Welcome to our Getting Ahead of Respiratory Disease event with GSK Management. As usual, the presentation was emailed to our distribution list earlier today and is available on gsk.com. Please turn to slide two. This is the usual cautionary and forward-looking statements. Please turn to slide three. Today's speakers are our Chief Scientific Officer, Tony Wood, and Chief Commercial Officer, Luke Miels, and our presentation will last approximately 30 minutes today, followed by 30 minutes for Q&A. Turning to slide four, I will now hand the call over to Tony. Hi, everyone, and welcome to our Respiratory Meet the Management event. As you know, GSK prevents and treats disease in four therapy areas. Most recently, we spoke to you about HIV. Today, we'll focus on respiratory, where we have assets across vaccines, specialty, and general medicines product areas. Please turn to the next slide. In this deep dive, we'll cover the following areas. Firstly, our expertise in respiratory disease, where our leadership and innovation have advanced treatment from symptom control to disease state stabilization, with a path towards clinical remission now becoming apparent. Secondly, I'll briefly cover the role of eosinophils in respiratory disease and the importance of IL-5 in treatment, as shown by our first biologic, NUCALA, and our ongoing development of depemokimab as a long-acting solution, driving new potential in the respiratory market. Our expectations for depemokimab have increased from GBP 1 billion- GBP 2 billion, to now more than GBP 3 billion in peak year sales. Next, I'll turn to the significant unmet need and market potential in refractory chronic cough and camlipixant's differentiation as a best-in-class asset, with potential to deliver more than GBP 2.5 billion in peak year sales, before finally reviewing key respiratory data readouts from 2024 to 2026 and beyond. Next slide, please. GSK has been a leader in the prevention and treatment of respiratory disease more than five decades. In asthma and COPD, we started in 1969 with small molecules, primarily to address symptomatic relief through bronchodilation in easy-to-use devices, including most recently with TRELEGY, our once-daily triple therapy in a single inhaler. In 2015, we launched NUCALA for severe asthma, the first monoclonal antibody to target IL-5, which added symptom relief by reducing disease exacerbation. This has led to greater disease stabilization and reduces the need for oral steroids. We're also a leader in seasonal respiratory infection, having launched the world's first RSV vaccine. We have a heritage in flu, with ongoing studies using mRNA for high-dose flu and COVID vaccines. While this is not a focus for today, it contributes to our deep understanding of respiratory disease. Lastly, in addition to reducing exacerbations in severe asthma, we've pursued lifecycle management in other eosinophil-related diseases, specifically EGPA, AGS, and chronic rhinosinusitis with nasal polyps. For the future, we're looking at the next wave of innovation, including long-acting options and further evaluation of the role of the eosinophils in asthma in pursuit of clinical remission and, ultimately, disease modification. Next slide, please. Together, our respiratory medicines and vaccines are driving competitive sales growth, delivering over GBP 11 billion in 2022, with TRELEGY and NUCALA as major contributors. TRELEGY is the most prescribed single inhaled triple therapy worldwide and is on track to deliver over GBP 2 billion in 2023. NUCALA has already contributed over GBP 1 billion in sales this year and continues to grow in a market with low biological penetration. We'll talk more on this later. Next slide, please. Even with these major advances, respiratory disease remains an area of high unmet need and significant burden for patients and health systems. In particular, today, we'll talk about the role of the eosinophils in asthma, COPD, and chronic rhinosinusitis, and the unmet need in refractory chronic cough. Low T2 disease, which I'll explain later, also remains poorly addressed, and this will be one area of BD focus for us. Please. For over five decades, our ambition in respiratory has been to prevent and treat disease by reducing signs and symptoms, addressing treatment resistance, and slowing disease progression. We've addressed symptom relief with bronchodilation, reduced exacerbations with a first-in-class biologic targeting IL-5, and are now on a path towards clinical remission. This means helping patients who suffer from asthma achieve four things: to be exacerbation and OCS-free, and to live with symptom control and stabilized lung function. Ultimately, our goal is to change the course of disease, slowing it down, stopping progression, and even reversing previous damage. Let's hear more about this from a patient's perspective. I had never heard of clinical remission until about two months ago, but I do believe that clinical remission is possible in severe eosinophilic asthma. If I could speak to a younger version of myself, I think, I would just say not to lose hope. There was definitely a moment when I was trying medication after medication, and it just wasn't helping, and I didn't want to go on any more medications because it was just a letdown each time. So I would say not to lose hope. My hope of all hopes is that she would eventually achieve clinical remission. Thank you. Turning now to the biology of IL-5. Understanding IL-5 biology is important to achieve even more for patients, and a better appreciation of its role will create more opportunity. So let's step back and talk about this biology and its importance in treating eosinophilic disease. Next slide, please. In our development of NUCALA, we've shown that T2 inflammation is a key driver of exacerbations in severe asthma. What do I mean by T2 inflammation? This is how the immune system reacts to pathogens and antigens. It's especially important in the lung, where a large surface area allows massive exposure. A key immune cell in T2 inflammation is the eosinophil, and IL-5 is a powerful pro-inflammatory cytokine that is responsible for the maturation, proliferation, activation, and migration of eosinophils. Importantly, IL-5 is also involved in the healthy resolution of inflammation, including the programming of wound healing versus fibrosis. With NUCALA, we've shown the clinical effects of modulation of T2 inflammatory response, deepening our understanding of the role of the eosinophils and laying a foundation to better understand the science of disease modification. Next slide, please. Our leading work on clinical remission with NUCALA creates unique insights for the next phase of innovation and indeed our BD focus. In a post-hoc analysis of our REALITI-A study, NUCALA demonstrated that 37% of patients with severe asthma achieved all four components of clinical remission. Let me remind you of those again. That is exacerbation and OCS-free, symptom control, and stabilized lung function, which was sustained for over two years. Following this, we have a comprehensive evidence generation program to further examine clinical remission and explore T2 biology at the interface of healthy wound healing and fibrosis. Next slide, please. As part of the lifecycle management, we're also continuing to evaluate eosinophilia in COPD. Our previous phase III trials, METREX and METREO, were the first to attempt the demonstration of efficacy with a biologic in COPD, showing a reduction of 24% in moderate and severe exacerbations in patients with high blood eosinophils of greater than 300 cells per microliter. As you're aware, only one of these studies demonstrated statistical significance, and we received a complete response letter for the application. To address this, we initiated a third trial, taking into account FDA feedback. Our MATINEE phase III trial focuses on patients with higher eosinophil counts, which have been associated with higher exacerbation rates and poorer outcomes. It's also a purer COPD population and includes patients with emphysema. Seeking to confirm the efficacy of NUCALA in COPD, MATINEE is expected to read out at the end of next year. A positive outcome will inform our approach for further lifecycle management for depemokimab in COPD, a potential best-in-class, next-generation IL-5 treatment for eosinophilic-led disease. Let's talk about that next. Next slide, please. Next slide. Building on insights from NUCALA, we're developing depemokimab with more potent pharmacology, a longer half-life, and ultimately, an improved twice-yearly dosing schedule. In phase I, in the higher doses tested, we saw a sustained reduction of eosinophils for six months following depi treatment. Backed by extensive PK/PD modeling, we progressed straight to phase III in four indications: asthma, chronic rhinosinusitis with nasal polyps, eosinophilic granulomatosis with polyangiitis, and hypereosinophilic syndrome. We expect depemokimab to demonstrate efficacy benefits due to improved adherence from twice-yearly dosing, and our clinical plan will review outcomes associated with remission. We'll build on this with a comprehensive real-world evidence program starting at launch. This is just one example of smart risk-taking in R&D, using our knowledge from NUCALA and accelerating development of a next-generation biologic in two versus seven years. We'll have our first readout in asthma with SWIFT-1 and SWIFT-2 in the first half of 2024. With that, let me hand over to Luke. Thanks, Tony. So the core assumption that we have when we look at how this market's likely to evolve in asthma and COPD is that we're gonna see a higher usage of biologics. And as you can see on the chart here on asthma on the left and COPD on the right, this is going to drive a material level of growth. And it's our central hypothesis that depemokimab is going to be a key component of that adoption. Next slide, please. And if we look at, you know, what are the components of depemokimab that are likely to drive that change in practice, I mean, it is intriguing right now. This sort of reminds me in sort of mid-1990s when you looked at TNFs and other biologics, as you know, we're in the foothills of or early stages of an adoption of biologics within asthma and of course, more recently, nasal polyps. Interestingly, with ENTs seem to pick this up quite quickly, in contrast to where we are today with, you know, biologics in rheumatoid arthritis. So I think it's fair to say that we'll ultimately see this level of penetration over time, particularly as you see, you know, physicians, HCPs in training, adopting biologics and having that experience right from the start of their clinical practice, in pulmonology and allergy, in particular. If you look specifically at the profile of depemokimab, and of course, we've tested this intensively, we'll go through this shortly. But if you look at in a nutshell and why we think this is going to shift practice, I mean, the first one is, you know, lower frequency of, of shots. You're gonna have better compliance, and so that's likely, we know, consistently, across multiple targets and multiple settings, this is likely to translate into better efficacy. The other interesting, element, as Tony mentioned earlier, this concept of, of clinical remission and embedding that in our studies, and this is something that could be very attractive to physicians in the medium term. And then ultimately, when we look at the other elements specific at the patient level, I mean, real-world practice, you know, we look at artificial things, which are clinical trials. When we look at NUCALA in the real world, and this is consistent with longer-acting drugs, and we've seen this in psoriasis, and of course, people on the call are very familiar with those analogs. These do materially improve the experience of patients and ultimately the efficacy. And it's interesting when we look at NUCALA, and it's true for other biologics in asthma, if you go 12 months out, typically you lose six out of 10 patients at that point. And that's a complex component, but a big part of that is the burden on the patient from multiple shots and physician visits. So again, to go down from 12 shots to two per year, for example, the complexity around co-pays, the Part B versus Part D element, just the logistics for physicians offices to administer this and navigate reimbursement pathways, these are all elements which simplify the experience for the patient and the physician and should drive a better outcome in terms of efficacy. Next slide, please. Now, the other element here, so not only are we gonna see the broader penetration and expansion of the use through a simpler offering, which depemokimab is. When you look at the life cycle program for NUCALA, it's taken about eight years from the initial indication to get through to this set of indications you can see here, with nasal polyps being the most recent. In contrast with depemokimab, because the targets have been de-risked, and we've just taken a more proactive approach to life cycle management, it's gonna take about two years, from the initial indication in eosinophilic asthma, right through to HES. Now, obviously, then we'll have COPD, which is de-risked, hopefully with NUCALA and what we've learned with the Sanofi program. So it's going to compress this uptake, and so physicians will be able to use this in a broader number of patients, in a broader number of settings, and will also be able to, obviously, of course, interact around the label with different physician groups who could influence the usage of this product. And it's a very broad offering, as you can see, in contrast to the alternatives for physicians on the right-hand side of the slide. Next slide, please. This is reflected in the market research. This is obviously, you can imagine we do a lot of work around the target medicine profile and what we expect that we'll realize through the clinical program. I think this first line for me was very compelling. We asked 200 physicians, "On a score of one to seven, how do you score the profile of depemokimab in severe eosinophilic asthma?" You know, one being no difference, six and seven being defined as highly beneficial. You can see there, 73% of physicians picked either a six or a seven score, which is, again, I think, very compelling, and you don't typically see this level of favorability for a product at this point. Then when we looked in different market research around, okay, where would you use this product? What type of patients would you employ depemokimab in? And it's interesting, you see here, you know, 57% said they would look at biologic-naive patients, which is, I think makes sense on many levels, for which I'll get into shortly. But intriguingly, and I think also encouragingly, 66% of them said: "I'd also consider switching current patients to depemokimab." And so I think they're not mutually exclusive. You know, you've got an existing bolus of patients who, as I said, we're losing a lot of these patients after six months, after 12 months, so they could be ripe for rechallenging with a simpler, more effective agent. And then when you asked patients themselves, and you can see here, six out of 10 say that a six-month injection would be attractive. I mean, it's. I think that's relatively common sense. Most people would rather have two injections a year rather than 12 or six. And then when you look at whether how they would behave if their HCP recommended, you can see 87% would indicate that they would be open to that. And that becomes important because there is a material number of patients that are resistant to biologics because of fear of needles. It's not an inconsequential number. It's about one in five, depending on the data that you look at. So this, again, when you aggregate all of these elements, you start to see an attractive product. If we go to the next slide, please. One of the questions we often get asked, meaning with investors: "Okay, well, is this just going to ablate NUCALA?" And, you know, it brings back memories because when we were launching TRELEGY, I had a lot of similar questions. You know, "Are you just going to cannibalize your own business?" And what we've shown in the same target population of physicians is that that's not the case. And, you know, I think it's, it's more than 60% of our business on TRELEGY is coming from non-GSK products. And I think we can replicate this here with depemokimab, and in many ways, actually feel more, more confident about that. And the stats here tell the truth. So if you look at about 50% of the business will come from IL-5s, either NUCALA or FASENRA. When we look at the usage of FASENRA, the main driver, at least in the stats that we collect, the market research that we collect, is frequency of administration. So I think this is right for targeting, either those on FASENRA or physicians that favor FASENRA because of the frequency of administration. But interestingly, it's really only about a quarter of these patients that physicians would imagine either not using NUCALA and replacing with depemokimab or shifting patients off NUCALA and employing depemokimab in its place. And you can see there, the TSLPs, dupilumab, XOLAIR, they're also right for targeting in this area and represent a sizable portion of the patients. And also, I think what is exciting here is that, you've got a, you know, a sizable population, which is naive and not been treated before. And you can also see that 20% I was mentioning earlier, that's really largely driven by fear of injection. So I think these are encouraging numbers. We have to obviously achieve this profile in the clinical program. It is compelling. Next slide, please. So pulling all this together, so you've got a product which is simpler to use, offers the potential in the real world of demonstrating sustained efficacy with simpler ways of administration, simpler ways of navigating reimbursement, lower burden for commercial patients and Medicare patients in terms of reimbursement and co-pays. And when you build this picture up and look at the interplay between NUCALA and depemokimab, this is our estimate, of course, it's a forecast, of what the pattern would be. So in 2022, once depemokimab is introduced, we would see some erosion as the market research earlier would indicate. But we expect that actually to be offset by the successful implementation of a NUCALA COPD label as we enter a new subset of patients. And if you remember the first slide I presented, there appears to be a high level of interest, and that's certainly been what we've seen in some of the analyst notes around the news that Sanofi has signaled over the last couple of days. And then you look at depemokimab as really driving the bulk of this uptake in severe asthma, and then the life cycle, so EGPA, HES, nasal polyps, and then COPD are incremental above that. But we expect the bulk of this business to be driven by that classic eosinophilic asthma, severe asthma patient, where there's still a very high unmet need and about half these patients still aren't adequately controlled on their current treatment. So that's the full picture there. And if we aggregate all of that, you're looking at about GBP 3 billion or more than GBP 3 billion in revenue for depemokimab at peak. And when you also include NUCALA there with this, you know, relatively stable base business of NUCALA, then that figure is above GBP 4 billion. Next slide, please. But now, before we go in depth into the clinical and commercial arguments for camlipixant, I think it's appropriate that we give you a perspective from the patient. So you'll hear from Cherise, who is suffering from refractory chronic cough. So we'll just now go to the video, and then after that, I'll come back, and we'll get in with Tony into some more depth into this program. A chronic cough trigger can last for me. It happens like this, like in spurts, but the spurts can last up to like, at times, like six minutes, depending on what caused it, and also depending on if I'm not near water. So imagine I'm teaching, and I keep running into these fiv to six-minute cough spurts and having to pause my classroom while I go handle a chronic cough. So eventually, they had me just doing admin work in the office. So as of current, I am fully disabled because I am unable to do what it is that I am experienced and trained to do. So, I mean, thank you to Cherise. Hopefully, that was illuminating for you and gives you more of a practical demonstration of what the burden is like for a patient suffering from refractory chronic cough. If you look at the numbers, I mean, when we did do the BELLUS deal, a number of investors contacted us and said, "Well, how big is this population? You know, I don't hear people coughing around me every day. You know, what's the epi here?" And you can see on the top left-hand side, if you just look at people who have been coughing for more than eight weeks in the larger countries, you can see a population of 28 million. That's not a population that we use in our models. We then take a more strict slice, where you look at individuals who've been diagnosed with symptoms for more than one year, and you can still see that's a very material number of 10 million people. When you look at the profile and the burden that these patients have, so typically two-thirds of them are females and 50-65 years of age, you can see, you know, 500 coughs a day. Obviously, some people are a lot higher than that, some people are lower than that. Urinary incontinence is very typical, so the social consequences of that, of not only coughing, but the psychological, you know, downstream effects of that and depression, you can see here, is in about half those patients because of the anxiety, impact on their partner, insomnia, and also just the social isolation that comes with coughing and particularly fits of coughing. And of course, in more extreme situations, you can see some of the elements below on the slide in terms of vomiting and fainting. So it is a disease with a lot of burden. If we go to the next slide. So if we look at the treatment pathway that these patients typically have to navigate, and this may be partly because there are no licensed therapies available, but typically it is, it's a disease of exclusion. So when someone presents with a chronic cough more than eight weeks, the first reflex of the physician, of course, very sensibly, is to try and remove or exclude more serious diseases such as lung cancer, asthma, bronchitis, COPD, IPF. Reflux, of course, is very common as a reason for cough. And ultimately, if they get there or there's no underlying disorder that's identifiable, then they are classified as having refractory chronic cough. Now, the challenge here is, if you look on the bottom right-hand side of the slide, typically, these patients have to navigate, you know, three or more specialists in 50% of the cases, sometimes it's more than that. And even if they are diagnosed as a refractory chronic cough, they tend to rotate different options because the therapies here, you can see three or more therapies. So difficult to get a diagnosis and frustrating to get an outcome that is, that is satisfactory for that patient. If we go to the next slide, this is direct surveys of physicians. So, you know, A, is this a serious disease? Again, going back to the original question that I mentioned at the start of this section is, you know, is, is this a sizable disease? Is it a real disease with material burdens that would encourage treatment? And you can see 91% of people, physicians managing refractory chronic cough, say it's extremely burdensome. And then if you ask them, "Well, what are the options that you have for treating these patients?" You can see 3% are satisfied with the options, so 97% say they're very unsatisfied. And then when you ask them, "Okay, if assuming the drug is well-tolerated and there was a new treatment approach, would you employ it in these patients even if you were not deeply and fully familiar with it?" You can see, you know, over 3/4 of pulmonologists and allergists who treat the bulk of these patients would say, "Yes, I agree or strongly agree in terms of trying a therapy." So you've got a high unmet need, you've got a sizable population, you've got physicians who are frustrated with the options available, so it is ideally prime for an effective and well-tolerated treatment. And with that, I'll hand over to Tony. Let me now describe the biology of camlipixant. P2X3 validated biological target implicated in cough reflex hypersensitization. We know that activation of P2X3 receptors increases the excitability of airway sensory nerve fibers, contributing to excessive cough. Inhibition of P2X3 receptors, therefore, could normalize the overactive cough reflex and reduce cough frequency. In this medicine class, we also know that selectivity for the P2X2/3 receptor has proven difficult, with a consequence of taste disturbance, given the presence of P2X2 on sensory taste nerves. Camlipixant's high selectivity for P2X3 therefore provides potential efficacy and tolerability benefits. Camlipixant is 1,000-fold more selective than its current competitor, so has the potential to be a best-in-class medicine for RCC. In order to assess the true potential of camlipixant, a placebo-adjusted reduction in cough frequency is used. As illustrated here, camlipixant demonstrated a clinically relevant reduction in cough frequency at all doses tested in the phase II-B SOOTHE trial. Importantly, across all doses, there are low rates of taste-related adverse events, less than 6.5%, and zero discontinuations related to taste. Next slide, please. Looking ahead, data from our phase III CALM program for the 25 mg and 50 mg doses is expected in the second half of 2025. Following the FDA's Advisory Committee on gefapixant on the 17th of November, committee members acknowledged the significant unmet medical need in RCC, but suggested that a more robust difference from placebo and the removal of potential confounding by taste effect would have been more compelling. They also suggested looking at different endpoints that better reflect the patient experience. These evidence requirements identified by the committee are well considered in our program for camlipixant. In fact, the camlipixant phase III design was optimized post-deal close to ensure we capture the true efficacy of the molecule. The optimization was done in close collaboration with the FDA and includes a number of key elements. First, prior to dosing, all patients recruited into the CALM program must be adjudicated by an independent panel. This panel looked closely at the patient's medical history to confirm a diagnosis of refractory chronic cough. Second, the dosing phases of the trial includes a placebo run-in period prior to randomization in treatment groups. We know that cough trials typically experience a placebo effect, and by including this placebo run-in phase, we'll reduce both baseline variability and anticipated placebo effect. Third, we're enriching the trial with patients with a higher cough frequency. And finally, the high selectivity of the acid is expected to reduce off-target effects like dysgeusia, which could lead to unblinding. With these points in mind, we're confident that the phase III program can assess the true potential of camlipixant. With that, I'll now hand it back to Luke to wrap up the presentation. Thanks, Tony. I mean, I think what is always compelling and engaging when we look at an asset is that you've got a viable hypothesis, that the underlying mechanism makes sense for physicians as to why they would see efficacy, and then secondly, why would there be a differentiation between our molecule and a potential option available to physicians within the same class? This is market research that we've done based on the profile of gefapixant and also with real-world experience of physicians using gefapixant in Japan. You can see here that, you know, taste disturbance is a problem. And so we spent a lot of time looking at the data during the due diligence with BELLUS to really understand mechanistically, we, you know, we have a high confidence of seeing a difference here between gefapixant and camlipixant. And that then presents itself when you look at the HCP preference. So you can see here 73% believe that camlipixant is the best-in-class molecule. And you can see, again, 85% prefer it because of the taste disturbance. So even with neutral efficacy, they prefer camlipixant because of the lower consequences around off-target taste disruption. So for me, this is very exciting, and if we go to the last couple of slides, when you look at this for the consequence, structurally strategic for the business, again, we think we can keep NUCALA growing, and that it is a very durable business and it has a position. But the, the bulk of, of practice will shift to these longer-acting, products like depemokimab. And I, I mentioned the analogs that we had before in a number of very similar settings, where longer-acting treatments have really shifted practice. We've seen more people treated, staying on longer, and physicians electing to use these products ahead of the shorter-acting products, and we're very confident that will occur with depemokimab. And again, with camlipixant, you know, a high number of patients, a higher met need, and a compelling profile, of a product which is attractive to physicians and should help patients. If we move now to the last slide before Q&A, if we look at the forthcoming catalysts, of course, COPD, the readout there, as Tony covered earlier, we have a high level of confidence on this based on the insights we got from our own program and the recent success that Sanofi has had is further increased that confidence. With depemokimab, SWIFT-1 and SWIFT-2 are on track for readout in the first half of next year, and then we've got nasal polyps. NIMBLE is the switch study, where we're taking people on FASENRA and NUCALA and switching them across to dupilumab, so an important study for us. And then we've got the other life cycle programs that I said to get this two-year timeframe post-launch for depemokimab. And then CALM-1 and CALM-2 for camlipixant reading out in 2025. And again, to reinforce, as Tony has covered, and I've also mentioned, we have taken the insights from our discussions with the regulator and the public information that's available on Merck and have enabled these programs to be designed to give us confidence that they're gonna read out as we expect with the target medicine profile. So with that, I'll go to questions with Tony. Thanks, Luke. Tony, obviously, great overview of respiratory and particularly the significant opportunities that we have ahead of us for both dupilumab and camlipixant. Given obviously just where we are in terms of time, we'll now start the Q&A, but we'll aim to try and finish around two o'clock. Obviously, depends on demand. We'll see where we get to. But as a reminder to ask the question in Zoom, please raise your hand using the icon in the menu bar. I'll then open your line so that we can obviously have you ask your question. If you have joined Zoom using the telephone, please press star nine to register a question and star six to unmute if needed. Can I just also remind everyone to limit questions, at least in the first instance, to one or two, just to be fair to all participants. With that, we'll take our first question from Simon Baker. Over to you, please, Simon. Thank you, Nick, and thank you for the presentation. Two questions, if I may. Firstly, on depemokimab, in reengineering the antibody, you increased the affinity by about 30-fold, which you slowed the clearance from about to two-fold. So I was just wondering, how generalizable is that approach to other antibodies? And because I was looking, and you've not disclosed much of what you did for probably understandable reasons. And specifically onto depemokimab, what do you think is the key driver of the six-monthly dosing? Is it the higher affinity or is it the lower clearance? And then on to a more general question on eosinophilic asthma. Could you give us an idea of current testing rates by severity to determine the eosinophils are driver of asthma in mild, moderate, and severe? Thanks so much. Nick, why don't I get started on Simon's question with regards to depemokimab and extension of the pharmacodynamic effect? Simon, there's nothing special about this that would mean it's solely applicable to depemokimab. It's fairly straightforward. We, in depemokimab‘s case, of course, we had confidence in measuring the efficacy of the molecule because of what we'd learned in translational sense from assays from NUCALA. But in general, the reason why you see the extended dosing frequency is a combination of intrinsic half-life and also the ability to, let's say, overdose because of the increased potency, giving us a longer pharmacodynamic effect as well. Both make a contribution that is entirely calculable on the basis of the PK/PD models that we have, and we're able, of course, to go to that higher dose in the first instance, because we're so confident in the safety of the mechanism. So generally applicable, and following very, I would call, standard but sophisticated modeling behind it in terms of our approach to confidence and translation. Yeah, and Simon, I mean, the bulk of patients that are being managed by pulmonologists, so those at the severe end of the spectrum, are tested. As you know, it's a relatively simple blood test, and the guidelines are very clear on that factor. They also encourage multiple testing because we know, we've used this insight in our COPD program, that these levels can move over time. And if you look at the background epi, it's around 85% of severe patients are eosinophilic. The disease is eosinophilic in nature, so it's very rational to test for that. For the milder patients, the penetration is less, as you would expect, but it's something that we've actually been trying to shift in the U.S. with promotion to NUCALA, in high-user primary care doctors, and had some success, on that front. Thanks, both. We take our next question from Richard Parkes at BNP Paribas. So over to you, Richard. Thanks, Nick. Hopefully, you can hear me okay. Yes, I'll stick to the two questions. Firstly, can you talk about what percentage of COPD patients are likely to be eligible for biologics treatment based on entry criteria to MATINEE and how that compares to the DUPIXENT studies? And just clarify the differences in recruitment criteria between MATINEE and the previous studies. Is it just eosinophil cutoff, or any other differences? And then secondly, one of the advisory committee concerns over gefapixant was not just the dysgeusia, but maybe that high discontinuation rate really reflects what the benefit patients was experiencing was modest and maybe just reflecting an imperceptible change in cough frequency. So, how confident are you that you will ultimately have a profile where you'll have a more meaningful clinical benefit in addition to less incidents of dysgeusia? Thank you. Thanks, Richard. Tony, shall we come to you first? Yeah, let me and look, Mike, want to comment on the general population considerations to COPD, but I'd make a couple of points in answering your question, Richard. And let's talk first of all about the difference in patient populations between the DUPIXENT studies, BOREAS, and NOTUS and our ongoing studies. The important difference to stress is we've included a broader COPD population, and that includes emphysemic patients. About 30% of the COPD population. What we've also done in response, and the MATINEE design was in response to the CRL. So as well as higher EOs, as you've indicated, we've also been careful to recruit a purer COPD population. If you look at the impact of both of those things and what that might do in terms of relative reduction in exacerbation rates compared to the DUPIXENT studies, you can find a sort of indicator of that in some of our published phase II data that shows that when we look at a more bronchitic population, which is the one that DUPIXENT addressed, those individuals have more reactive and responsive airways. And with that in mind, we achieve in our phase II studies, looking at that selected population efficacy in terms of exacerbation reduction, which is very much in line with the sort of results that you're now seeing reported out for DUPIXENT. I mean, what I'd also emphasize, of course, is that we also have extensive patient safety for the use of IL-5 in that population as well. We're now out at more than 100 weeks, and we don't have the high eosinophilia observation that comes with DUPI. So I'm confident in terms of our design, addressing a broader population, achieving efficacy, and continuing to underscore the role of eosinophilia in COPD, which is actually something that's important to stress when we look at the latest data for DUPIXENT. That, if anything, just increases my confidence that eosinophilia as an approach in COPD is important. I'll pause there and let Luke add what he wants to in COPD before we go on and talk about the magnitude of clinical benefit in the CALM studies. Yeah. I mean, the only thing I would add is, you know, peak patient population at the time of expiry is between, well, it's over 100,000, and it's under 250,000 because of emphysema, the EOS cutoff, et cetera. So it's a specific population, but that's the number range you should model for COPD. Yeah, Richard, and then in terms of magnitude of clinical effect and what's deemed as significant relative to placebo in refractory chronic cough, there are a couple of features that I just want to re-emphasize in terms of our design that I think play into the reality of efficacy. So first of all, just let me go back to the three features that I mentioned earlier in the presentation. It's important to recognize that cough is quite a heterogeneous disease, and therefore, our focus to an independent committee adjudicating the entry of individuals as presenting with refractory chronic cough is important. The placebo run-in that looks at the trajectory of baseline effects is also important. And then lastly, as I mentioned, we've recruited into CALM -1 and CALM -2, in a way in which we're enriching for those individuals for which we think the mechanism is likely to have the greatest therapeutic effect. So with all of that together, and then I just direct you back to the efficacy that we saw in the phase II SOOTHE study, which is indicative of a higher reduction in chronic cough frequency than is the case in the general population. So this is a matter of a better study design, a better molecule, and then to ultimately that allowing us to target it at a likely more responsive patient population who will see greater clinical effect. Thanks, Tony. Can we take our next question from Andrew Baum at Citi? Over to you, Andrew. Yeah, thank you. Question for Luke in relation to depemokimab. Given the method of administration, it's obviously gonna be done by the clinician. Could you just remind us for NUCALA and the incumbent competitors, what percentage is self-administered versus physician-administered? And given this will require a buy-and-bill dynamic with the clinicians, how problematic is that in transitioning patients from one to the other? Yeah. So Andrew, for self-administration, DUPIXENT is 100%, which is, I guess, expected. For FASENRA, based on our figures, is about 80% self-administered. NUCALA is 73% on the latest numbers we have, and then TEZSPIRE is 55%. But of course, the self-admin, I think from memory, only came in February. In terms of moving patients back and forth, that certainly influences some of the assumptions that we make, you know, naive versus switch patients. If you look at the total insurance spread, linked to that, we think at peak, about 1/3 of these patients, just over a third of these patients are going to be commercial. So that Part B, Part D dynamic is important. But, you know, I think the bulk of the business for this product ultimately will come from Part B, B for Bravo. And we've got some thoughts there around access and making that very compelling for the physician and the patients as well. Thanks, Luke. Next question is gonna come from Jefferies, and in particular, Peter Welford. So over to you, please, Peter. You may need to- Hi. Yeah. Perfect. So, two questions. Firstly, just on NUCALA. I'm curious, when you look at the graph you showed of the peak sales potential, I guess, given everything you've said, is the $500 million -$1 billion peak in COPD, which is unrisk adjusted, is that conservatism on your part, or is it something we should be bearing in mind when we consider why, I guess, given the size of the population you just talked about, you see that as an eligible COPD peak sales for the drug? And I guess related to that, what have you assumed for NUCALA to do with potential either biosimilars or I guess possible IRA impact? And then secondly, on camlipixant, and just on the phase III, to, I guess, to do with the trial design. Firstly, the unexplained chronic cough element. I think another thing that was introduced by the FDA, the advisory committee, was whether or not potentially by including unexplained cough, you're sort of potentially hiding, I guess, an undiagnosed condition. Is could the study potentially be analyzed in the separate populations respectively, so refractory versus unexplained or any thoughts, I guess, as how you could potentially assuage the FDA's concerns on that issue? First question for you, Luke, and then the second question for you, Tony. Sure. So Peter, based on our intelligence, I mean, there's two biosimilars in the clinic, very early stages in China. I think there's one in preclinical, and outside of China. So our modeling is, you know, we would not expect to see a biosimilar before 2031. So there will be some IRA effects that we've modeled in that number. Our numbers that we give you are always at the midpoint, so by definition, conservative. In terms of COPD, yeah, I mean, it's interesting. When you look at the IL-5 class, it's a bit of a coin toss, but when it comes to physicians' favorability between FASENRA and NUCALA, it's about 1/4 of the HCPs love NUCALA and use it extensively and don't use FASENRA, and it's about 1/4 of the doctors that use FASENRA and don't use NUCALA as much. But the other 50% are agnostic. They like the mechanism. They use both products. So, there is, you know, you don't have this embedded group, so that's why we think when you look at the market research there, it lines up with it. About 25% of the business will come from NUCALA. We think because NUCALA is gonna obviously launch in COPD early, it will pick up those patients. There is a segment of patients that physicians don't wanna move, and there's also patients that say: "Look, I'm stable, don't move me." But the other thing, as I mentioned in earlier, is it's a lot more dynamic than we think. And we lose six out of 10 patients, as I said earlier, at 12 months. So you know, these patients are moving back and forth between options or out of the biologic class and back into the biologics class. In terms of depemokimab and IRA impact, we've got pretty clear sense that payers will see this as differentiated. And following the core clinical program, our intention is to be very aggressive with the real world evidence program. We've got some great data from NUCALA, more coming up. It clearly shows, as you'd expect, a correlation with adherence and efficacy. And we also know that lower shots lead to higher adherence, so if you connect those components up, we should see better results in the real world and working with payers in the U.S. Thanks, Luke. Tony? Peter, let me, yeah, and it was an interesting comment, I thought, because look, there are two ways to look at unexplained. The first one is an individual who has not gone through a full diagnosis cascade to identify underlying pathology. As you can see from our clinical study design, there is an independent adjudication committee that is addressing that particular issue with regards to entrance for the CALM-1 and CALM-2 studies. For those who have been triaged and for which there is no then determined underlying effect, I think you're in the simple position of then reflecting that camlipixant is the best opportunity they have ahead of them to reduce remaining cough. I mean, indeed, you know, one might look at this as the emergence of a cough class that we might call neuropathic cough, in which the origins of the enhanced coughing frequency are associated with a change in the distribution of receptors in the upper respiratory tract. So, in terms of that aspect of unexplained, which we can deal with, it's accounted for in the phase III design. In terms of that which remains of unknown origin, showing that we can reduce coughing frequency in that class with an agent that is addressing a particular aspect of potential neuropathic pain, I would argue, is an appropriate approach for those folks. Thanks, Tony. Okay, just before we go to our next question, just as a brief reminder, if you need to ask a question on Zoom, please raise your hand using the icon in the menu bar, and obviously we'll then open your line. If you are on the telephone, please use star nine to register for a question, and you may need to use star six to unmute. But our next question will come from, Seamus Fernandez at Guggenheim. So over to you, please, Seamus. Hi. Thanks for the question. So, just wanted to go through the opportunity in chronic cough more from an access and payer perspective, and how you're thinking about, you know, the pricing that would be realistic in the market. I know you're unlikely to talk about price, but maybe just help us understand if you see this as a product that would fall above the specialty tier, in terms of pricing or below that relative to the Medicare pricing dynamics. And then, you know, also uptake in new areas like this tends to be quite slow from an access perspective. Just hoping to get a better understanding of how you see the launch of this product, you know, evolving over time. I see the opportunity from an upside perspective, but the pace of uptake, I think, is something that everybody'd like to try and understand a little bit better. Thank you. Yeah, sure, Seamus. So, yeah, I mean, the typical patient, about 3/4 of them are a commercial patient. So in our models, we've a lot of insight from this, obviously from NUCALA and TRELEGY. So we assume, you know, classical abandonment rates of, you know, about 1/4 to 1/3 of patients at that point, and I'll get to the pricing range in a second. Adherence, you should model, you know, more than 70% adherence, we believe, based on the market research, because this lines up with classical high morbidity diseases. And there's lots of analogues that we use there, ranging from rheumatoid arthritis, you know, complicated diabetes, et cetera. So yeah, you've got those commercial patients. We can assist them with co-pays. Now, in terms of the pricing range, we are very deliberately, you know, pricing below that threshold. So, you know, the, the price is, is somewhere between $600-$800 in our models, which our market research, and we've done a lot of that with payers. We've spoken to over 45 payers, it's probably more than that now, indicates that they are very receptive to the introduction of this because, of course, they're, you know, the unmet need is very high. In terms of the adoption, all the market research from pulmonologists, allergists, and again, these are the primary drivers for refractory chronic cough are very clear that they will adopt it and adopt it quickly. We know these individuals very well from our existing business. The other intriguing thing is we've looked at analogues like triptans with migraine, where you've got, you know, unmet need, pretty, you know, non-existent standard of care, and you see very rapid uptake. So, you know, acceptable price range, established population. The other thing, when you look at the patient populations, we are really looking at the cohort of people who have been coughing for more than one year and who are being managed by specialists, so that is under two million in the U.S., and similar numbers in Europe. So when you add all of these things up, as well as the other figures I've given you, that's how you end up in the range of numbers that we've disclosed with the peak forecast. And then ultimately, we've also modeled that there may be one or two other novel classes in there, but we would expect that the, the P2X3s get at least 60% of these, of these severe patients. Thanks, Luke, for that comprehensive answer. I'm gonna take our next question from Kerry Holford at Berenberg. So, Kerry, over to you, please. Thank you, Nick. Hi. So I have two questions, please. Firstly, on depemokimab, given the high potency you've discussed, do you ultimately expect that drug to deliver higher efficacy than NUCALA and FASENRA? Or should we really be thinking about that more convenient dosing regimen as the key differentiator to ultimately improving adherence and results in that way? And then secondly, I guess my question is kind of on replacement power. So today, you've discussed what we see as a solid late-stage pipeline in respiratory. But I suggest in contrast that early to mid-stage pipeline in this disease area at GSK looks relatively sparse. So I wonder if you would perhaps disagree, and whether there were any phase I, phase II respiratory pipeline assets that we should keep an eye on, might be accelerated at GSK? Alternatively, should we be thinking of respiratory as a key area for your business development team, considering external opportunities? Thank you. Nick, do you want me to get started on that? Hi, Kerry. Please, Tony. Yeah. So let me just pick that apart, if I may, let's start with depi relative to NUCALA in the first instance. I think the potential advantage on top of the dosing frequency that Luke described is really about compliance. And if you like, we're moving to a point where a sense of freedom from the disease is gonna be important for these patients, and you saw that to a degree in the video. I do wanna just draw out a distinction, 'cause we haven't had a chance to talk about this yet, between NUCALA and FASENRA. The way I look at the biology here in general, and I'll come on and answer your second question about portfolio and BD in a minute in the context of this, is you can divide it into T2 and low T2 biology. T2 biology is typically that associated with the eosinophilia, and in T2 biology, you get to take two options at it. You either go for the cytokine IL-5 or you go for the receptor. So this is the NUCALA depi versus FASENRA comparison. And what seems to be the case in this instance, that we're learning from the profile that we're developing for NUCALA, is that there is advantage associated with targeting the cytokine because of the deeper tissue effects. You see that across a range of outcomes when you compare NUCALA and FASENRA, not only in with regards to example, OCS sparing status in asthma, but also with regards to efficacy in broader eosinophilia. So I think we have an advantage in the side of the axis that we've chosen on IL-5 versus the IL-5 receptor. To your point, bringing in a longer acting agent is largely going to be associated with compliance. With regards to the pipeline itself, we have a number of earlier assets coming through that in time we'll be able to talk about. I wanna stress, though, you know, we really have focused our efforts, and you can see we've got a pretty active phase III pipeline, developing a better understanding of the role of IL-5 in T2 disease, in moving the treatment paradigm on for severe eosinophilic asthma from symptom reduction to exacerbation reduction, and ultimately to clinical remission. And one might imagine that, you know, you bookend that, for example, in other areas of the biology. We have a TG2 molecule that is in phase I that will allow us to begin to ask questions about the role of development of fibrosis building on top of T2 biology. Alarmin, as at the other axis of the important biology in lung disease, either from IL-33 or from BD activities in the alarmin class, I won't describe that in more detail for obvious reasons, also become part of our focus. So I would say we have a comprehensive program aimed at positioning new mechanisms in the context of what we're learning about IL-5 in the clinic, and therefore, where the most important medical need and opportunity would sit in follow-on agents. Thanks, Tony. Can we take our next question from Graham Parry, please, at Bank of America? Graham, over to you. Great. Thanks for squeezing me in. So just a quick question on camlipixant. So you talk about the enriched patient population in your phase III study relative to gefapixant. And obviously one of the key things the FDA was saying is they were struggling to see a clinically meaningful reduction. So if you can just help us understand the differences in the patient population in your phase III versus the gefapixant phase III, and then the extent to which that then also reduces the addressable patient population from a commercial point of view. And then secondly, on the NUCALA COPD study, you know, DUPIXENT obviously set a very high bar here, 30s reduction, but in a narrower patient population, arguably. Would you sort of characterize your expectations around NUCALA's phase III study as being that the inclusion of more emphysematous patients broadens your addressable population, but perhaps reduces the effect size you're gonna see in the study? Thank you. Thanks, Graham. Yeah, thank- Tony, do you wanna take the first part of camlipixant with, and then Luke, and then over to the NUCALA question? Yeah, let's do that. And Graham, I'm not gonna get into the details of the phase III design. That's something that is still subject to broader conversation with regulators and an aspect of our positioning of the agent that I don't want to share more broadly. But if I can just bring you back to the points that I made earlier. The emphasis for achieving greater treatment effect comes from two broad approaches. The first one's the trial design. That's very much around ensuring that we're admitting those individuals who are more likely to have frequent cough associated with neuropathic origins playing to the mechanism. The higher the frequency of cough, the greater effect one is likely to see, and we have looked to enrich our patient population with that in mind. Well, we're also taking account of the fact that there is clearly a placebo effect here, and the greater extent to which one understands the trajectory of that moving into the study, the greater the opportunity to show a difference. And then lastly, it's probably worth emphasizing, 'cause I didn't when I answered the question earlier, that the vastly improved selectivity of dysgeusia will also help confounding features associated with unblinding. But at this point, Graham, I wouldn't wanna go any further than that. Perhaps the only other thing to stress in terms of the regulatory feedback was there was also commentary on the relevance of the patient-reported outcomes, and we have engaged closely with the regulator on that, particularly with regards to the Leicester Cough Questionnaire, and you'll see that accounted for in the relative size of the two phase III populations. Yeah. Graham, Luke, are you gonna do NUCALA? 'Cause I, I've, you might have to. Yeah Remind me of the questions, Graham. Sorry, sorry, go ahead, Luke. Yeah, no worries. Thanks, Tony. So Graham, I mean, all of this was largely visible during the due diligence process with BELLUS as well, because there obviously had been an earlier attempt at approval with gefapixant. And as Tony said, I mean, if you look at the selectivity, camlipixant is around 1,500-fold more selective for P2X3, in contrast to gefapixant, which is, you know, 3x-8x. So, when we did the modeling and the forecast that you see and the background to the deal, the same way we did with Sierra, we take a conservative assumption in the population and the label. and so the numbers that you see exclude these milder and, and non-neuropathic coughing populations, and it's very much a severe end of the population with established extensive disease for more than a year, and that's what we've modeled it on. Just back to, Seamus's question as well, I was just reminded of another analog that we looked at, which is obviously the OFEV, Esbriet, IPF, analog, where you saw within three years, it was around 60% of those patients were being treated with a novel agent. So, you know, similar prescriber base, high unmet need, difficult disease, et cetera. Just coming back to the question. It was around NUCALA inclusion criteria, Tony, for COPD, in terms of DP high bar, and whether it was a narrower, a patient population. Okay, super. Let me just make one more point on the PROs for camlipixant as well, you know, that they're based on what we've learned from the Ad Com as well, so there's a different PRO set, as well as a trial designed to enable a more extensive demonstration of patient benefit associated with those. In terms of NUCALA and the COPD inclusion, you can think about this as follows. So we have a broader population, Graham, you're right, that is aiming for a broader label. It brings a more difficult to treat population in the emphysemics, but what we've also done is been careful to enrich that study with regards to eosinophil count and to be sure that we've gone for a purer population of individuals. So the broader population, if you like, the tougher choice associated with that has been countered by a more careful selection on the basis of eosinophils in COPD. And we've shown, Graham, that that high eosinophilia is associated with poorer outcomes in that COPD population. So we're confident based on the data that we've got in that more general population, and indeed, as I mentioned earlier, the phase II data in a more bronchiectasis population, that we have at least equivalent efficacy to DUPIXENT. Super. Thanks, Tony. Okay, we've got two last questions. I'm gonna come to Ben Jackson at Jefferies first, and then I'll finalize with Emmanuel Papadakis at Deutsche Bank. But Ben, over to you in the first instance. Perfect. Thank you very much for squeezing me in. Just on camlipixant, aware of the comments that you just made about trial design, but I was wondering if there's any further thoughts on the specific comments made by the Ad Com with regards to cough clusters as well as the frequency of cough there. And then, I guess, off the back of that, are there any thoughts longer term about potentially additional follow-on studies or additional indications that could be gone into from here, in the same way that Merck have looked at developing their asset as well? Thank you. Yeah, I'll keep it quick, Ben. And Luke, I'll, if you wanna pick up after the additional indication comment, so I'll make it a quick one. The way to think about cough clusters is this is all about the analytical method applied to the cough counter. We've taken careful account of that in our interactions with the regulators, so in terms of the analytical framework that we'll go forward. So I don't expect to see the desire to recalculate that resulted in one of the trial failures for Merck. And then with regards to additional indications, you know, one can imagine a number of alternative sensory afferent-based indications, like, for example, urinary incontinence, which of course, is not only a consequence of cough, but a feature of the target patient population here, who are likely to be women in their 50s and more, who tend to report with a refractory chronic cough. Luke, I'll hand over to you if you want to embellish on that at all. Yeah, sure, Tony. Yeah, definitely. And we didn't model those populations in the valuation of BELLUS, so these are all upside, but I intend to explore them. Probably less enthusiastic around pain. And then in the chronic cough population, you know, we're planning an extensive post-approval real world evidence phase IV program. So for example, you know, is there an opportunity for primary care doctors to use this mechanism empirically when a patient presents, say, at eight weeks with chronic cough, before sending them off to more invasive or more expensive investigations, even if it's just to attempt to provide some relief? And so there's obviously enormous synergies there with our established infrastructure. And then, you know, the same way, we wanna do the same thing with depemokimab, back to Kerry’s question, because, as we've done with NUCALA, there are opportunities in the real world setting to demonstrate, you know, higher levels of efficacy. And that in our modeling, we assume initially at launch in the target medicine profile, and all the market research you've seen in these presentations assumes there's equivalent efficacy. But we think there is an opportunity in a real world setting and to publish this, to assert the benefits of the profile of the drug, which could result in better outcomes for patients and a better efficacy claim. Thanks, both. Okay, final question to Emmanuel Papadakis then. Over to you. Thank you, sir. A couple of quick follow-ups, if I may. IL-5s and COPD, given the rerun for FASENRA study, RESOLUTE and COPD is employing many of the same modifications that you've made in MATINÉE. Is there any reason why we shouldn't assume that will also work? And have you assumed that in your peak sales assumption? And then a couple of follow-ups on camlipixant, and Tony, I didn't really understand your comments around the population. I mean, the trials are already running, so you're telling us you're discussing with the FDA what precisely will be the population included in the primary endpoint? Then a connected question, apologies if I missed this, are you hoping to show or replicate the 30%, approximately, placebo-adjusted improvement you saw in the phase II SOOTHE study, or would that only be in a subgroup of the population you've enrolled in CALM-1 and CALM-2? Thank you. Yeah. Let me just see if I can clarify that, Emmanuel. So first of all, in terms of the FASENRA and its likely profile in COPD, I'm back to the point I just made to Kerry, that it's important to recognize that across the breadth of performance we see for IL-5 versus IL-5R, IL-5 seems to be the preferred mechanism. So I would suggest that if there is a deeper effect associated with disease modification, that we might see an improved benefit for NUCALA, but we will see how that plays out. In terms of the point, the studies are indeed already running. What I was talking to in that particular comment was the ongoing negotiations we'd had with the FDA during the time period before that study design. And what we were keeping in mind there was particularly the point that you make with regards to the distribution of patients who are most likely to benefit from the mechanism, those with higher cough, those adjudicated to have no underlying conditions. And as a consequence of that, aiming to be able to evaluate efficacy across a range of different stratified populations to. And then, of course, what we're aiming for there is a sort of placebo-adjusted efficacy that you can see from the phase II study. But I would expect to see a range across different populations. All of that is accounted for in the CALM-1, 1 and 2 design. Super. Thanks, Tony. Thanks, Luke, especially for highlighting the significant opportunities we have ahead of us. Clearly, to all of those that have attended, thank you for your interest and attendance. If there's any follow-up questions, don't hesitate to email us at irteam@gsk.com. And with that, we will now close the call, so you're good to disconnect. Thank you very much.