing, things like this by that point. Got it. Okay. And, and when we think about the... So the dosing you did, I think in the phase II, was monthly dosing. Mm-hmm. On the maintenance period, was that three-monthly dosing afterwards, as the regimen in the maintenance period? No, in this study, it's just withdrawal versus the same dosing. But I think both having different doses at Q4, 'cause you could match exposures to lengthening dosing, but also the withdrawal period. Both of those things add information about how what kind of actual dosing period and dosing intervals we could eventually have. Got it. I think you're running an asthma study where you have gone for a three-monthly dosing. Mm-hmm. What was the rationale behind that versus doing monthly dosing for atopic dermatitis? Yeah. I mean, asthma is. It's a little bit more of a periodic disease. So, we were a little bit more aggressive in saying: Hey, let's potentially consider Q12 dosing in asthma for maintenance with an upfront Q4 regimen. Because in AD, the disease tends to break through much quicker when you stop, we have two different designs, 'cause in asthma, we thought we could even get there sooner, but the potential is that in for both, we'll probably potentially land in the same place. We'll see. Okay. Potentially up to three-monthly dosing on the profile, so you could even be longer than that for phase IIIs? We'll have to see. I think from asthma, I think it's clearly like Q12W would be something to think about. Got it. Okay. One of the things when you're bringing a new drug into a space, often that you can bring differentiation on is safety. DUPIXENT, probably one of the biggest selling points is- Mm. Safety. So how do you see the safety profile of amlitelimab, especially given sort of broad mechanism versus DUPIXENT? Yeah. So far, I think, from what we released in the press release over the summer, the drug has been very well tolerated up to the 24-week duration we had in that phase II-B study. So we're very potentially hopeful that we could have a great safety profile. To contrast that, I think some of the other OX40 receptor agents, not only fever chills, but all sorts of other things that could be indicative of T cell depletion. We haven't seen that with our drugs. So hopefully we have sort of threaded the needle there with something that's efficacious, but also more immunomodulatory and potentially well tolerated. Got it. And do you think we'll see the phase II data at EADV? Is that- Not ready to say that yet, but at a medical conference, hopefully in the second half of this year. Got it. Okay. I'm gonna quickly wrap through a couple of the other immunologic classes, because we want to get onto vaccines as well. So if we look at rilzabrutinib, is the other product where we could get some phase II data- Mm-hmm. Fairly soon. You talked about oral being the other sort of part of the segment of the AD market, where you're... that there's an unmet need. You're also running CSU asthma as well. Mm-hmm. But obviously, BTKs have a liver issue. So perhaps can you just put the context of rilzabrutinib into a class that looks like there might be a liver safety issue, and what do you need to show on safety in an oral agent to work in atopic dermatitis? Absolutely. I mean, the nice thing about rilzabrutinib is it's a different type of molecule in terms of the tailored covalency. So there is, in the small molecule, there's an area that binds to the kinase domain that actually inhibits the molecule, but there's another binding domain that gives it a little bit more specificity and less risk for off-target effects. And And that second binding domain also increases the residence time on the target without requiring systemic exposure. And so, having that specificity and increased residence time, potentially, will drive safety differentiation in terms of sitting on a BTK, but not sitting on other off-target effects that may drive some of the liver effects we're seeing with many of the others are irreversible. And so, this, when you also stop it, the drug goes away. So we think there's potential for safety differentiation in that sense, versus other BTKs. We'll have to see where the data lead us. And the interesting thing about the BTK inhibitors driving very quite diverse diseases, right? We're talking about MS, which is a B-cell driven disease, and other autoimmune diseases, but then also CSU, which is a mast cell-driven disease. And because of the fundamental importance of BTK in not only driving B-cell differentiation signaling, but also IgE signaling on mast cells, so allergic and atopic inflammation. And that's part of the underlying rationale for studying in not only CSU, but asthma and AD. Obviously, CSU is probably—it's been validated by other BTKs, so the... We're hoping to see, we should see positive data on that. Asthma is also partially a mast cell-driven disease, so that there's more validation. And if you take XOLAIR, which has many of the common signaling pathways as a BTK inhibitor, we should see a signal there, but we'll have to see. And AD is probably the one that has less validation. XOLAIR is not in AD, and slightly different signaling pathways, but mast cell, there's a lot of literature suggesting mast cells, especially, contribute to itch in AD. So we'll have to see where the readout leads us, and it'll be in the second half of this year that we're ready to share those data, but we're looking forward to it. You've had a failed study in pemphigus. Mm-hmm. Does that sort of dent your enthusiasm in dermatological setting? Perhaps just compare and contrast, study design, indication versus AD. Yeah, no, that's a great question. I think pemphigus, the study was something Principia designed, and if I were to go back, it should have been a longer study. The reason is that in that treatment paradigm, we're treating on top of steroids. So even the placebo patients were getting steroids, which that disease, pemphigus, is very responsive to. And in general, it took about six months to withdraw steroids, even on the placebo patients. And so it's not long enough to see a difference of the drug if it was only a six-month study. It's the full duration of the study withdrawing steroids. So I think there are definite biomarker signals that of activity. We saw a decrease in the anti-DR3 pemphigus autoantibodies in that study, that the drug was having effect, and maybe if it was a bit longer, we could have seen. So I think we're still quite confident that the drug is an active drug, that. And if we design the right trial and the right diseases, we're going to see efficacy. Got it. Itepekimab, Mm-hmm. We just had Roche talking there, ST2, just compare and contrast what we see with Astra, what we see with Roche ST2, pathway inhibitor, the receptor inhibitor, how you see IL-33 and your IL-33 in particular, competing in with those products on profile, at least? Yeah, I mean, the... So we're, of course, dupilumab will get the type 2, we're seeing it as getting the Type 2 COPD population, which is about a third of COPD, but the majority of COPD is non-type 2 COPD, low eosinophil count. And with itepekimab, the only one to have this largest study in phase II in COPD, what we saw in that study on patients who are already on inhaled therapy, a greater than 40% reduction in exacerbations, which is a fantastic huge number in patients that are already frequently exacerbating despite inhaled therapy. And that gave us a lot of confidence where, unlike dupilumab, when we staggered the two phase III studies and had an interim analysis, we started both phase III studies concurrently, and today it's the only IL-33 with data in COPD. Roche, with the anti-ST2, does have data, but a much smaller 80-patient trial than the 300-odd patients we had for itepekimab. And earlier this year, we also had a similar type of futility interim analysis, and we announced that we passed that. And so, we're really excited about the potential here, and we have the best data to be even able to look at subgroups, where the Roche study could not really do that. We think we have the right population of patients who are former smokers, irrespective of baseline eosinophil status. And that, together with dupilumab, potentially get greater than 80% of COPD patients, where today, third leading cause of death, there's no, really no new advanced therapies in years and years and years. There's lots more assets we could talk about. I'm just going to ask one more, because I get asked about this a lot, is the oral TNF? Mm-hmm. Just rationale for going oral in a market that is very well served in going biosimilar? ... Yeah. So, I think first of all, being a scientist, I have to start with the mechanism, which is really interesting. And this was a difficult compound to develop. Many failures because of preclinical toxicities and off-target side effects. But we finally got to a compound that what it does is, it actually... TNF exists in the blood as a trimer that binds to TNFR1, and TNFR1 is a receptor that generally causes most of the inflammatory effects of TNF. And what this compound does is, it binds that trimer and change the 3D conformation, so it no longer can signal through the TNFR1, but it leaves TNFR2 intact, which binds to membrane-bound TNF. The beauty of that is that we demonstrate this in preclinical models, where you can get efficacy equal to an anti-TNF in an arthritis model, and equivalent to a biologic. But if you looked at a model of bacterial infection to see the effect on immunosuppression, that this molecule, 'cause it leaves R2 intact, actually does not affect immunity to this specific bacterial model, where the biologic caused 50% mortality in mice. And we have this in one of our previous slide sets that we've shared at one of our Immunology Days. And so not only do we have efficacy, at least as good as TNF, but a potential safety differentiation. And lay that on top of that, if you look at both in RA and IBD, especially, TNFs often lose activity over time, and part of that is likely due to, for some reason, TNF biologics tend to have a high level of immunogenicity. And being a small molecule, there's no immunogenicity to worry about. And so we could actually have better long-term efficacy with a small molecule approach than the biologic, plus overlaid better safety. And plus, as a small molecule, it doesn't need to be priced necessarily at biologic levels. It can be priced so it's competitive versus even generics that may come on into biologic. Because the market's so huge, we're talking about RA, we're talking about psoriasis, we're talking about IBD, psoriatic arthritis, such a huge swath of patients with TNF, we don't necessarily need to price it at, at maybe, a biologic level. So differentiation and efficacy, safety, plus competitive pricing, we think it's a really potentially huge opportunity, across a number of therapeutic areas. Great. Okay, I'll give Naimish a break in there. Move to vaccines. So, I guess, the most common question at the moment on vaccines is the flu market. So we've obviously seen a slowdown post-COVID. Just help us understand the dynamic there. Yep. Is that just vaccine fatigue and a slowdown, and do you expect that to recover again? Yeah. Thanks, thanks for having me here. Yes, for those who are following 2009 pandemic, we saw that what we call the flu went over as well, so. It took us, say, three to four years to go back to the VCR we had before. This being said, these are a couple of percentage here and there, depending on country of VCR up, that is partly offset by the demographic of the population. Of course, year after year, we have more elderly in those very mature market. So, so that's where we are. The interest of the flu portfolio of Sanofi is the differentiated flu. This being said, our intent is to increase the value behind flu vaccination, and we are making huge progress with Efluelda in Europe, and of course, also in the international area, where we are switching from trivalent to quadrivalent. So yes, slowdown in some vaccine coverage in mature market, but increase of value through product differentiation and switch towards QIV in international area. So that's the dynamic at play. If you look at the split of flu sales for Sanofi, it's very big in the U.S. compared to other regions. Right. Is that just the mix of those high-dose, just less adopted ex-U.S., and is that still therefore a big potential revenue and value driver for the, for the flu business? It's a very good question. So we need to step back and build a 20-year story. So Fluzone High-Dose has been launched 2010 in the U.S. And for the first few years, we've been limited by capacity. You know, that's the vaccine story. So you basically had no Fluzone High-Dose capacity to export and to start launching outside the U.S. We were also very successful in the U.S. So we are invested, we are catching up, and now we are capable of expanding. So we launched Efluelda, which is the Fluzone High-Dose in Europe three years ago. And we've been growing that franchise very significantly in three years. We are about... If you compare to the U.S. right now, we are realizing 2/3 of their volume markets. Of course, there's a difference on price, Europe and the US, but we're getting there when it comes to the Fluzone High-Dose market here in Europe as well. We've had 10 years lead time due to capacity. Got it. As you think ahead towards, mRNA vaccines- Right. If you're contracting with European governments- Yes. Do you think that the ability to do better strain selection, speed of manufacture, et cetera, will be a differentiator with European governments in particular, or is it just a straight price negotiation with Europe? Okay. First, flu is super serious. Flu is a devastating disease. I think we lose sight of that. We all went through that COVID pandemic, and we saw what it was to face a respiratory disease with no infection. The value of immunization is you don't see what you prevent, right? So flu is a devastating disease. If you get flu, days after that, the risk you have to get cardiovascular and pulmonary complication is extremely high. So my point is you need prevention, and you need solid prevention. So what governments out there, especially in Europe, are asking is outcome-based proof that their investment will end up preventing flu complication. Because these are the flu complications that's going to yield, I would say, the budget impact, if you wish, of flu, right? More hospitalization, more spending, direct and indirect, absenteeism. So the value of Efluelda is that we've demonstrated via that differential, outcome-based approach on the flu complications. So what matters out there is first, science behind the—we talked a lot about science with Naimish, science behind the prevention. And then, yes, then safety is also very important because it's a yearly immunization, and the least we can say is that we need to improve the mRNA first generation we had on COVID. So we are also, while Center of Excellence, working on that. mRNA, new generation, need to be safer, and they need to be thermostable, and they need probably to offer protection that is of bigger duration. I would say clinical proof, safety for sure, value for money, and then you have all the pragmatic, I would say, points that are important as well. I mean, they want their fridge filled as early as possible, for sure, but I think there is an order in the conversation we're having with payers out there in Europe. Got it. Okay. I'm going to move to pneumococcal vaccine, unless there's a question on flu. And so, going to move to pneumococcal vaccine. Obvious gap in Sanofi's portfolio. Yeah. you know, recently published phase II data on PCV 21. Yep. Perhaps you can just explain how that's differentiated from Prevnar 20- Sure. Which is clearly the dominant player in the pediatric market in pneumococcal vaccines. I see the time is running, so let me try to, to do the executive summary here. Very excited by the phase II data, by the way. We, we presented extensively on June 29, I think, the progress we're making on the portfolio, so I'm sure you guys had the time to catch up. PCV21, we're adding 9 N, which is one serotype that is providing 5%-7% extra protection compared to the standard of care, so we think we have a window of opportunity to differentiate that, that offer. We've chosen to go pediatric simply because pediatric is 80% of the served market in pneumo conjugate. Now, 80% of the served market in 2022 were the pediatric sales. Of course, because also we see synergy with our current portfolio, we are far the number one hexavalent provider in the world, so we do promote pediatric vaccination. We have also a contractual synergy there. So we also see a value adding a pneumo conjugates portfolio completing our current offer. So yeah, so exciting. We're going to start phase III next year, and we plan to submit by 2027, so that we can fill the gap in our portfolio, as you said. Yep. You, you didn't mention serotype 3, but that seems to be something that comes up, and if I eyeballed the chart, it looks a lot better on serotype 3 as well. Is that important? Yeah, well, every detail will matter, so it's a phase II. Let's see what phase three will matter. But yes, if we can have... If you take as a parallel of Menveo quad as we speak, MenQuadfi, we have a superior response on C, one of the four, and we know that's a differentiating factor, especially for a country doing a C only. So you're right as well. There is a number of serotype and your performance per serotype that will be looked at by regulator. So we'll see what we have in the label, but that can be another area of differentiation, for sure. Okay. RSV is another hot, hot topic at the moment. Yeah. So you've got two vaccines, obviously, we've got Beyfortus- Right. Coming as well. But just in terms of the toddler space, that was also something which we saw some data on at the vaccines event. Can you just talk through the perceived unmet need there? Right. Because I think that's where we get the most pushback on, is there actually a market for a toddler vaccine? Let me start by Beyfortus. I know it's not the question, Graham, but- Yeah. We are so excited to launch that first and best in class. You all saw the results, I mean, the reduction of hospitalization by 80%. You know, this is mind-blowing. So we're getting ready to—and you saw, I'm sure, the ACIP third recommendation that are very positive for the intervention. So we're ready to launch in H2 2023, both in Europe and the U.S., and very excited about it. So that will protect the infant in their first year of life, to your point, where most of the burden is, but I'll come back on that. So Beyfortus is an important prevention tool for the protection of those babies, and also, by the way, to avoid the jamming of the pediatric infrastructure. We're discussing with a lot of the European government as we speak, and if you follow the news, the past two years have been very, very difficult in south of Europe in particular, when it comes to emergency reanimation. So that will help alleviate some of those overwhelming number of patients coming every year. The toddler approach is a complement. There is a burden, and when you develop a vaccine, you develop a vaccine against a burden, against so that you met needs, that will bring a collective benefit, most often for states. So first year is not enough. You also need to prevent in the second year of life, we call toddler, 12-24 months, and we are extremely excited by the data we share in June 29 on the kind of the efficacy that we see with the vaccine capable of controlling that second year of life. So in short, baby will be immunized first years with or protected with Beyfortus, and then after the season, you will protect them second year of life with the vaccine. So we see a complement here to really protect the full the full RSV exposure position of our of our infants and toddler. ... and then I'm just gonna wrap up actually on, on Beyfortus. So obviously, you've got the, as you referred to, the impressive data and approval ACIP, in the U.S. convened a, you know, an ad hoc meeting to- Yep. -get it recommended. So it looks like the U.S. launch is gonna be in full effect. Just perhaps give us an update on ex-U.S. markets. Yeah. Where do you expect to be in this season, or, or are a lot of them gonna be delayed until next year to get reimbursement? No, we will launch in Europe as well. So I talk Efluelda, 10 years delayed. The beauty of Beyfortus is that we've been capable of launching in Europe at the same time of the U.S. So that's. We're very pleased about it. Of course, the U.S. will be the number one market for us, there is no question about it. But we are having very positive conversation with both Spain and France that will certainly launch what we call public program toward all infant protection. So really trying to protect the most of the cohort in the first year of launch, which is a good signal that Europe is adopting innovation a bit quicker than in the past, so we're very pleased about it. Spain and France only, or is there any option that you could see a public program in, in any other countries? We'll launch in Europe. It's a European registration, but the public conversation we're having, are mainly in France and Spain, as we speak. Got it. So, for a country where you don't have a public program, that would be a private market? Yeah, that would be a private market on board and, and yeah. Got it. Okay, and then last question on manufacturing. So big, big launch everywhere. Yep. Presumably, the plants have been working very hard. Right. Any kind of manufacturing bottlenecks, which you use or- Less than what we see in vaccines. So it's a mAb. So first, it's an alliance that we have with AstraZeneca. So AstraZeneca is the manufacturer here. But compared to our experience in vaccine, we see less bottleneck, to your point, than what we see on other compound. And we took very early, I would say, bets on volume available for that launch, knowing the product profile. So we will not launch everywhere, to your point, but where we think we have an interest, we are gearing up so that we can meet the demand. Great. Thank you. I think we're just about on time, so, yeah. Thanks very much, Naimish and François. It's great to see you today, and enjoy the rest of the conference. Thank you. Thank you, Graham. Yeah. Thank you. Thank you.